Unnamed: 0 int64 0 2.34M | titles stringlengths 5 21.5M | abst stringlengths 1 21.5M |
|---|---|---|
2,332,500 | Rate dependence of the effect of antiarrhythmic drugs delaying cardiac repolarization: an overview. | Prolongation of the cardiac action potential and refractoriness (class III effect) is a potentially beneficial electrophysiological mechanism of action. However, this effect may be diminished or eliminated at rapid heart rates, so-called 'reverse rate dependence' of prolongation of repolarization. Action potential duration normally shortens as heart rate increases, due to increases in outward repolarizing currents, and/or decreases in inward depolarizing currents. The assessment of the effect of drugs on action potential duration is complicated by inter-species differences in ionic currents mediating repolarization, heterogeneity within the heart in repolarizing currents, and differential effect of drugs in different species, during differing experimental conditions, and at different rates of stimulation. In general, most drugs which predominantly block the IKr repolarizing current exhibit reverse rate-dependent effects on cardiac repolarization. Drugs or combinations of drugs which produce multiple ionic channel blocks and possibly those which block the IKs current, may be less prone to this potentially undesirable effect. |
2,332,501 | The p38 MAPK inhibitor, SB203580, abrogates ischaemic preconditioning in rat heart but timing of administration is critical. | There is debate concerning the involvement of p38 mitogen activated protein kinase (MAPK) in the mediation of ischaemic preconditioning. Pharmacological inhibition of p38 MAPK with SB203580 has been reported to block preconditioning in some studies but not in others. We hypothesised that this divergence could be due to differences in the timing of inhibitor administration. Isolated rat hearts were perfused in the Langendorff mode and subjected to 35 min regional ischaemia followed by 120 min reperfusion. Hearts were then double stained with Evans' blue and triphenyltetrazolium chloride to determine risk (R) and infarct zones (I), expressed as I/R% ratios. Preconditioned hearts were subjected to 2 times 5 min global ischaemia with 10 min intervening reperfusion. SB203580 10 microM was perfused either during the preconditioning protocol (PC+/-SB-early),just prior to and during the first 15 min of the lethal ischaemia (PC+/-SB-late) or prior to regional ischaemia in the absence of preconditioning. Ischaemic preconditioning significantly limited infarct size (I/R 38.9 +/- 3.0% in control vs 13.4 +/- 2.4%, P < 0.01). In the PC+/-SB-early group, preconditioning was still fully protective (I/R% 14.6 +/- 1.0). However, in the PC+/-SB-late group, SB203580 completely blocked the protection afforded by preconditioning (I/R% 33.6 +/- 4.4%, P < 0.01 vs 13.4 +/- 2.4% in preconditioned hearts, p < 0.05). SB203580 alone did not affect infarct size when given prior to and during regional ischaemia (I/R 36.2 +/- 2.7%). These histological data are corroborated by a significant increase in p38 MAPK activation in the preconditioned hearts during sustained ischaemia in comparison with the controls. In conclusion the activation of p38 MAPK during lethal ischaemia, but not during the ischaemic preconditioning protocol, is essential for the mediation of protection and may resolve some of the earlier controversy surrounding the use of SB203580 in preconditioning studies. |
2,332,502 | Adenosine-induced late preconditioning in mouse hearts: role of p38 MAP kinase and mitochondrial K(ATP) channels. | We investigated the role of p38 mitogen-activated protein kinase (MAPK) phosphorylation and opening of the mitochondrial ATP-sensitive K(+) [(K(ATP))(mito)] channel in the adenosine A(1) receptor (A(1)AR)-induced delayed cardioprotective effect in the mouse heart. Adult male mice were treated with vehicle (5% DMSO) or the A(1)AR agonist 2-chloro-N(6)-cyclopentyladenosine (CCPA; 0.1 mg/kg ip). Twenty-four hours later, hearts were subjected to 30 min of global ischemia and 30 min of reperfusion in the Langendorff mode. Genistein or SB-203580 (1 mg/kg i.p.) given 30 min before CCPA treatment was used to block receptor tyrosine kinase or p38 MAPK phosphorylation, respectively. 5-Hydroxydecanoate (5-HD; 200 microM) was used to block (K(ATP))(mito) channels. CCPA produced marked improvement in left ventricular function, which was partially blocked by SB-203580 and 5-HD and completely abolished with genistein. CCPA caused a reduction in infarct size (12.0 +/- 2.0 vs. 30.3 +/- 3.0% in vehicle), which was blocked by genistein (29.4 +/- 2.3%), SB-203580 (28.3 +/- 2.6%), and 5-HD (33.9 +/- 2.4%). CCPA treatment also caused increased phosphorylation of p38 MAPK during ischemia, which was blocked by genistein, SB-203580, and 5-HD. The results suggest that A(1)AR-triggered delayed cardioprotection is mediated by p38 MAPK phosphorylation. Blockade of cardioprotection with 5-HD concomitant with decrease in p38 MAPK phosphorylation suggests a potential role of (K(ATP))(mito) channel opening in phosphorylation and ensuing the late preconditioning effect of A(1)AR. |
2,332,503 | Tone of sympathetic nerves and regulation of heart activity. | Tone of sympathetic nerves to the heart was studied in rats and guinea pigs. Experiments with pharmacological blockade of the sympathetic nervous system and vagotomy confirmed the general notion on the absence of tonic effects of sympathetic nerves on the heart. Reduction of the heart rate reported previously probably attests to various experimental designs (type and depth of anesthesia, possible hypothermia, duration of observations, and pharmacological preparations). As differentiated from the vascular tone, the heart rate under rest conditions depends on the vagal tone and circulating humoral substances. |
2,332,504 | The EGF-CFC family: novel epidermal growth factor-related proteins in development and cancer. | The EGF-CFC gene family encodes a group of structurally related proteins that serve as important competence factors during early embryogenesis in Xenopus, zebrafish, mice and humans. This multigene family consists of Xenopus FRL-1, zebrafish one-eyed-pinhead (oep), mouse cripto (Cr-1) and cryptic, and human cripto (CR-1) and criptin. FRL-1, oep and mouse cripto are essential for the formation of mesoderm and endoderm and for correct establishment of the anterior/posterior axis. In addition, oep and cryptic are important for the establishment of left-right (L/R) asymmetry. In zebrafish, there is strong genetic evidence that oep functions as an obligatory co-factor for the correct signaling of a transforming growth factor-beta (TGFbeta)-related gene, nodal, during gastrulation and during L/R asymmetry development. Expression of Cr-1 and cryptic is extinguished in the embryo after day 8 of gestation except for the developing heart where Cr-1 expression is necessary for myocardial development. In the mouse, cryptic is not expressed in adult tissues whereas Cr-1 is expressed at a low level in several different tissues including the mammary gland. In the mammary gland, expression of Cr-1 in the ductal epithelial cells increases during pregnancy and lactation and immunoreactive and biologically active Cr-1 protein can be detected in human milk. Overexpression of Cr-1 in mouse mammary epithelial cells can facilitate their in vitro transformation and in vivo these Cr-1-transduced cells produce ductal hyperplasias in the mammary gland. Recombinant mouse or human cripto can enhance cell motility and branching morphogenesis in mammary epithelial cells and in some human tumor cells. These effects are accompanied by an epithelial-mesenchymal transition which is associated with a decrease in beta-catenin function and an increase in vimentin expression. Expression of cripto is increased several-fold in human colon, gastric, pancreatic and lung carcinomas and in a variety of different types of mouse and human breast carcinomas. More importantly, this increase can first be detected in premalignant lesions in some of these tissues. Although a specific receptor for the EGF-CFC proteins has not yet been identified, oep depends upon an activin-type RIIB and RIB receptor system that functions through Smad-2. Mouse and human cripto have been shown to activate a ras/raf/MAP kinase signaling pathway in mammary epithelial cells. Activation of phosphatidylinositol 3-kinase and Akt are also important for the ability of CR-1 to stimulate cell migration and to block lactogenic hormone-induced expression of beta-casein and whey acidic protein. In mammary epithelial cells, part of these responses may depend on the ability of CR-1 to transactivate erb B-4 and/or fibroblast growth factor receptor 1 through an src-like tyrosine kinase. |
2,332,505 | Primary hyperoxaluria type 1 causing end-stage renal disease in a 45-year-old patient. | Primary hyperoxaluria type 1 (PH1) is caused by deficiency of peroxisomal alanine-glyoxylate aminotransferase which is in humans exclusively expressed in liver cells. The disease is inherited as an autosomal recessive trait, and initial symptoms usually occur in early childhood. Up to the age of 25 years, 90% of the patients are symptomatic, and many patients develop end-stage renal failure. Pronounced medical care is necessary in PH1 patients to prevent generalized oxalosis with complications due to bone disease and peripheral gangrene. The rather short survival of patients on hemodialysis is caused by sudden arrhythmias and heart block. As no dialysis procedure is able to remove the daily produced oxalate, early transplantation is mandatory. Our 45-year-old patient is remarkable on the basis of the late manifestations of PH1. The diagnosis was delayed by unspecific symptoms of nephrolithiasis with recurrent pyelonephritis. Clinical course and diagnostic cornerstones of primary hyperoxaluria are outlined. The principles of conservative treatment and experiences with dialysis and transplantation are discussed. |
2,332,506 | Cardiovascular responses to microinjections of nicotine into the caudal ventrolateral medulla of the rat. | This study focuses on the role of nicotinic receptors located in the caudal ventrolateral medullary depressor area (CVLM) in regulating/modulating cardiovascular function. Blood pressure and heart rate were monitored by standard techniques in urethane-anesthetized, artificially ventilated, adult male Wistar rats. Multi-barreled glass-micropipettes (tip size 20-40 microm) were used to make microinjections (100 nl) into the CVLM. Concentrations of nicotine ranging from 250 micromto 10 mM were microinjected unilaterally into the CVLM. The maximum depressor and bradycardic responses were elicited by a 1 mM concentration of nicotine. Sequential microinjections of mecamylamine (1 mM), an antagonist for nicotinic receptors containing alpha3beta4 subunits, then alpha-bungarotoxin (1 microm), an antagonist for nicotinic receptors containing alpha-7 subunits, were made into the CVLM. Microinjecting a combination of a nicotinic receptor blocker and toxin resulted in the complete blockade of the cardiovascular responses induced by nicotine (1 mM, 100 nl). These results indicate that: (1) nicotinic receptors are present in the CVLM; (2) activation of these receptors results in depressor and bradycardic responses; (3) for a complete blockade of nicotine-induced cardiovascular responses, it is necessary to use a combination of mecamylamine and alpha-bungarotoxin; (4) since mecamylamine and alpha-bungarotoxin are known to block nicotinic receptors containing alpha3beta4 and alpha-7 subunits, respectively, two different subtypes of nicotinic receptors (one which contains a combination of alpha3beta4 subunits, and one which contains alpha-7 subunits) must be present in the CVLM; and (5) it is not clear whether these two subtypes of nicotinic receptor are located on the same or different populations of CVLM-neurons. |
2,332,507 | Acute cigarette smoking reduces vasodilative effect induced by sympathetic block in dogs. | The aim of this study is to clarify the influence of acute cigarette smoking on vasodilation induced by sympathetic block.</AbstractText>We measured mean arterial pressure, heart rate, left brachial artery blood flow (BABF), right femoral artery blood flow (FABF), and plasma catecholamines in dogs to examine the effect of acute cigarette smoking after stellate ganglion block (SGB). The experimental protocol was: (1) Left SGB using 1.0 mL 0.5% mepivacaine without smoking (sham smoking); and (2) left SGB using 1.0 mL 0.5% mepivacaine followed by a single cigarette smoking (nicotine 1 mg) 15 minutes after the block.</AbstractText>SGB induced a significant increase of BABF during the study (baseline, 100%; peak at 10 minutes after SGB, 176% +/- 9%; P <.05) in sham smoking and a significant decrease of FABF from 10 minutes after the block to 20 minutes after sham smoking (baseline, 100%; bottom at 5 minutes after sham smoking, 82% +/- 8%; P <.05). Smoking after SGB induced a significant decrease of BABF 60 minutes after smoking (baseline, 100%; 69% +/- 11%; P <.05) and a significant decrease of FABF during the study (baseline, 100%; bottom at 20 minutes after smoking, 74% +/- 20%; P <.05). Smoking significantly increased plasma norepinephrine and epinephrine through the study.</AbstractText>Sympathetic block induces a significant increase of peripheral blood flow, but smoking produces a significant decrease in the blood flow in the SGB-induced dilated vessels.</AbstractText> |
2,332,508 | [Characteristics of atrial electrograms recorded in radiofrequency induced block lines in an experimental model]. | To analyze and quantify atrial electrogram modifications following the induction of linear lesions in the atrial wall using radiofrequency ablation procedures.</AbstractText>An epicardial multiple electrode (221 unipolar electrodes) was used in 12 Langendorff perfused rabbit hearts to analyze atrial activation before and after radiofrequency induction of a linear lesion in the left atrial wall. After confirming the existence of conduction blockade in the lesion zone by epicardial mapping and propagation vector analysis, six electrodes each were selected in the lesioned and non-lesioned zones in all experiments, comparing the amplitude, maximum negative slope and morphology of the electrograms in both zones, before (control) and after radiofrequency delivery.</AbstractText>Analysis of the reproducibility of the measurements in two consecutive cycles showed a variation of 1 +/- 5% for amplitude (NS) and 1 +/- 9% for maximum negative slope (NS). In the non-damaged zone, amplitude (105 +/- 22%) and slope (92 +/- 16%) (values normalized with respect to those recorded before radiofrequency) did not vary significantly following radiofrequency, and simple electrograms were the most frequent recordings (82 vs 83% in control; NS). Amplitude (19 +/- 7%, p < 0.001) and slope (24 +/- 11%; p < 0.001) decreased significantly in the lesion zone, as did the percentage of simple electrograms (6 vs 86% in control; p < 0,001). In this same zone the morphology could not be determined in 12% of the recordings, while multiple electrograms were obtained in 15% (vs 2% in control; p < 0.01), and the most frequent type corresponded to double electrograms (67 vs 12% in control, p < 0.001), with both components coinciding in time with atrial activation in the zones proximal and distal to the lesion line.</AbstractText>Electrograms recorded directly in radiofrequency induce block lines show a significant decrease in amplitude and maximum negative slope. Double electrograms predominate in these recordings, both components of which represent activation on either side of the lesion. In a small proportion of cases simple and multiple electrograms can also be recorded in the block line.</AbstractText> |
2,332,509 | Do saw palmetto extracts block human alpha1-adrenoceptor subtypes in vivo? | To test whether saw palmetto extracts, which act as alpha1-adrenoceptor antagonists in vitro, also do so in vivo in man.</AbstractText>In a placebo-controlled, double-blind, four-way cross-over study 12 healthy young men were treated with three different saw palmetto extract preparations (320 mg o.d.) for 8 days each. On the last day, before and 2, 4 and 6 hr after drug intake blood pressure and heart rate were determined and blood samples obtained, which were used in an ex vivo radioreceptor assay with cloned human alpha1-adrenoceptor subtypes.</AbstractText>Saw palmetto extract treatment did not result in alpha1-adrenoceptor subtype occupancy in the radioreceptor assay. Although the saw palmetto extracts caused minor reductions of supine blood pressure, they did not affect blood pressure during orthostatic stress testing and did not alter heart rate under either condition. Moreover, plasma catecholamines remained largely unaltered.</AbstractText>Despite their alpha1-adrenoceptor antagonist effects in vitro, therapeutically used doses of saw palmetto extracts do not cause alpha1-adrenoceptor antagonism in man in vivo.</AbstractText>Copyright 2001 Wiley-Liss, Inc.</CopyrightInformation> |
2,332,510 | The acute effects of stellate ganglion block on circulation in human ocular fundus. | To study the acute effects of local-anesthetic stellate ganglion block (SGB) on tissue circulation in the human fundus.</AbstractText>Eleven patients with Bell's palsy (age 56+/-6 y, mean+/-SD) who underwent SGB for its treatment participated in the study. Using the laser speckle method, normalized blur (NB) value, a quantitative index of tissue blood velocity, was measured every 0.125 s over an area located halfway between the macula and the optic nerve head (ONH) with no discrete visible vessels and averaged over 3 pulses when fixation was satisfactory (NB(ch-ret)). NB(ch-ret) and intraocular pressure (IOP) in both eyes, blood pressure (BP), and pulse rate (PR) were measured before, and 10, 20, 30, and 60 min after SGB. SGB was induced by injecting 1% mepivacaine hydrochloride (5 ml) into the vicinity of the seventh cervical vertebra on the paralyzed side.</AbstractText>The IOP in the blocked side significantly decreased between 20 and 60 min following SGB, compared to the baseline, while IOP in the unblocked side remained unchanged. The NB(ch-ret) was significantly increased after 10 min by about 8% in the blocked side, but its effect almost disappeared at 60 min. There was no significant change in NB(ch-ret) in the unblocked side, BP or PR throughout the experimental period.</AbstractText>SGB increased tissue circulation in the fundus in the blocked side, but its effect was thought to be small and transient.</AbstractText> |
2,332,511 | The initial mode of action of copper on the cardiac physiology of the blue mussel, Mytilus edulis. | Previous studies have shown that low levels of copper (down to 0.8 microM) induce bradycardia in the blue mussel (Mytilus edulis) and that this is not caused by prolonged valve closure. The aim of this study was to determine the precise mechanism responsible. To establish if copper was directly affecting heart cell physiology, recordings of contractions from isolated ventricular strips were made using an isometric force transducer, in response to copper concentrations (as CuCl2) ranging between 1 microM and 1 mM. Inhibition of mechanical activity only occurred at 1 mM copper, suggesting that the copper-induced bradycardia observed in whole animals cannot be attributed to direct cardiotoxicity. Effects of copper on the cardiac nerves were subsequently examined. Following removal of visceral ganglia (from where the cardiac nerves originate), exposure to 12.5 microM copper had no effect on the heart rate of whole animals. The effect of copper on the heart rate of mussels could not be abolished by depletion of the monoamine content of the animal using reserpine. However, pre-treatment of the animals with alpha-bungarotoxin considerably reduced the sensitivity of the heart to copper. These results indicated that the influence of copper on the heart of M. edulis might be mediated by a change in the activity of cholinergic nerves to heart. In the final experiments, mussels were injected with either benzoquinonium or D-tubocurarine, prior to copper exposure, in an attempt to selectively block the inhibitory or excitatory cholinoreceptors of the heart. Only benzoquinonium decreased the susceptibility of the heart to copper, suggesting that copper affects the cardiac activity of blue mussels by stimulating inhibitory cholinergic nerves to the heart. |
2,332,512 | Progress in the prevention of breast cancer: concept to reality. | In 1936, Professor Antoine Lacassagne suggested that breast cancer could be prevented by developing drugs to block estrogen action in the breast. Jensen discovered the physiologic target, the estrogen receptor, that regulates estrogen action in its target tissues and Lerner discovered the first nonsteroidal antiestrogen MER25. However, the success of tamoxifen as a treatment of breast cancer opened the door for the testing of the worth of tamoxifen to reduce breast cancer incidence in high-risk women. In 1998, Fisher showed that tamoxifen could reduce breast cancer incidence by 50%. Nevertheless, only half the women who develop breast cancer have risk factors other than age, so what can be done for women without risk factors? The recognition that nonsteroidal antiestrogens have the ability to modulate estrogen action selectively has advanced the design and development of new drug for multiple diseases. Tamoxifen and raloxifene maintain bone density and raloxifene is now used to prevent osteoporosis and is being tested as a preventive for coronary heart disease and breast cancer. The drug group is now known as selective estrogen receptor modulators (SERMs) and the challenge is to design new agents for multiple applications. If the 20th century was the era of chemotherapy, the 21st century will be the era of chemoprevention. |
2,332,513 | Pharmacological comparison of native mitochondrial K(ATP) channels with molecularly defined surface K(ATP) channels. | Many mammalian cells have two distinct types of ATP-sensitive potassium (K(ATP)) channels: the classic ones in the surface membrane (sK(ATP)) and others in the mitochondrial inner membrane (mitoK(ATP)). Cardiac mitoK(ATP) channels play a pivotal role in ischemic preconditioning, and thus represent interesting drug targets. Unfortunately, the molecular structure of mitoK(ATP) channels is unknown, in contrast to sK(ATP) channels, which are composed of a pore-forming subunit (Kir6.1 or Kir6.2) and a sulfonylurea receptor (SUR1, SUR2A, or SUR2B). As a means of probing the molecular makeup of mitoK(ATP) channels, we compared the pharmacology of native cardiac mitoK(ATP) channels with that of molecularly defined sK(ATP) channels expressed heterologously in human embryonic kidney 293 cells. Using mitochondrial oxidation to index mitoK(ATP) channel activity in rabbit ventricular myocytes, we found that pinacidil and diazoxide open mitoK(ATP) channels, but P-1075 does not. On the other hand, 5-hydroxydecanoic acid (5HD), but not HMR-1098, blocks mitoK(ATP) channels. Although pinacidil is a nonselective activator of expressed sK(ATP) channels, diazoxide did not open channels formed by Kir6.1/SUR2A, Kir6.2/SUR2A (known components of cardiac sK(ATP) channels) or Kir6.2/SUR2B. P-1075 activated all the K(ATP) channels, except Kir6.1/SUR1 channels. Glybenclamide potently blocked all sK(ATP) channels, but 5HD only blocked channels formed by SUR1/Kir6.1 or Kir6.2 (IC(50)s of 66 and 81 microM, respectively). This potency is similar to that for block of mitoK(ATP) channels (IC(50) = 95 microM). In addition, HMR-1098 potently blocked Kir6.2/SUR2A channels (IC(50) = 1.5 microM), but was 67 times less potent in blocking Kir6.1/SUR1 channels (IC(50) = 100 microM). Our results demonstrate that mitoK(ATP) channels closely resemble Kir6.1/SUR1 sK(ATP) channels in their pharmacological profiles. |
2,332,514 | Irreversible block of human heart (hH1) sodium channels by the plant alkaloid lappaconitine. | The roots from Aconitum sp. plants have long been used in Chinese herbal medicine for treating pain and various heart conditions. The principal component of Aconitum remedies is usually aconitine, a site 2 neurotoxin that may induce severe neurological symptoms and cardiovascular collapse. Some Aconitum species also contain lappaconitine, the structure of which is remarkably similar to that of aconitine. In contrast to aconitine, a sodium channel agonist, lappaconitine reportedly blocks voltage-gated sodium channels in heart tissue. The results in the present study demonstrate that lappaconitine blocks cloned human heart (hH1) sodium channels under whole-cell, voltage-clamp conditions. Lappaconitine binding has several characteristics in common with the binding of site 2 neurotoxins, such as aconitine and batrachotoxin. For example, lappaconitine binds almost exclusively to open channels, but has little affect on resting or inactivated channels. Moreover, lappaconitine binding is inhibited by bupivacaine, a tertiary amine local anesthetic. Whereas site 2 neurotoxins often irreversibly modify channel kinetics, lappaconitine irreversibly blocks the channels. Finally, channels containing lysine substitutions within the local anesthetic receptor region at residues F1760 or N1765 are resistant to block by bupivacaine or lappaconitine. Given that site 2 neurotoxins and local anesthetics have nonidentical but overlapping binding regions, these data suggest that lappaconitine irreversibly blocks hH1 channels by binding to the site 2 receptor. |
2,332,515 | Pathophysiological role of cytokines in congestive heart failure. | Heart failure is a complex neurohumoral and inflammatory syndrome. Recent studies have shown that proinflammatory cytokines (interleukin-1, interleukin-2, interleukin-6, interleukin-10, and tumor necrosis factor) are involved in cardiac depression and in the complex syndrome of heart failure. Understanding the involvement of these cytokines may enable us to reverse cardiac depression and heart failure by the use of monoclonal antibodies directed against specific cytokines to block the downhill progression of heart failure. |
2,332,516 | Effects of bupivacaine and a novel local anesthetic, IQB-9302, on human cardiac K+ channels. | We have studied and compared the effects of bupivacaine with those induced by a new local anesthetic, IQB-9302, on human cardiac K+ channels hKv1.5, Kv2.1, Kv4.3, and HERG. Both drugs have a close chemical structure, only differing in their N-substituent (n-butyl and cyclopropylmethyl, for bupivacaine and IQB-9302, respectively). Both drugs blocked Kv2.1, Kv4.3, and HERG channels similarly. Bupivacaine inhibited these channels by 48.6 +/- 3.4, 45.4 +/- 12.4, and 43.1 +/- 9.1%, respectively, and IQB-9302 by 48.1 +/- 3.3, 36.1 +/- 3.7, and 50.3 +/- 6.6%, respectively. However, bupivacaine was 2.5 times more potent than IQB-9302 to block hKv1.5 channels (EC(50) = 8.9 +/- 1.4 versus 21.5 +/- 4.7 microM). Both drugs induced a time- and voltage-dependent block of hKv1.5 and Kv2.1 channels. Block of Kv4.3 channels induced by either drug was time- and voltage-dependent at membrane potentials coinciding with the activation of the channels. IQB-9302 produced an instantaneous block of Kv4.3 and hKv1.5 channels at the beginning of the depolarizing pulse that can be interpreted as a drug interaction with a nonconducting state. Bupivacaine and IQB-9302 induced a similar degree of block of HERG channels and induced a steep voltage-dependent decrease of the relative current. These results suggest that 1) bupivacaine and IQB-9302 block the open state of hKv1.5, Kv2.1, Kv4.3, and HERG channels; and 2) small differences at the N-substituent of these drugs do not affect the drug-induced block of Kv2.1, Kv4.3, or HERG, but specifically modify block of hKv1.5 channels. |
2,332,517 | Wnt signals from the neural tube block ectopic cardiogenesis. | It has long been observed that repressive signals from the neural tube block cardiogenesis in vertebrates. Here we show that a signal from the neural tube that blocks cardiogenesis in the adjacent anterior paraxial mesoderm of stage 8-9 chick embryos can be mimicked by ectopic expression of either Wnt-3a or Wnt-1, both of which are expressed in the dorsal neural tube. Repression of cardiogenesis by the neural tube can be overcome by ectopic expression of a secreted Wnt antagonist. On the basis of both in vitro and in vivo results, we propose that Wnt signals from the neural tube normally act to block cardiogenesis in the adjacent anterior paraxial mesendoderm. |
2,332,518 | alpha(4) integrin-dependent eosinophil recruitment in allergic but not non-allergic inflammation. | 1. Although anti-alpha(4) integrin mAbs reduce eosinophil accumulation in several models of allergic inflammation, it is not clear whether this occurs via a direct action to block eosinophil alpha(4) integrins or indirectly on another cell type. The role of alpha(4) integrins on the accumulation of (111)In-labelled eosinophils in allergic and non-allergic inflammation in guinea-pig skin was therefore investigated. 2. Intradermal injection of antigen in sensitized skin sites induced accumulation of (111)In-eosinophils that was reduced up to 70% by two anti-alpha(4) integrin mAbs. In contrast, accumulation of (111)In-eosinophils to intradermal chemoattractants was unaffected by the same mAbs. 3. Accumulation of (111)In-eosinophils in allergic and non-allergic conditions was partly inhibited by a low dose of an anti-beta(2) integrin mAb. In combination with anti-alpha(4) integrin mAb, responses were not further reduced suggesting that these adhesion pathways are not additive or synergic. 4. Pretreating skin sites with antiserum or contaminating LPS did not reveal an alpha(4) integrin dependent pathway for chemoattractant-induced (111)In-eosinophil accumulation. These data suggest that alpha(4) integrins are involved in the response to antigen in sensitized skin sites. 5. Pretreating (111)In-eosinophil with alpha(4) integrin mAb blocked their adhesion to fibronectin in vitro but did not inhibit their accumulation in allergic inflammation suggesting that the blocking effect in vivo was eosinophil independent. 6. These data support the concept that targeting alpha(4) integrins on cells other than eosinophils could control eosinophil accumulation and have therapeutic potential in allergic diseases such as asthma and atopic dermatitis. |
2,332,519 | Stereoselective effects of the enantiomers of a new local anaesthetic, IQB-9302, on a human cardiac potassium channel (Kv1.5). | 1. The N-substituent of IQB-9302 has the same number of carbons as bupivacaine, but it exhibits a different spatial localization (n-butyl vs cyclopropylmethyl). Thus, the study of the effects of IQB-9302 enantiomers on hKv1.5 channels will lead to a better knowledge of the determinants of stereoselective block. 2. The effects of the IQB-9302 enantiomers were studied on hKv1.5 channels stably expressed in LTK:(-) cells using the whole-cell configuration of the patch-clamp technique. Drug molecular modelling was performed using Hyperchem software. 3. Block induced by IQB-9302 was stereoselective with the R(+) enantiomer being 3.2-fold more potent than the S(-) one (K(D) of 17.8+/-0.5 microM vs 58.6+/-4.0 microM). 4. S(-)- and R(+)IQB-9302 induced-block was time- and voltage-dependent consistent with an electrical distance from the cytoplasmic side of 0.173+/-0.022 (n=12) and 0.181+/-0.018 (n=10), respectively. 5. Potency of block of pipecoloxylidide local anaesthetics was linearly related to the length between the cationic tertiary amine and the end of the substituent. 6. Molecular modelling shows that only when S(-) and R(+) enantiomers are superimposed by their aromatic ring, their N-substituents are in opposite directions, which can explain the stereospecific block induced by bupivacaine and IQB-9302 with hKv1.5 channels. 7. These results suggest that: (a) IQB-9302 enantiomers block the open state of hKv1.5 channels, and (b) the length of the N-substituent in these local anaesthetics and not its volume determines the potency and degree of their stereoselective hKv1.5 channel block. |
2,332,520 | Blocker state dependence and trapping in hyperpolarization-activated cation channels: evidence for an intracellular activation gate. | Hyperpolarization-activated cation currents (I(h)) are key determinants of repetitive electrical activity in heart and nerve cells. The bradycardic agent ZD7288 is a selective blocker of these currents. We studied the mechanism for ZD7288 blockade of cloned I(h) channels in excised inside-out patches. ZD7288 blockade of the mammalian mHCN1 channel appeared to require opening of the channel, but strong hyperpolarization disfavored blockade. The steepness of this voltage-dependent effect (an apparent valence of approximately 4) makes it unlikely to arise solely from a direct effect of voltage on blocker binding. Instead, it probably indicates a differential affinity of the blocker for different channel conformations. Similar properties were seen for ZD7288 blockade of the sea urchin homologue of I(h) channels (SPIH), but some of the blockade was irreversible. To explore the molecular basis for the difference in reversibility, we constructed chimeric channels from mHCN1 and SPIH and localized the structural determinant for the reversibility to three residues in the S6 region likely to line the pore. Using a triple point mutant in S6, we also revealed the trapping of ZD7288 by the closing of the channel. Overall, the observations led us to hypothesize that the residues responsible for ZD7288 block of I(h) channels are located in the pore lining, and are guarded by an intracellular activation gate of the channel. |
2,332,521 | The role of nitric oxide in the coronary vasoconstriction caused by growth hormone in anaesthetized pigs. | Intravenous injection of growth hormone in anaesthetized pigs has been shown to cause coronary vasoconstriction by antagonizing the vasodilatory effects of 2-adrenergic receptors. Because nitric oxide is believed to modulate or mediate 2-adrenergic effects, the present study was undertaken in the same experimental model to determine the role of nitric oxide in the above response to growth hormone. In fourteen pigs anaesthetized with sodium pentobarbitone, changes in left circumflex or anterior descending coronary blood flow caused by intravenous injection of 0.05 i.u. kg-1 of growth hormone at constant heart rate and arterial blood pressure were assessed using electromagnetic flowmeters. In a first control group of six pigs, growth hormone caused a decrease in coronary blood flow which averaged 13.1 % of the baseline values. In a second group of eight pigs, intravenous administration of N-nitro-L-arginine methyl ester (L-NAME) was used to block the endothelial release of nitric oxide. In these pigs, the subsequent injection of growth hormone did not cause any significant changes in coronary blood flow, even when performed after reversing the increase in arterial blood pressure and coronary vascular resistance caused by L-NAME with continuous intravenous infusion of papaverine. These results indicated that the coronary vasoconstricting effect of growth hormone, known to involve antagonism of 2-adrenergic vasodilatory effect, was mediated by inhibition of nitric oxide release. |
2,332,522 | [The effect of aldosterone of promotion on proliferation of ventricular fibroblasts]. | To study the effect of promoting aldosterone on proliferation of ventricular fibroblasts.</AbstractText>Assay of [3H]-TdR incorporation rate and RT-PCR were used.</AbstractText>Aldosterone could promote [3H]-TdR incorporation of ventricular fibroblasts, the effective dose of aldosterone was among (1 x 10(-9)-1 x 10(-6))mol/L, and had dose-dependent manner, the c-fos gene was expressed after stimulated by aldosterone for 15 min, and studied the highest in 1 h, then reduced later. Spironolactone, aldosterone receptor antagonist could block the effect of aldosterone.</AbstractText>Aldosterone promotes the proliferation of ventricular fibroblasts, mediated by aldosterone receptor.</AbstractText> |
2,332,523 | Pharmacological block of the slow component of the outward delayed rectifier current (I(Ks)) fails to lengthen rabbit ventricular muscle QT(c) and action potential duration. | 1. The effects of I(Ks) block by chromanol 293B and L-735,821 on rabbit QT-interval, action potential duration (APD), and membrane current were compared to those of E-4031, a recognized I(Kr) blocker. Measurements were made in rabbit Langendorff-perfused whole hearts, isolated papillary muscle, and single isolated ventricular myocytes. 2. Neither chromanol 293B (10 microM) nor L-735,821 (100 nM) had a significant effect on QTc interval in Langendorff-perfused hearts. E-4031 (100 nM), on the other hand, significantly increased QTc interval (35.6+/-3.9%, n=8, P<0.05). 3. Similarly both chromanol 293B (10 microM) and L-735,821 (100 nM) produced little increase in papillary muscle APD (less than 7%) while pacing at cycle lengths between 300 and 5000 ms. In contrast, E-4031 (100 nM) markedly increased (30 - 60%) APD in a reverse frequency-dependent manner. 4. In ventricular myocytes, the same concentrations of chromanol 293B (10 microM), L-735,821 (100 nM) and E-4031 (1 microM) markedly or totally blocked I(Ks) and I(Kr), respectively. 5. I(Ks) tail currents activated slowly (at +30 mV, tau=888.1+/-48.2 ms, n=21) and deactivated rapidly (at -40 mV, tau=157.1+/-4.7 ms, n=22), while I(Kr) tail currents activated rapidly (at +30 mV, tau=35.5+/-3.1 ms, n=26) and deactivated slowly (at -40 mV, tau(1)=641.5+/-29.0 ms, tau(2)=6531+/-343, n=35). I(Kr) was estimated to contribute substantially more to total current density during normal ventricular muscle action potentials (i.e., after a 150 ms square pulse to +30 mV) than does I(Ks). 6. These findings indicate that block of I(Ks) is not likely to provide antiarrhythmic benefit by lengthening normal ventricular muscle QTc, APD, and refractoriness over a wide range of frequencies. |
2,332,524 | The efficacy of intraoperative internal intercostal nerve block during video-assisted thoracic surgery on postoperative pain. | Video-assisted thoracic surgery (VATS) is widely used for many thoracic surgical procedures. Post-operative pain is less after VATS than after conventional thoracic surgery, but is still significant. The objective of this study was to assess the efficacy of thoracoscopic, internal intercostal nerve block in alleviating immediate postoperative pain.</AbstractText>Thirty-two patients underwent VATS bilateral sympathectomy for the treatment of hyperhidrosis. The patients were randomly divided into two groups with similar demographic and preoperative physiologic parameters. Group A (n = 16) was submitted to thoracoscopic, internal intercostal nerve blocks performed at T2, T3, and T4 intercostal levels using 3 cc of 0.5% bupivacain in each intercostal space. The injections were performed bilaterally, immediately after the sympathectomy, through the same port. Group B (n = 16) underwent bilateral thoracic sympathectomy without the block. During the immediate postoperative period, heart rate, blood pressure, respiratory rate, pain score, and analgesic requirements were monitored every 30 minutes.</AbstractText>No morbidity was recorded in association with the thoracoscopic, internal intercostal nerve block. The mean heart rates (77 +/- 6 vs 89 +/- 12 beats per minute, p < 0.001), respiratory rates (15 +/- 2 vs 18 +/- 3 respirations per minute, p < 0.01), pain score (1.9 +/- 0.6 vs 2.7 +/- 0.5, p < 0.01), and postoperative analgesic requirements (20 +/- 18 vs 50 +/- 21 mg pethidine HCL, p < 0.001) were significantly lower in group A. There was no significant difference in blood pressures.</AbstractText>Thoracoscopic, internal intercostal nerve block with bupivacain 0.5% during VATS is safe and effectively reduced the immediate postoperative pain and analgesic requirements.</AbstractText> |
2,332,525 | Expression and function of colonic epithelial KvLQT1 K+ channels. | 1. KvLQT1 (KCNQ1) is a voltage-gated K+ channel essential for repolarization of the heart action potential. Defects in ion channels have been demonstrated in cardiac arrhythmia. This channel is inhibited potently by the chromanol 293B. The same compound has been shown to block cAMP-dependent electrolyte secretion in rat and human colon. Therefore, it was suggested that a K+ channel similar to KvLQT1 is expressed in the colonic epithelium. 2. In the present paper, expression of KvLQT1 and its function in colonic epithelial cells is described. Reverse transcription-polymerase chain reaction analysis of rat colonic mucosa demonstrated expression of KvLQT1 in both crypt cells and surface epithelium. When expressed in Xenopus oocytes, KvLQT1 induced a typical delayed activated K+ current. 3. As demonstrated, the channel activity could be further activated by increases in intracellular cAMP. These and other data support the concept that KvLQT1 is forming a component of the basolateral cAMP-activated K+ conductance in the colonic epithelium. |
2,332,526 | Nuclear factor-kappaB transcription factor decoy treatment inhibits graft coronary artery disease after cardiac transplantation in rodents. | Nuclear factor-kappaB (NF-kappaB) is a transcription factor that upregulates adhesion molecules ICAM-1, VCAM-1, and ELAM-1. We hypothesized the use of ex vivo pressure-mediated delivery of transcription factor decoys (TFD) to NF-kappaB binding sites would decrease expression of adhesion molecules, and decrease reperfusion injury, acute rejection, and graft coronary artery disease (GCAD) in rat cardiac allografts.</AbstractText>Heterotopic heart transplants were performed on donor hearts treated with saline, 10 mg/kg LPS, 160 micromol/L NF-kappaB TFD, or 160 micromol/L scrambled sequence (NF-SC) TFD for 45 min at 78 psi (6 atm). Transfection efficiency was determined with FITC-labeled TFD. Reverse transcription-PCR and immunohistochemistry was used to analyze adhesion molecule mRNA and protein expression, respectively. Apoptosis was measured with DNA fragmentation analysis. Reperfusion injury was assessed with cardiac edema, neutrophil infiltration, and histology. Acute rejection was determined by daily palpation. Allografts were assessed at POD 90 for the development of GCAD by computer-assisted image analysis to determine intimal:medial ratio and myointimal proliferation.</AbstractText>Hyperbaric pressure was an effective method of NF-kappaB TFD delivery (P<0.001 vs. controls). NF-kappaB TFD treatment led to decreased mRNA and protein expression of adhesion molecules. Treatment with NF-kappaB TFD led to a significant decrease in all reperfusion injury parameters compared to saline and NF-SC controls (P<0.01 vs. controls). Higher levels of apoptosis were seen in allografts treated with NF-kappaB TFD compared to control allografts. NF-kappaB TFD treatment prolonged allograft survival over saline and NF-SC controls (P<0.05). Myointimal proliferation and intimal:medial ratios in NF-kappaB TFD-treated allografts were significantly decreased compared to saline and NF-SC treatment (P<0.00001).</AbstractText>Ex vivo pressure-mediated delivery of NF-kappaB TFD is an effective method to block adhesion molcule expression and reperfusion injury in the immediate posttransplant period. Further, NF-kappaB TFD treatment prolongs allograft survival and decreases GCAD.</AbstractText> |
2,332,527 | Continuous positive pressure ventilation during epidural blockade--effects on cardiac output distribution. | It has been shown that when cardiac output (CO) decreases during continuous positive pressure ventilation (CPPV), its regional distribution adapts with a favouring of vital organs. Does epidural blockade modify this adaptation?</AbstractText>Regional blood flows were assessed by the microsphere technique (15 microm) in 17 anaesthetised pigs during spontaneous breathing and CPPV with 8 cm H2O end-expiratory pressure (CPPV8) before and after epidural blockade. The block was induced at either the Th6-7 (Thep) or the L6-S1 (Lep) level with 1 ml of lidocaine 40 mg x ml(-1).</AbstractText>When Lep was combined with CPPV8, mean arterial pressure and CO decreased significantly, and they decreased even more when combined with Thep. In contrast, the relative perfusion of the central nervous system, heart and kidneys remained stable during the four conditions studied. The adrenal perfusion during CPPV8 was obviated by epidural blockade. The absolute and relative perfusion of the skeletal muscle decreased during epidural blockade. The administered doses of epidural lidocaine did not affect blood flow in the spinal cord.</AbstractText>The locally mediated nutritive vasoregulation of vital organs outweighed the sympathetic blockade induced by epidural blockade. During Thep blockade the animals were less capable of responding to the haemodynamic changes induced by CPPV8, probably due to the blockade of the cardiac part of the sympathetic nervous system.</AbstractText> |
2,332,528 | A single-injection, multi-segmental paravertebral block-extension of somatosensory and sympathetic block in volunteers. | It is our experience that a deposition of an anesthetic solution in the ventral area of the paravertebral space near the parietal pleura and the sympathetic trunk produces extended unilateral block. Because sympathetic block effects in this extended paravertebral block are not reported yet, we undertook this singly blinded, controlled study on the sympathetic change in volunteers.</AbstractText>A total of 22 ml 1% lidocaine was injected at the T11 level into the ventral area of the right-sided paravertebral space in 16 volunteers. The distribution of analgesia, heart rate, blood pressure and body temperature (measured by 12 skin sensors) was monitored. On a later occasion the volunteers underwent a control injection of saline.</AbstractText>Unilateral analgesia (with no contralateral element) was induced in every subject injected with lidocaine, contrasted with no block induction with saline. Loss of pin-prick sensation was observed within 10 min after injection and involved a mean of 12 (range 8-13) dermatomes. A sympathetic block was indicated by cutaneous temperature increase within at least 6 dermatomes. Increase of arterial blood pressure was obtained in all volunteers with no change in pulse rate. No side effects or complications occurred. Epidural spread of the local anesthetic was unlikely because of the absence of contralateral cutaneous analgesia and temperature increase.</AbstractText>One-sided extended analgesia (sensory loss) follows the paravertebral injection of lidocaine. A large ipsilateral sympathetic block is observed without change in pulse rate and with no hypotension. These are all characteristics of an optimal regional block.</AbstractText> |
2,332,529 | Effects of endothelium/leukocytes/platelet interaction on myocardial ischemia--reperfusion injury. | Platelet fibrinogen receptor (GPIIb/IIIa) antagonists clinically improve the effectiveness of thrombolysis or PTCA in treatment of acute myocardial infarction. 7E3Fab, the chimeric Fab fragment of a monoclonal GPIIb/IIIa antibody, reduces the incidence of death, reinfarction or restenosis in patients and may improve blood flow and regional wall motion in reperfused myocardium. Besides inhibition of platelet aggregation, 7E3Fab may block fibrinogen bridging between the polymorphonuclear neutrophil (PMN) adhesion molecule MAC-1 and platelet GP IIb/IIIa, thus attenuating interaction of platelets with PMN. Experimentally, the interaction of platelets with PMN exacerbated postischemic myocardial stunning. In our own studies in isolated guinea pig hearts, human PMN, platelets and fibrinogen where simultaneously infused during the initial reperfusion period after 15 min of global ischemia. FACS analysis of cells in the coronary effluant revealed that 7E3Fab reduced platelet GP IIb/IIIa expression to 10% of baseline. PMN-platelet aggregate formation in the coronary effluate was markedly reduced by 7E3Fab, parallel to a decrease of PMN-platelet aggregates found by in situ double fluorescence microscopy in the postischemic coronary vasculature. The inhibition of PMN-platelet aggregate formation by 7E3Fab treatment coincided with a significant improvement of external heart work, which suffered a 50% reduction after ischemia, reperfusion, and exposure to PMN, platelets and fibrinogen. Obviously, application of 7E3Fab inhibits formation and coronary retention of PMN-platelet aggregates in the postischemic, reperfused myocardium. This effect may contribute to the clinically observed beneficial effects of this adjuvant treatment after myocardial ischemia. |
2,332,530 | Selective phenylalkylamine block of I(Kr) over other K(+) currents in guinea-pig ventricular myocytes. | Previous studies on verapamil and D600 have established that the Ca(2+)-channel blockers also inhibit delayed-rectifier K(+) currents in cardiac tissues and myocytes. However, estimated IC(50) values range over two to three orders of concentration, and it is unclear whether this reflects a high selectivity by one or both of the phenylalkylamines for particular K(+) channels. The purpose of the present study was to determine the concentration-dependent actions of verapamil and D600 on three defined cardiac K(+) currents. Guinea-pig ventricular myocytes in the conventional whole-cell configuration were bathed with normal Tyrode's or K(+)-free solution, and pulsed from -80 mV for measurement of the effects of 0.01 microM to 3 mM verapamil and D600 on the inwardly-rectifying K(+) current (I:(Kl)) and the two delayed-rectifier K(+) currents, rapidly-activating I:(Kr) and slowly-activating I:(Ks). The phenylalkylamines inhibited both inward- and outward-directed I:(Kl). The IC(50) values for outward I:(Kl) were approximately 220 microM. Verapamil and D600 were approximately equipotent inhibitors of the delayed-rectifier K(+) currents. They inhibited I:(Kr) with IC(50) near 3 microM, and I:(Ks) with IC(50) > or =280 microM. These results are discussed in relation to previous findings on K(+) currents and to the clinical actions of the drugs. |
2,332,531 | Dynamic exercise discloses different time-related responses in stress hormones. | Responses to stressful events are generally regarded as reactions of the organism to accommodate to or compensate for stress. This reaction is classically described as an activation of the sympathoadrenal system and the hypothalamic-pituitary-adrenocortical (HPA) axis. Activation of the release of growth hormone and prolactin in blood also occurs during various types of stress. Assuming that the stress response is a neuroendocrine mechanism that occurs in anticipation of physical exercise, we investigated whether an incremental exercise protocol can be used as a model stressor to disclose a distinct pattern of activation in these hormonal systems, which would support the notion that these systems have different roles in preparing the organism for physical activity and recovery. Moreover, such a model may help improve our understanding of the endocrine expressions of psychological stress.</AbstractText>After an overnight fast, 8 healthy men (age, 19-26 years) cycled at 40, 60, 80, and 100% of the power output at VO2max in successive time blocks of 10 minutes each up to exhaustion. Venous blood was sampled immediately before exercise, at the end of each block, and during the recovery phase 5 and 30 minutes after exercise. Plasma adrenalin and noradrenalin were measured by high-performance liquid chromatography; plasma adrenocorticotropic hormone, beta-endorphin, cortisol, growth hormone, and prolactin were measured by specific immunoassays. Heart rate and levels of blood lactate and adrenalin were measured as markers of workload-related responses.</AbstractText>Results showed that increases in heart rate, lactate, adrenalin, noradrenalin, and growth hormone reflected the relative workload, in contrast to increases in adrenocorticotropic hormone, beta endorphin, and prolactin, which were observed only after exercise reached an intensity of 80% VO2max. Increases in cortisol were found just after exhaustion. The delayed response of cortisol may be initiated by a drop in blood glucose levels but may also be considered preparatory to vigorous muscular effort and protective against tissue damage.</AbstractText>Measurement of the cumulative response to exercise shows that activation of stress hormones occurs at different time points, supporting the notion that these hormones have different roles in preparing the organism for physical activity and recovery: ie, workload- and effort-related adaptation on one hand and protection against disturbed homeostasis on the other. The delayed response of the HPA axis during incremental exercise contrasts with the nondelayed HPA axis response observed during psychological stress and points to involvement of different neurobiological and cognitive emotional mechanisms.</AbstractText> |
2,332,532 | TEA(+)-sensitive KCNQ1 constructs reveal pore-independent access to KCNE1 in assembled I(Ks) channels. | I(Ks), a slowly activating delayed rectifier K(+) current through channels formed by the assembly of two subunits KCNQ1 (KvLQT1) and KCNE1 (minK), contributes to the control of the cardiac action potential duration. Coassembly of the two subunits is essential in producing the characteristic and physiologically critical kinetics of assembled channels, but it is not yet clear where or how these subunits interact. Previous investigations of external access to the KCNE1 protein in assembled I(Ks) channels relied on occlusion of the pore by extracellular application of TEA(+), despite the very low TEA(+) sensitivity (estimated EC(50) > 100 mM) of channels encoded by coassembly of wild-type KCNQ1 with the wild type (WT) or a series of cysteine-mutated KCNE1 constructs. We have engineered a high affinity TEA(+) binding site into the h-KCNQ1 channel by either a single (V319Y) or double (K318I, V319Y) mutation, and retested it for pore-delimited access to specific sites on coassembled KCNE1 subunits. Coexpression of either KCNQ1 construct with WT KCNE1 in Chinese hamster ovary cells does not alter the TEA(+) sensitivity of the homomeric channels (IC(50) approximately 0.4 mM [TEA(+)](out)), providing evidence that KCNE1 coassembly does not markedly alter the structure of the outer pore of the KCNQ1 channel. Coexpression of a cysteine-substituted KCNE1 (F54C) with V319Y significantly increases the sensitivity of channels to external Cd(2+), but neither the extent of nor the kinetics of the onset of (or the recovery from) Cd(2+) block was affected by [TEA(+)](o) at 10x the IC(50) for channel block. These data strongly suggest that access of Cd(2+) to the cysteine-mutated site on KCNE1 is independent of pore occlusion caused by TEA(+) binding to the outer region of the KCNE1/V319Y pore, and that KCNE1 does not reside within the pore region of the assembled channels. |
2,332,533 | Clonidine combined with a long acting local anesthetic does not prolong postoperative analgesia after brachial plexus block but does induce hemodynamic changes. | Clonidine in brachial plexus block prolongs analgesia of local anesthetics of short and intermediate duration. We performed a prospective randomized double-blinded study to determine the efficacy and adverse effects of clonidine mixed with a long-acting local anesthetic on postoperative analgesia. Sixty adult patients underwent elective rotator cuff repair using interscalene brachial plexus block combined with general anesthesia and were randomly divided into one of the following three groups. Placebo (n = 20): interscalene block with 40 mL of 0.5% bupivacaine with epinephrine (1/200000) and 1 mL of 0.9% saline, completed by 1 mL of 0.9% saline IM in the controlateral shoulder; Control (n = 20): interscalene block with 40 mL of 0.5% bupivacaine with epinephrine and 1 mL of 0. 9% saline, completed by 150 microg (=1 mL) of clonidine IM; Clonidine (n = 20): interscalene block with 40 mL of 0.5% bupivacaine with epinephrine and 150 microg (=1 mL) of clonidine, completed by 1 mL of 0.9% saline IM. During anesthesia hemodynamic variables and fractional expired isoflurane concentration (FeISO) were recorded. The following postoperative variables were assessed: duration of interscalene block, quality of pain relief on a visual analog scale, side effects, and consumption of morphine with a patient-controlled analgesia device over 48 h. Patient characteristics were comparable. During anesthesia mean arterial pressure, heart rate, and FeISO were significantly decreased in Clonidine and Control groups compared with Placebo group. Duration of analgesia, defined as the time elapsed from interscalene injection to the first morphine request, was 983 +/- 489 min in the Placebo, 909 +/- 160 min in the Control, and 829 +/- 159 min in the Clonidine groups. Pain scores and consumption of morphine at 24 h and 48 h showed no differences among the three groups. We conclude that adding 150 microg of clonidine in interscalene block does not prolong analgesia induced by 40 mL of bupivacaine 0.5% with epinephrine, but decreases mean arterial blood pressure and heart rate.</AbstractText>Clonidine in brachial plexus block does not improve postoperative analgesia when mixed with a long-lasting anesthetic. Nevertheless, with or without clonidine, bupivacaine in interscalene block provides a long-lasting analgesia of approximately 15 h.</AbstractText> |
2,332,534 | Adenosine induced direct negative inotropic effect is abolished during global ischemia: role of protein kinase C and prostacyclin. | Adenosine acts as a cardioprotective agent by producing coronary vasodilation, decreasing heart rate and by antagonizing the cardiostimulatory effect of catecholamines; adenosine also exerts a direct negative inotropic effect. Myocardial ischemia is known to be associated with enhanced levels of adenosine, increased protein kinase C (PKC) activity and prostacyclin (PGI2) release. The present study was conducted to determine if myocardial ischemia alters the cardioprotective effect of adenosine by increasing PKC activity and PGI2 release in the isolated rat heart perfused at 10 ml/min with Krebs-Henseleit buffer (KHB; 95% O2+5% CO2). Adenosine (10 mmol/min) reduced myocardial contractility as indicated by a decrease in contractility (dp/dtmax), heart rate (HR) and coronary perfusion pressure (PP). In hearts subjected to 30 min of ischemia (without perfusion) and then reperfused with KHB, adenosine failed to decrease dp/dtmax, HR or PP. However, during infusion of PKC inhibitor H-7 (1-(5-Isoquinolinesulfonyl)-2-methylpiperazine hydrochloride) (H-7; 6 mmol/min), which commenced 10 min before ischemia and continued throughout reperfusion, adenosine produced a decrease in dp/dtmax, HR and PP, similar to that before ischemia. Infusion of the PKC activator phorbol 12,13-dibutyrate (PDBu; 2 nmol/min) but not an inactive analogue in non-ischemic hearts prevented the adenosine induced decrease in dp/dtmax. During infusion of H-7, PDBu failed to block the direct negative inotropic effect of adenosine in non-ischemic hearts. In addition, pretreatment with H-7 or indomethacin (cyclooxygenase inhibitor) significantly reduced the PGI2 release following ischemia. This data suggest that PKC and PGI2 regulate the direct negative inotropic effect of adenosine, which is abolished during ischemia. |
2,332,535 | Improved epidural analgesia in the parturient in the 30 degree tilt position. | To compare the incidence of incomplete analgesia when epidural local anesthetic is administered with the parturient supine in a 30 degree leftward tilt or in the left lateral decubitus position.</AbstractText>After placement of a multiorifice catheter 5 cm into the epidural space, 293 women in active labour were randomly positioned either to the left lateral decubitus position (lateral group) or supine with a 30 degree leftward tilt (tilt group) and then received 13 mL bupivacaine 0.25%. The success of the epidural block was determined by asking the patient if she required additional medication 15 min later. The incidence of complications (fetal heart rate decelerations, hypotension, and ephedrine usage) was noted.</AbstractText>In the lateral group, 38% required additional medication compared with 24% in the tilt group (P = 0.006). There were no differences between groups in the incidence of maternal hypotension or fetal heart rate decelerations, but more women (10%) received ephedrine in the lateral than in the tilt group (4%), P = 0.035.</AbstractText>Placing the parturient supine with a 30 degree leftward tilt is associated with a greater success rate of labour epidural analgesia without an increase in complications than in women in the left lateral decubitus position. This advantage should be considered when positioning the parturient after epidural catheter placement.</AbstractText> |
2,332,536 | Sedative-hypnotic effects of midazolam in goats after intravenous and intramuscular administration. | To examine the effect of dose and route of administration on the sedative-hypnotic effects of midazolam.</AbstractText>Prospective randomized controlled study ANIMALS: Six indigenous, African bred goats.</AbstractText>Pilot studies indicated that the optimum dose of midazolam for producing sedation was 0.6 mg kg-1</sup> for intramuscular (IM) injection, while the optimum intravenous (IV) doses causing hypnosis without, and with loss of palpebral reflexes were 0.6 mg kg-1</sup> and 1.2 mg kg-1</sup>, respectively. These doses and routes of administration were compared with a saline placebo in a randomized block design in the main experiment, and the sedative-hypnotic effects evaluated according to pre-determined scales.</AbstractText>Intramuscular midazolam produced sedation with or without sternal recumbency in all animals with the peak effect occurring 20 minutes after administration. The scores for IM sedation with midazolam were significantly different (p < 0.05) from placebo. Intravenous midazolam at 0.6 mg kg-1</sup> resulted in hypnosis, and at 1.2 mg kg-1</sup> increased reflex suppression was observed. The maximum scores for hypnosis at both doses were obtained 5 minutes after IV injection. The mean (± SD) duration of lateral recumbency was 10.8 (± 3.8) minutes after IV midazolam (0.6 mg kg-1</sup>) compared to 20 (± 5.2) minutes after midazolam at 1.2 mg kg-1</sup>. Compared to baseline, the heart rate increased significantly (p < 0.05) after high dose IV midazolam.</AbstractText>Intramuscular midazolam (0.6 mg kg-1</sup>) produced maximum sedation 20 minutes after injection. Intravenous injection produced maximum hypnosis within 5 minutes. Increasing the IV dose from 0.6 to 1.2 mg kg-1</sup> resulted in increased reflex suppression and duration of hypnosis.</AbstractText>For a profound effect with rapid onset midazolam should be given IV in doses between 0.6 and 1.2 mg kg-1</sup>.</AbstractText>Copyright © 2001 Association of Veterinary Anaesthetists and American College of Veterinary Anesthesia and Analgesia. Published by Elsevier Ltd. All rights reserved.</CopyrightInformation> |
2,332,537 | Decreased depressor response mediated by calcitonin gene-related peptide (CGRP)-containing vasodilator nerves to spinal cord stimulation and levels of CGRP mRNA of the dorsal root ganglia in spontaneously hypertensive rats. | The depressor response to electrical stimulation of the spinal cord and the level of calcitonin gene-related peptide (CGRP) mRNA in the dorsal root ganglion (DRG) in the spontaneously hypertensive rat (SHR) was compared with the normotensive Wistar Kyoto rat (WKY) and Wistar rat (WR). The animals were pithed by inserting a stainless-steel rod into the spinal cord. Pithed rats were treated with hexamethonium (2 mg/kg/min i.v.) to block autonomic outflow, and mean arterial blood pressure (MBP) was maintained at approximately 100 mmHg with continuous infusion of methoxamine (10 to 15 microg/kg/min i.v.). Electrical stimulation (2 and 4 Hz for 30 s) of the lower thoracic spinal cord (T9-12) via the pithing rod caused a frequency-dependent depressor response without a change in heart rate. The depressor response to spinal cord stimulation was significantly smaller in SHR than in WKY and WR. Long-term treatment of 8 week-old SHR with captopril (0.1% in drinking water) for 7 weeks restored the reduced depressor response to spinal cord stimulation. The level of CGRP mRNA in DRG of SHR was significantly lower than that in WKY. These results suggest that the function of CGRP-containing nerves from the spinal cord decreases in SHR and captopril treatment prevents its reduction. |
2,332,538 | Lumbar epidural blocks: a case report of a life-threatening complication. | A case of life-threatening complication resulting from a lumbar epidural block is presented. A 70-year-old woman with spinal stenosis developed cardiac and respiratory arrest 5 minutes after receiving a lumbar epidural block containing 80 mg of triamcinolone acetonide and 6mL of 1.5% lidocaine. The patient received cardiopulmonary resuscitation and recovered without any sequelae. It is suggested that this complication was caused by subdural or intravascular injection of local anesthetics. It might be preventable by injecting a test dose of local anesthetics before injecting a full dose of local anesthetics and by using fluoroscopy. |
2,332,539 | Haemodynamic effects of subarachnoid blockade: 20% lignocaine versus 0.5% plain bupivacaine. | Our study compared the haemodynamic changes after spinal anaesthesia with 2% lignocaine and 0.5% plain bupivacaine.</AbstractText>A controlled, randomized trial was performed on 30 patients scheduled for arthroscopic knee surgery. Two percent lignocaine and 0.5% plain bupicacaine was used for spinal anesthesia. We measured cardiac output, blood pressure and level of sensory blockade before and for 25 minutes after spinal anaesthesia.</AbstractText>In patients developing sensory block below T6 there were no differences between the study drugs in heamodynamic measurements. In patients who developed a sensory block at or above T6 there was a greater drop in mean arterial pressure and cardiac output and a faster decrease in heart rate in patients receiving bupivacaine.</AbstractText>In patients developing a sensory block at or above the T6 dermatome, the decrease in cardiac output and mean arterial pressure in the first 25 min. after spinal anaesthesia is smaller if 2% lignocaine rather than 0.5% bupivacaine is used for blockade.</AbstractText> |
2,332,540 | A case of fetal complete heart block recorded by magnetocardiography, ultrasonography and direct fetal electrocardiography. | Fetal magnetocardiograms (FMCGs) were recorded in a case of fetal complete heart block (CHB) from the 30th to the 37th week of gestation using the multichannel SQUID system (Hitachi, Japan). M-mode ultrasonography and direct fetal electrocardiography using needle electrodes revealed fetal CHB. We identified independent fetal P-waves and QRS complexes in the FMCG recorded in the 32nd week of gestation when the fetal atriums were close to the FMCG sensor. We also recorded FMCG P-waves in the 37th week of gestation when the fetal heart was larger. Fetal heart position and size are important for obtaining a useful FMCG. To establish FMCG as a diagnostic tool of fetal arrhythmia, comparative studies with FECG are needed. |
2,332,541 | Interactions of a series of fluoroquinolone antibacterial drugs with the human cardiac K+ channel HERG. | Administration of certain fluoroquinolone antibacterials has been associated with prolongation of the QT interval on the electrocardiogram and, on rare occasions, ventricular arrhythmia. Blockade of the human cardiac K+ channel HERG often underlies such clinical findings. Therefore, we examined a series of seven fluoroquinolones for their ability to interact with this channel. Using patch-clamp electrophysiology, we found that all of the drugs tested inhibited HERG channel currents, but with widely differing potencies. Sparfloxacin was the most potent compound, displaying an IC50 value of 18 microM, whereas ofloxacin was the least potent compound, with an IC50 value of 1420 microM. Other IC50 values were as follows: grepafloxacin, 50 microM; moxifloxacin, 129 microM; gatifloxacin, 130 microM; levofloxacin, 915 microM; and ciprofloxacin, 966 microM. Block of HERG by sparfloxacin displayed a positive voltage dependence. In contrast to HERG, the KvLQT1/minK K+ channel was not a target for block by the fluoroquinolones. These results provide a mechanism for the QT prolongation observed clinically with administration of sparfloxacin and certain other fluoroquinolones because free plasma levels of these drugs after therapeutic doses approximate those concentrations that inhibit HERG channel current. In the cases of levofloxacin, ciprofloxacin, and ofloxacin, inhibition of HERG occurs at concentrations much greater than those observed clinically. The data indicate that clinically relevant HERG channel inhibition is not a class effect of the fluoroquinolone antibacterials but is highly dependent upon specific substitutions within this series of compounds. HERG channel affinity should be an important criterion for the development of newer fluoroquinolones. |
2,332,542 | Modulation of cardiac Na(+) current by gadolinium, a blocker of stretch-induced arrhythmias. | Gd(3+) blocks stretch-activated channels and suppresses stretch-induced arrhythmias. We used whole cell voltage clamp to examine whether effects on Na(+) channels might contribute to the antiarrhythmic efficacy of Gd(3+). Gd(3+) inhibited Na(+) current (I(Na)) in rabbit ventricle (IC(50) = 48 microM at -35 mV, holding potential -120 mV), and block increased at more negative test potentials. Gd(3+) made the threshold for I(Na) more positive and reduced the maximum conductance. Gd(3+) (50 microM) shifted the midpoints for activation and inactivation of I(Na) 7.9 and 5.7 mV positive but did not alter the slope factor for either relationship. Activation and inactivation kinetics were slowed in a manner that could not be explained solely by altered surface potential. Paradoxically, Gd(3+) increased I(Na) under certain conditions. With membrane potential held at -75 mV, Gd(3+) still shifted threshold for activation positive, but I(Na) increased positive to -40 mV, causing the current-voltage curves to cross over. When availability initially was low, increased availability induced by Gd(3+) dominated the response at test potentials positive to -40 mV. The results indicate that Gd(3+) has complex effects on cardiac Na(+) channels. Independent of holding potential, Gd(3+) is a potent I(Na) blocker near threshold potential, and inhibition of I(Na) by Gd(3+) is likely to contribute to suppression of stretch-induced arrhythmias. |
2,332,543 | Adenosine A(2A) receptors mediate cardiovascular responses to hypoxia in fetal sheep. | Nonselective adenosine (ADO) receptor antagonists block hypoxia-induced bradycardia and hypertension in fetal sheep. This study was designed to determine the ADO receptor subtype that is involved in these cardiovascular responses. In chronically catheterized fetal sheep (>0.8 term), fetal hypoxemia was induced by having the ewe breathe a hypoxic gas mixture (9% O(2)-3% CO(2)-88% N(2)) for 1 h. Intra-arterial infusion of ZM-241385, an antagonist highly selective for ADO A(2A) receptors, to eight fetuses during normoxia significantly increased mean arterial pressure (MAP) from 42.5 +/- 2.0 to 46.1 +/- 2.0 mmHg without altering heart rate (HR). Infusion of a selective antagonist of ADO A(1) receptors [1, 3-dipropyl-8-cyclopentylxanthine (DPCPX)] elevated MAP and HR only after the infusion was terminated, although administration of the vehicle for ZM-241385 or DPCPX had no effect on MAP or HR. Isocapnic hypoxia with infusion of DPCPX or the vehicle for DPCPX or ZM-241385 produced a transient fall in HR, a rise in MAP, and a decrease in plasma volume. In contrast, ADO A(2A) receptor blockade abolished the hypoxia-induced bradycardia and hypertension and blunted the decline in plasma volume. We conclude that fetal ADO A(2A) receptors: 1) modulate AP during normoxia, and 2) mediate cardiovascular responses during acute O(2) deficiency. |
2,332,544 | Distribution of, and immune response to, chicken anti-alpha Gal immunoglobulin Y antibodies in wild-type and alpha Gal knockout mice. | Chicken antibodies (immunoglobulin Y; IgY) to the alpha Gal epitope (galactose alpha-1,3-galactose) bind to alpha Gal antigens of mouse and porcine tissues and endothelial cells in vitro and block human anti-alpha Gal antibody binding, complement activation and antibody-dependent cell-mediated lysis mechanisms. The activities and toxicity of anti-alpha Gal IgY have not been tested in vivo. In this study, we tested the effects of multiple injections of affinity-purified anti-alpha Gal IgY (AP-IgY) in both wild-type (WT) and alpha-1,3-galactosyltransferase knockout (Gal KO) mice. WT and Gal KO mice were injected once, twice, three, or four times intravenously (i.v.) with AP-IgY and killed at 1 hr or 24 hr. Mice displayed no toxicity to four injections of AP-IgY. Heart, lung, liver, kidney, spleen and pancreatic tissue were evaluated using immunohistochemical techniques for the presence of the alpha Gal epitope using the GSI-B4 lectin, and for bound IgY, as well as mouse IgM and IgG. The binding of AP-IgY antibodies to the endothelium of WT mouse tissues was essentially identical to the pattern of binding of the GSI-B4 lectin after injection of WT mice and death at 1 hr. WT mice killed 24 hr after i.v. injection of AP-IgY showed little remaining bound IgY in their endothelia, indicating that IgY is cleared over that time period. We also evaluated the blood drawn at the time of death for the presence of anti-alpha Gal IgY, anti-IgY IgM and anti-IgY IgG by enzyme-linked immunosorbent assay. Anti-alpha Gal IgY was almost undetectable in WT mouse sera at all injection and killing times. In contrast, Gal KO mouse sera showed increasing anti-alpha Gal IgY levels until 24 hr after the fourth injection, when anti-alpha Gal IgY levels were almost undetectable. Anti-IgY IgM and IgG levels in WT and Gal KO mouse sera showed a typical increase in anti-IgY IgM 24 hr after the second injection (3 days after the first injection) and an increase in anti-IgY IgG 24 hr after the third injection (5 days after the first injection). These results show that IgY binds to alpha Gal epitopes in the WT mice and is cleared sometime over a 24-hr time period and that IgY is an expected immunogen in mice eliciting a rather typical anti-IgY IgM and IgG response. |
2,332,545 | Use of CMV transcripts for monitoring of CMV infections in transplant recipients. | The development of the nucleic acid sequence-based amplification (NASBA) technology has allowed qualitative determination of human cytomegalovirus (HCMV) immediate-early (IE) and late (pp67) transcripts for monitoring of HCMV infections in the post transplantation period. pp67-mRNA NASBA was shown to be less sensitive than pp65 antigenemia and leukoDNAemia, yet more sensitive than viremia in (i) detecting HCMV infection in both patients and blood samples and (ii) anticipating diagnosis of HCMV infection in solid organ (heart, lung) transplant recipients (SOTR). Use of pp67-mRNA NASBA, as a parameter for initiation of pre-emptive therapy, could be employed as an alternative to detecting antigenemia or DNAemia in SOTR, whereas in bone marrow transplant recipients (BMTR) its use would be too risky because of the delayed detection of HCMV infection. On the other hand, IE-mRNA NASBA was shown to be largely superior to the other assays both in detecting HCMV infection in patients and blood samples and in anticipating diagnosis of HCMV infection. This appears particularly useful in BMTR, where early initiation of antiviral treatment is mandatory in order to prevent the appearance of HCMV interstitial pneumonia. Pre-emptive therapy in BMTR, however, if based upon IE-mRNA NASBA would imply treatment of a greater number of patients as compared with antigenemia- or DNAemia-guided treatment. The clinical usefulness of this approach should be evaluated in prospective trials in the near future, pp67-mRNA NASBA in SOTR with reactivated HCMV infections and IE-mRNA NASBA in BMTR could represent two new virologic parameters to be used as a cutoff for pre-emptive therapy control of HCMV infections in the post-transplant period. Viral transcripts are more direct markers of viral replication in vivo and their disappearance indicates block of the replication process. |
2,332,546 | Molecular pharmacology of P2Y-receptors. | Membrane-bound P2-receptors mediate the actions of extracellular nucleotides in cell-to-cell signalling. P2X-receptors are ligand-gated ion channels, whereas P2Y-receptors belong to the superfamily of G-protein-coupled receptors. So far, the P2Y family is composed of eight cloned and functionally defined subtypes. Five of them (P2Y1, P2Y2, P2Y4, P2Y6 and P2Y11) are present in human tissues. The P2Y3-, p2y8- and tp2y-receptors may be species orthologues. The principal physiological agonists of the cloned human P2Y-receptors are ADP (P2Y1), UTP/ATP (P2Y2), UTP (P2Y4), UDP (P2Y6) and ATP (P2Y11). The rat P2Y4-receptor is activated by both UTP and ATP. Specific patterns of polar amino acid residues in the exofacial portions of transmembrane domains (TMs) 6 and 7 of the P2Y-receptors may account for the ligand specificity of the subtypes. Suramin acts as an antagonist at most P2Y-receptors with the exception of P2Y4- and tp2y-receptors. PPADS has been shown to block P2Y1-, the human P2Y4- and P2Y6-receptors. The nucleotide analogue 2'-deoxy-N6-methyladenosine-3',5'-bisphosphate (MRS 2179), in contrast, seems to be a potent and selective antagonist at the P2Y1-receptor. All cloned and functionally expressed P2Y-receptors are able to couple to phospholipase C. The P2Y11-receptor mediates in addition a stimulation of adenylate cyclase and the tp2y-receptor an inhibition of this signal transduction pathway. Other functionally defined subtypes, e.g., the receptor mediating an inhibition of adenylate cyclase in blood platelets, are not yet cloned. The distribution of P2Y1 mRNA is widespread. The receptor plays a crucial role in blood platelet aggregation and mediates the adenine nucleotide-induced release of the endothelium-derived relaxing factor nitric oxide. P2Y1-receptors may also be involved in the modulation of neuro-neural signalling transmission. P2Y2 transcripts are abundantly distributed. One important example for its functional role is the control of chloride ion fluxes in airway epithelia. The P2Y4-receptor is highly expressed in the placenta. The distribution of the P2Y6-receptor is widespread including heart, blood vessels and brain. The P2Y11-receptor may play a role in the differentiation of immunocytes. |
2,332,547 | [An alternative method for the diagnosis of an anterosuperior hemiblock]. | To develop and validate a rapid method for diagnosing superior anterior hemiblock, comparing it with the system seen as standard.</AbstractText>Comparison study of two diagnostic tests.</AbstractText>Urban health centre.</AbstractText>Adult population with prior diagnosis of superior anterior hemiblock included in a computer file of clinical records.</AbstractText>The presence or otherwise of superior anterior hemiblock was found by applying the standard criteria for electrocardiograms contained in the clinical records of the participating patients. The proposed test was then applied by finding the precise cardiac axis and the confirmation or rejection of the diagnosis of superior anterior hemiblock. Out of the 121 histories analysed, 40 had superior anterior hemiblock according to the standard criteria, and 81 did not. The system proposed detected 38 of the 40 hemiblock cases, 95% sensitivity, and rejected as normal 76 of the 81 electrocardiograms without superior anterior hemiblock according to the standard pattern, specificity of 93.8%.</AbstractText>Superior anterior hemiblock can be diagnosed by an alternative method which was quicker than the standard pattern, so markedly simplifying the analysis of this feature of the electrocardiogram.</AbstractText> |
2,332,548 | The resolution of fetal hydrops using combined maternal digoxin and dexamethasone therapy in a case of isolated complete heart block at 30 weeks gestation. | The development of hydrops fetalis in cases of isolated complete heart block is associated with a very poor prognosis. Various pharmacological strategies have been proposed, involving both direct fetal access and transplacental therapy, with inconsistent results in small numbers of subjects. The optimal antenatal management will remain uncertain until multicentre controlled trials are organised. We report the complete resolution of fetal hydrops at 30 weeks of gestation using combination of maternal digoxin and dexamethasone therapy, despite persistence of the complete heart block. A Caesarean section was performed at 37 weeks of gestation due to evidence of fetal intrauterine growth restriction. The baby girl is now 8 months of age and remains well, with a heart rate of 45-50 beats per minute on no medication and without pacing. |
2,332,549 | Single breath-hold 3D contrast-enhanced method for assessment of cardiac function. | Cardiac MRI function measurements are typically performed using 2D sequences and require multiple breath-holds to image the entire heart. A single 3D acquisition using a T(1)-shortening agent has many potential advantages over techniques that acquire multiple 2D images, including more consistent contrast and precise slice coverage. However, 3D techniques currently require much longer than a single breath-hold to complete. It has been shown that for MR angiography undersampled projection reconstruction can acquire much higher resolution per unit time than Fourier imaging with acceptable artifacts. By employing a gated, undersampled projection technique, high-resolution 3D multiphase volumes of the heart can be acquired in a single breath-hold. Short repetition times result in good myocardial suppression and a temporal aperture of 60 ms. |
2,332,550 | Block of wild-type and inactivation-deficient cardiac sodium channels IFM/QQQ stably expressed in mammalian cells. | The role of inactivation as a central mechanism in blockade of the cardiac Na(+) channel by antiarrhythmic drugs remains uncertain. We have used whole-cell and single channel recordings to examine the block of wild-type and inactivation-deficient mutant cardiac Na(+) channels, IFM/QQQ, stably expressed in HEK-293 cells. We studied the open-channel blockers disopyramide and flecainide, and the lidocaine derivative RAD-243. All three drugs blocked the wild-type Na(+) channel in a use-dependent manner. There was no use-dependent block of IFM/QQQ mutant channels with trains of 20 40-ms pulses at 150-ms interpulse intervals during disopyramide exposure. Flecainide and RAD-243 retained their use-dependent blocking action and accelerated macroscopic current relaxation. All three drugs reduced the mean open time of single channels and increased the probability of their failure to open. From the abbreviation of the mean open times, we estimated association rates of approximately 10(6)/M/s for the three drugs. Reducing the burst duration contributed to the acceleration of macroscopic current relaxation during exposure to flecainide and RAD-243. The qualitative differences in use-dependent block appear to be the result of differences in drug dissociation rate. The inactivation gate may play a trapping role during exposure to some sodium channel blocking drugs. |
2,332,551 | Interaction of lidocaine with the cardiac sodium channel: effects of low extracellular pH are consistent with an external blocking site. | Brief extracellular application of millimolar concentrations of lidocaine affected sodium currents recorded in isolated rat ventricular myocytes in two ways: 1) a reduction of the maximum current consistent with a channel blocking action, and 2) a negative shift in the voltage dependence of inactivation consistent with an interaction with the inactivated state of the channel. Both effects occurred very rapidly (<< 1 s). Decreasing extracellular pH to 6.4 increased the potency for channel block (EC50 1.8 +/- 0.2 mM at pH 7.4 and 0.8 +/- 0.1 mM at pH 6.5) and decreased the potency to shift inactivation (V(1/2) shift -42 mV by 1 mM lidocaine at pH 7.4 and -12.6 mV at pH 6.5). Channel block was slightly less at +90 mV compared to -40 mV at either pH (not statistically significant). The increase in potency for block at decreased extracellular pH, while intracellular pH is buffered, and the lack of voltage dependence of block, suggest that the charged form of lidocaine can block the channel by interacting with a site near the extracellular mouth, although alternative explanations are discussed. |
2,332,552 | [0.2% ropivacaine vs. 0.1% ropivacaine plus fentanyl in obstetric epidural analgesia]. | To compare the analgesic efficacy of epidural administration of 0.2% ropivacaine alone to that of 0.1% ropivacaine plus 0.0002% fentanyl during childbirth.</AbstractText>We performed a prospective, randomized single-blind study of 84 women in labor (aged 16 to 40 y, ASA I-II, weight over 110 kg, height over 150 cm, gestational age 37 to 42 weeks). The women were randomly assigned to two groups: group I consisted of 42 patients who received an initial bolus of 10 ml of ropivacaine 0.2% followed by continuous perfusion of ropivacaine 0.2% at a rate of 6 to 10 ml/h; group II was composed of 42 women who received an initial bolus of ropivacaine 0.2% with 50 micrograms of fentanyl followed by continuous infusion of ropivacaine 0.1% and fentanyl 2 micrograms/ml at a rate of 6 to 10 ml/h. Data recorded were parity and type of delivery, blood pressure, heart rate (HR), time to onset of pain relief, motor blockade on a modified Bromage scale, pain on a visual analog scale (VAS) and fetal HR, Apgar score and arterial and venous pH of umbilical blood.</AbstractText>We found no significant differences in demographic or hemodynamic data in mothers or fetuses, in type of delivery or motor block, although the latter tended to be slightly lower in group II. In group II, the total anesthetic dose used was significantly lower (p = 0.003); time until onset of pain relief was significantly shorter (p = 0.044); and VAS scores were significantly lower at 15 min (p = 0.005), 30 min (p = 0.029), 60 min (p = 0.017) and 90 min (p = 0.002). The number of top-up boluses needed for deliveries involving instruments was significantly greater in group II (p = 0.37).</AbstractText>The protocol of ropivacaine 0.1% with 2 micrograms/ml of fentanyl provides satisfactory analgesia throughout labor, allowing lower doses of local anesthetic to be used, with shorter onset of pain relief and reduced motor blockade; however the analgesia provided is insufficient for deliveries assisted by instruments.</AbstractText> |
2,332,553 | Glucose- and arginine-induced insulin secretion by human pancreatic beta-cells: the role of HERG K(+) channels in firing and release. | The human ether-a-go-go-related genes (herg) are expressed in tissues other than heart and brain where the HERG K(+) channels are known to regulate the repolarization of the heart action potential and the neuronal spike-frequency accommodation. We provide evidence that herg1 transcripts are present in human pancreatic islets that were used to study both insulin secretion and electrical activity with radioimmunoassay and single cell perforated patch-clamp techniques, respectively. Glucose- and arginine-induced islets insulin secretion data suggested a net increase of release under perfusion with antiarrhythmic drugs known to selectively block HERG channels. Indeed we could routinely isolate a K(+) current that was recognized as biophysically and pharmacologically similar to the HERG current. An analysis of the glucose- and arginine-induced electrical activity (several applications during 30 min) in terms of firing frequency and putative insulin release was done in control and in the presence of selective blockers of HERG channels: the firing frequency and the release increased by 32% and 77%, respectively. It is concluded that HERG channels have a crucial role in regulating insulin secretion and firing of human beta-cells. This raises the possibility that some genetically characterized hyperinsulinemic diseases of unknown origin might involve mutations in the HERG channels. |
2,332,554 | Perioperative myocardial ischemia in cataract surgery patients: general versus local anesthesia. | Patients having cataract surgery are usually elderly and have risk factors for ischemic heart disease. We sought to determine the incidence of perioperative myocardial ischemia in patients having cataract surgery and compare the influence of local anesthesia (LA) and general anesthesia (GA). Eighty-one patients undergoing cataract surgery with at least two risk factors for ischemic heart disease were monitored continuously for 24 h by using electrocardiogram leads II and V5 and a Holter recorder (Medilog 4500, Oxford Ltd, UK). Patients were randomly allocated to two groups, either LA (n = 39) or GA (n = 42). In the LA group, a peribulbar block was performed, whereas a similar block was performed in the GA group after tracheal intubation. The study demonstrated that cataract patients suffered from a frequent incidence of perioperative myocardial ischemia (31%). There was no difference in the incidence rate between the groups: 12 of 39 in the LA group and 13 of 42 in the GA group (P: = NS). However, the number of ischemic episodes was significantly increased in the GA group (18 vs. 13 in the LA group) (P<0.05), and there were significantly more intraoperatively in the GA group (8 vs. 1) (P<0.01). All intraoperative ischemic events were associated with tachycardia (> or =20% of baseline), whereas postoperative ischemic changes were mostly independent of heart rate. Only one of the ischemic patients (in the GA group) was admitted as a result of intractable chest pain. There were significantly less intraoperative episodes in the LA group, suggesting that LA may be safer than GA in patients during this type of surgery. |
2,332,555 | Work of breathing during spontaneous ventilation in anesthetized children: a comparative study among the face mask, laryngeal mask airway and endotracheal tube. | Work of breathing (WOB) increases during general anesthesia in adults, but such information has been limited in pediatric patients. We studied WOB in 24 healthy children (mean age 2+/-1.9 yrs), during elective urogenital surgery under 1 minimum alveolar anesthetic concentration halothane-nitrous oxide anesthesia with a caudal block while breathing spontaneously. WOB was measured with an esophageal balloon, miniature flowmeter, and a computerized (Bicore) system. In each patient, WOB was computed under four conditions: a mask without oral airway (-AW), a mask with oral airway (+AW), a laryngeal mask airway (LMA), and an endotracheal tube (ETT). With each apparatus WOB was studied both with continuous positive airway pressure (CPAP) (5-6 cm H(2)O) and without CPAP (or zero end-expiratory pressure [ZEEP]). Under ZEEP, WOB (g x cm/kg) among the four apparatus were (mean +/- SEM): mask (-AW) (64 +/-19.2) > mask (+AW) (44+/-17.2), LMA (42+/-15.6) > ETT (25.4+/- 12.4) (P<0.05). WOB with CPAP significantly (P<0.05) decreased from WOB with ZEEP in three groups (mask [-AW], mask [+AW], and LMA), but not in the ETT group. Tidal volume (both ZEEP and CPAP) and end-tidal PCO(2) (with CPAP only) were significantly (P<0.05) decreased only in the ETT group, whereas no significant difference was found in respiratory rate or minute volume among the four airway apparatus groups, either with or without CPAP. The reduction in WOB, when breathing through ETT was primarily attributable to decreases in tidal volume and volume work. The finding that WOB decreases with CPAP in all groups except for the ETT group suggests that the decrease is a result of improved patency of the upper airway rather than of increases in functional residual capacity and lung compliance. |
2,332,556 | Prolongation of epidural anaesthesia in dogs with bupivacaine in a lipid emulsion. | An aqueous solution and a lipid emulsion of bupivacaine were administered epidurally in doses of 1.8 mg/kg to six beagle dogs following a randomised two-phase crossover design. The aqueous solution was absorbed rapidly and the mean (sd) peak venous plasma concentration of bupivacaine, 1.4 (0.4) microg/ml, was detected after five minutes. After administration of the lipid emulsion, the peak plasma concentration of bupivacaine, 0.6 (0.2) microg/ml, was detected after 30 minutes. The mean (sd) t1/2beta of the aqueous preparation was 149.1 (32.6) minutes, and of the lipid emulsion 119.2 (34.0) minutes. Both preparations had a similar bioavailability. The mean time to the onset of motor block after the administration of the aqueous solution, 2.3 (2.2) minutes, was significantly shorter (P=0.028) than after the administration of the lipid emulsion, 9.4 (1.9) minutes, and the duration of the motor block induced by the lipid emulsion, 217.6 (26.2) minutes, was significantly longer (P=0.043) than for the aqueous solution, 158 (48.8) minutes. During anaesthesia, the plasma concentrations of bupivacaine ranged between 1.3 and 0.2 microg/ml. Non-significant changes in systolic blood pressure and heart rate were observed which coincided with the peak plasma concentrations of bupivacaine. |
2,332,557 | Hepatic and extra-hepatic stimulation of glutathione release into plasma by norepinephrine in vivo. | Studies were conducted to determine the effect of norepinephrine (NE) on reduced glutathione (GSH) and oxidized glutathione (GSSG) export from hepatic and extra-hepatic tissues in vivo. Anesthetized Single Comb White Leghorn (SCWL) males were implanted with cannulae in the carotid artery, hepatic vein (HV) and hepatic portal veins (PV), and the left bile duct. In Experiment 1, GSH and GSSG in hepatic and portal venous plasma and bile were determined prior to, during, and following two 20-min infusions of NE (2 and 10 microg/min per kg BW) into the hepatic PV. The lower NE infusion rate increased hepatic venous GSH (indicative of increased GSH export into liver sinusoids) without affecting systemic or hepatic vascular pressures; however, it had no affect on portal venous GSH. The higher NE infusion rate increased GSH in the HV and hepatic PV (indicative of extra hepatic export of glutathione) as well as systemic pressure, hepatic and portal venous pressures, and the transhepatic pressure gradient. Biliary secretion of GSH and GSSG was unaffected by either rate of NE infusion in Experiment 1. In Experiment 2, pretreatment of birds with phentolamine, an alpha-adrenergic receptor blocker (alpha-block), abolished sinusoidal export GSH as well as the ability of NE to stimulate GSH release from hepatic and extra-hepatic tissue. Although HV and PV pressures were lower in alpha-block birds compared with controls, there were no differences in the transhepatic pressure gradient between groups. Plasma GSSG was below the limits of detection in Experiments 1 and 2. The combined results of Experiments 1 and 2 indicate that hepatic export of GSH was independent of changes in systemic or hepatic vascular pressures or changes in the transhepatic pressure gradient. The results of these studies are the first to demonstrate that export of GSH into plasma in vivo is mediated by an alpha-receptor-mediated mechanism in hepatic and extra-hepatic tissues. The findings may be particularly important with regard to antioxidant homeostasis of animals during periods of stress. |
2,332,558 | 18-Methoxycoronaridine (18-MC) and ibogaine: comparison of antiaddictive efficacy, toxicity, and mechanisms of action. | 18-MC, a novel iboga alkaloid congener, is being developed as a potential treatment for multiple forms of drug abuse. Like ibogaine (40 mg/kg), 18-MC (40 mg/kg) decreases the intravenous self-administration of morphine and cocaine and the oral self-administration of ethanol and nicotine in rats; unlike ibogaine, 18-MC does not affect responding for a nondrug reinforcer (water). Both ibogaine and 18-MC ameliorate opioid withdrawal signs. Both ibogaine and 18-MC decrease extracellular levels of dopamine in the nucleus accumbens, but only ibogaine increases extracellular levels of serotonin in the nucleus accumbens. Both ibogaine and 18-MC block morphine-induced and nicotine-induced dopamine release in the nucleus accumbens; only ibogaine enhances cocaine-induced increases in accumbal dopamine. Both ibogaine and 18-MC enhance the locomotor and/or stereotypic effects of stimulants. Ibogaine attenuates, but 18-MC potentiates, the acute locomotor effects of morphine; both compounds attenuate morphine-induced locomotion in morphine-experienced rats. Ibogaine produces whole body tremors and, at high doses (> or = 100 mg/kg), cerebellar damage; 18-MC does not produce these effects. Ibogaine, but not 18-MC, decreases heart rate at high doses. While 18-MC and ibogaine have similar affinities for kappa opioid and possibly nicotinic receptors, 18-MC has much lower affinities than ibogaine for NMDA and sigma-2 receptors, sodium channels, and the 5-HT transporter. Both 18-MC and ibogaine are sequestered in fat and, like ibogaine, 18-MC probably has an active metabolite. The data suggest that 18-MC has a narrower spectrum of actions and will have a substantially greater therapeutic index than ibogaine. |
2,332,559 | [Premedication and sedation complications during ophthalmic anesthesia]. | Sedation allows patients to tolerate unpleasant procedures while maintaining adequate cardiorespiratory function and the ability to respond purposefully to verbal command. For ophthalmic surgery patient's anxiety and discomfort can be relieved during placement of a peribulbar block and during surgery by intravenous sedation. Intravenous sedation should only be administered by an anesthetist. Three different classes of drugs are used for intravenous sedation: analgesics (fentanyl and alfentanil), benzodiazepines (midazolam) and profofol, an intravenous anesthetic. Sedation may result in ventilatory, cardiovascular and neurologic complications. Excessive sedation can induce hypoventilation from central ventilatory depression or airway obstruction. Uncontrolled and unexpected movements of the head could result in major surgical complications. For the prevention of the complications related to sedation the same monitoring as for general anesthesia is essential. |
2,332,560 | Subcellular mechanisms of the positive inotropic effect of angiotensin II in cat myocardium. | 1. Cat ventricular myocytes loaded with [Ca2+]i- and pHi-sensitive probes were used to examine the subcellular mechanism(s) of the Ang II-induced positive inotropic effect. Ang II (1 microM) produced parallel increases in contraction and Ca2+ transient amplitudes and a slowly developing intracellular alkalisation. Maximal increases in contraction amplitude and Ca2+ transient amplitude were 163 +/- 22 and 43 +/- 8 %, respectively, and occurred between 5 and 7 min after Ang II administration, whereas pHi increase (0.06 +/- 0.03 pH units) became significant only 15 min after the addition of Ang II. Furthermore, the inotropic effect of Ang II was preserved in the presence of Na+-H+ exchanger blockade. These results indicate that the positive inotropic effect of Ang II is independent of changes in pHi. 2. Similar increases in contractility produced by either elevating extracellular [Ca2+] or by Ang II application produced similar increases in peak systolic Ca2+ indicating that an increase in myofilament responsiveness to Ca2+ does not participate in the Ang II-induced positive inotropic effect. 3. Ang II significantly increased the L-type Ca2+ current, as assessed by using the perforated patch-clamp technique (peak current recorded at 0 mV: -1.88 +/- 0.16 pA pF-1 in control vs. -3.03 +/- 0.20 pA pF-1 after 6-8 min of administration of Ang II to the bath solution). 4. The positive inotropic effect of Ang II was not modified in the presence of either KB-R7943, a specific blocker of the Na+-Ca2+ exchanger, or ryanodine plus thapsigargin, used to block the sarcoplasmic reticulum function. 5. The above results allow us to conclude that in the cat ventricle the Ang II-induced positive inotropic effect is due to an increase in the intracellular Ca2+ transient, an enhancement of the L-type Ca2+ current being the dominant mechanism underlying this increase. |
2,332,561 | Sulfonylurea sensitivity of adenosine triphosphate-sensitive potassium channels from beta cells and extrapancreatic tissues. | Sulfonylureas are widely used to stimulate insulin secretion in type 2 diabetic patients because they close adenosine triphosphate-sensitive potassium (K(ATP)) channels in the pancreatic beta-cell membrane. This action is mediated by binding of the drug to the sulfonylurea receptor (SUR1) subunit of the channel. K(ATP) channels are also present in a range of extrapancreatic tissues, but many of these contain an alternative type of SUR subunit (SUR2A in heart and SUR2B in smooth muscle). The sulfonylurea-sensitivity of K(ATP) channels containing the different types of SUR is variable: gliclazide and tolbutamide block the beta cell, but not the cardiac or smooth muscle types of K(ATP) channels with high affinity. Glibenclamide and glimepiride, on the other hand, block channels containing SUR1 and SUR2 with similar affinity. The reversibility of the different sulfonylureas also varies. Tolbutamide and gliclazide produce a reversible inhibition of Kir6.2/SUR1 and Kir6.2/SUR2 channels, whereas glibenclamide has a reversible effect on cardiac, but not beta-cell, K(ATP) channels. In this article, we summarize current knowledge of how sulfonylureas act on K(ATP) channels containing the different types of sulfonylurea receptor, and discuss the implications of these findings for the use of sulfonylureas in the treatment of diabetes mellitus. |
2,332,562 | Case 4: a patient with symptomatic bradycardia. | Both the clinical and electrocardiographic presentations of sick sinus syndrome are highly variable. As illustrated by this month's case of Interactive Grand Rounds, the initial challenge to the clinician is to establish the correct diagnosis in the patient who has symptomatic bradyarrhythmias. |
2,332,563 | Neurohormonal factors in heart failure. | Currently there are 4 to 5 million people with congestive heart failure in the United States. They consume greater than 7% of the total health care dollar of which a significant portion is directly related to hospitalization expenses alone. Most patients with chronic congestive heart failure can be managed efficiently outside the hospital setting by the proper use of nonpharmacologic therapies. Neurohormonal pathways have a significant impact on the progression of congestive heart failure. Medications, which include alpha-blockers, beta-blockers, digoxin, spironolactone, and diuretics, now can block, modify, or manage most of these neurohormonal effects, and therefore, have a stabilizing effect on the patient with congestive heart failure. Understanding the physiology and medications involved for optimal treatment of congestive heart failure is a must to ensure the quality of life that these patients deserve. |
2,332,564 | Intrathecal alfentanil with and without bupivacaine for analgesia in labour. | Combined spinal-epidural (CSE) for analgesia in labour is widely used as a method of providing pain relief while minimising motor blockade. Aiming to further reduce the associated motor weakness, we investigated the use of alfentanil alone as the initial intrathecal injection in a double-blind study. Thirty women were randomly allocated to receive either alfentanil 0.25 mg with bupivacaine 2.5 mg intrathecally, or alfentanil 0.25 mg in the same volume. Onset of analgesia did not differ significantly between groups but duration was significantly longer in those receiving alfentanil-bupivacaine (mean 55 min vs. 40 min; p < 0.05). Quality of analgesia was satisfactory for all women, although the cumulative analgesia scores were significantly lower in the women receiving the alfentanil-bupivacaine mixture (p = 0.003). More women in the alfentanil-bupivacaine group developed both a sensory level (15/15 vs. 6/15; p < 0.01) and sympathetic block (12/15 vs. 4/15; p < 0.01). Sixty per cent of women receiving the alfentanil-bupivacaine mixture demonstrated an impaired ability to straight leg raise compared with none of the women in the alfentanil-saline group (p < 0.01). The incidence of adverse effects in mother and fetus was similar in both groups. We conclude that intrathecal alfentanil 0.25 mg alone as part of a CSE technique provides rapid analgesia of satisfactory quality without detectable motor blockade. |
2,332,565 | Anti-SSA/Ro52 autoantibodies blocking the cardiac 5-HT4 serotoninergic receptor could explain neonatal lupus congenital heart block. | The 52-kDa SSA/Ro (Ro52) ribonucleoprotein is an antigenic target strongly associated with the autoimmune response in mothers whose children develop neonatal lupus and congenital heart block. When sera from patients with systemic lupus erythematosus were used as autoimmune controls in an enzyme immunoassay to screen for antibodies against the human serotoninergic 5-HT4-receptor, a high correlation was found between the presence of anti-Ro52 protein antibodies in such sera and antibodies reacting with a synthetic peptide, corresponding to the second extracellular loop of the human 5-HT4 receptor (amino acid residues 165-185). Homology scanning between the 5-HT4 peptide and the sequence of the Ro52 protein indicated two potential common epitopes located between residues 365 and 396 of the Ro52 protein. Cross-reactivity was found between the peptide derived from the 5-HT4 receptor, and a peptide corresponding to residues 365-382 of the Ro52 protein. Autoantibodies, affinity-purified on the 5-HT4 receptor peptide, specifically recognized both the Ro52 protein and the 5-HT4 receptor protein in immunoblots. The affinity-purified antibodies antagonized the serotonin-induced L-type Ca channel activation on human atrial cells. This effect could explain the electrophysiological abnormalities in neonatal lupus. |
2,332,566 | Coronary arteritis with marked fibrous periarteritis: case report. | A case is presented of a 43-year-old man who died suddenly and unexpectedly from cardiac malignant arrhythmia. Autopsy revealed isolated coronary arteritis involving primarily the left coronary stem and extending into the proximal half of its anterior descending branch. The most striking feature of the disease was marked fibrous periarteritis. Similar changes were present segmentally in the peripheral third of the right coronary artery, and also as small isolated foci of adventitial fibrosis in the aortic base. With some hesitation, we classify the case as coronary Takayasu's arteritis. |
2,332,567 | Effects of theophylline on exercise indices in a patient with chronotropic incompetence. | Several investigators have documented the successful use of oral sustained-release theophylline in treating symptomatic bradycardia and sick sinus syndrome. This paper reports a case of chronotropic incompetence in which specific exercise indices, including the chronotropic response index, were used to measure the therapeutic efficacy of theophylline. |
2,332,568 | New and emerging pharmacologic strategies in the management of chronic heart failure. | Chronic heart failure (CHF) is a complex syndrome involving activation of multiple cellular, metabolic, and neurohumoral pathways following the initial myocardial insult. Recently, there have been considerable advances in the pharmacologic management of CHF. The current approach to treatment recognizes the need to target neurohormonal activation, and the use of angiotensin-converting enzyme (ACE) inhibitors and beta blockers should now be regarded as part of standard therapy in many patients with CHF. However, because of the complexity of the disease, blockade of additional pathways is likely to be required to maximize the therapeutic benefit of intervention. To this end, there are several agents under active late-phase clinical evaluation. The most advanced of these new strategies (beyond renin-angiotensin-aldosterone blockade) is inhibition of the endothelin system. There is a substantial body of evidence that this system is intimately involved in CHF disease progression. Early-phase clinical data are very encouraging and support the potential utility of long-term endothelin inhibition. Other novel approaches involve the use of cytokine antagonists (e.g., agents that block tumor necrosis factor-alpha activity) and the augmentation of natriuretic peptides. If all these potential agents prove to be of benefit in CHF, the question of which agent or combination of agents to use in which patients will arise. There is therefore a need to develop scientific approaches in order to be able to identify more accurately patients who will obtain benefit from specific classes or combinations of drugs. |
2,332,569 | Tricyclic antidepressant poisoning. | Tricyclic antidepressant poisoning causes predictable electrocardiographic abnormalities and can be lethal. Cardiac arrhythmias, hypotension, seizures, and coma are common. Sodium bicarbonate is still considered the treatment of choice for severe toxicity, although a variety of supportive measures may be taken. Hypertonic saline appears to be a promising alternative. A QRS interval longer than 100 ms appears to be a better predictor of serious complications than is an elevated serum tricyclic antidepressant level. Cardiovascular toxicity is classically manifested as ventricular dysrhythmias, hypotension, heart block, bradyarrhythmias, or asystole. Activated charcoal binds tricyclic antidepressants. Give 30 to 50 g orally or by nasogastric tube with or without a cathartic (sorbitol 0.5 g/kg or 30 g of magnesium sulfate). Sodium bicarbonate is indicated if the QRS duration is more than 100 ms or the terminal right-axis deviation is more than 120 degrees. The suggested dosage is 1 to 2 mEq/kg, repeated as needed. Tricyclic antidepressants are used not only for depression but also for chronic pain syndromes, obsessive-compulsive disorder, panic and phobic disorders, eating disorders, migraine prophylaxis, and peripheral neuropathies. |
2,332,570 | [Cutaneous neonatal lupus erythematosus: discordant expression in identical twins]. | Neonatal lupus erythematosus is a rare syndrome characterized essentially by cutaneous lesions and/or congenital heart block occurring in infants at birth, or shortly after. It is related to transplacental crossing of maternal auto antibodies (usually anti Ro/SS-A, La/SS-B or rarely anti-U(1) RNP) from the mother to the infant. Mothers of affected children have signs of systemic lupus erythematosus or other collagenosis or are asymptomatic.</AbstractText>We report a case of neonatal lupus erythematosus in one identical twin, revealed at the age of 3 months by erythematous and annular cutaneous lesions of the face and limbs. These lesions were preceded at birth by an asymmetrical livedo pattern of the lower limbs. Her twin sister was unaffected but both infants had a high rate of anti-Ro/SSA antibodies. The diagnosis of neonatal lupus erythematosus permitted to reveal a biological lupus syndrome in their asymptomatic mother. Cutaneous lesions cleared almost completely within 1 year whereas antiRo/SSA antibodies disappeared.</AbstractText>Cases of neonatal lupus erythematosus in twins are rare and mostly described in heterozygotic twins. Clinical discordance is usual and could partly be explained by genetic factors. In monozygotic twins, like in our case, chromosome X inactivation could be an explanation of the differences observed.</AbstractText> |
2,332,571 | Subtype identification and functional properties of inositol 1,4, 5-trisphosphate receptors in heart and aorta. | One of the major mechanisms by which hormones elevate intracellular Ca(2+)levels is by generating the second messenger inositol 1,4, 5-trisphosphate (InsP(3)), which activates a Ca(2+)channel (InsP(3)receptor) located in the endoplasmic reticulum (ER). This study undertakes to identify the InsP(3)receptor subtypes (isoforms) in heart and aorta and to characterize their functional properties. The InsP(3)receptor isoforms were identified from rat heart and aorta tissues using both reverse-transcriptase polymerase chain reaction (RT-PCR) to assess the presence of mRNA for the different isoforms and immunochemistry using InsP(3)receptor isoform-specific antibodies. Functional studies included ligand binding experiments using [(3)H]InsP(3)and InsP(3)-induced Ca(2+)release studies using Fluo-3 as the Ca(2+)sensing dye. All three isoforms of the InsP(3)receptor were identified using RT-PCR and immunochemical analyses. [(3)H]InsP(3)binding studies using microsomes derived from these tissues showed that heart had a 3-fold lower abundance of InsP(3)receptors than aorta, while both have considerably lower abundance than the well characterized cerebellar microsomes. The affinity of the InsP(3)binding to the receptor was also different in the three tissues. In cerebellum the K(d)was 60 nM, while aorta had a much higher K(d)of 220 nM. Heart microsomes, appeared to show two classes of binding affinity with K(d)s of 150 nM and 60 nM. Furthermore, the effects of free [Ca(2+)] on [(3)H]InsP(3)binding levels were also different for the three tissues. InsP(3)binding to both cerebellar and aorta microsomes decreased by 90% and 60%, respectively, above 30 nM free [Ca(2+)], while InsP(3)binding to heart was relatively insensitive to changes in [Ca(2+)]. At maximal InsP(3)concentrations, aorta microsomes were able to release about 5% of the accumulated Ca(2+), compared to 25% by cerebellar microsomes. Heart microsomes, however, showed only very little InsP(3)-induced Ca(2+)release ( <0.5%). The EC(50)concentration for InsP(3)-induced Ca(2+)release was 1.2 micro M for aorta while that for cerebellum was 0.3 micro M. Known agonists of the cerebellar InsP(3)receptor such as 3-deoxy InsP(3)and adenophostin A were also able to mobilize Ca(2+)from aorta microsomes. In addition, the competitive antagonist heparin and the non-competitive antagonists of the cerebellar InsP(3)receptor, tetracaine and tetrahexylammonium chloride, were also able to block InsP(3)-induced Ca(2+)release from aorta microsomes. |
2,332,572 | Antiarrhythmic agents and proarrhythmia. | The Vaughn Williams classification divides antiarrhythmic agents into four groups according to their effects on various ion channels. Class I agents block sodium channels and are subdivided into three groups. The use of class Ia agents is gradually on the decline, secondary to lack of a favorable risk/benefit ratio. Class Ib agents include lidocaine, which is extensively used for the acute treatment of ventricular tachyarrhythmias. Class Ic drugs are not advisable for patients with structural cardiac abnormalities secondary to a high risk of proarrhythmia. They are mainly used for supraventricular tachyarrhythmias. beta blockers form class II. Class III agents, such as amiodarone and sotalol, prolong action potential duration and repolarization and are among the most widely used antiarrhythmics. They are the subject of active research, and newer agents are being developed. Calcium-channel blockers are grouped under class IV. Digoxin and adenosine have unique antiarrhythmic properties, which can be useful in the management of selected patients. All antiarrhythmic drugs have the potential to provoke arrhythmias and, therefore, should be used with caution. The risk of proarrhythmia is increased in patients with abnormal cardiac substrate, with electrolyte abnormalities, and during drug initiation. Correction of electrolyte imbalance and prevention of bradycardia while the drug is metabolized and/or excreted are the cornerstones of proarrhythmia management. |
2,332,573 | In vitro evaluation of newly developed chalcone analogues in human cancer cells. | Among flavonoids, chalcones have been identified as interesting compounds having chemopreventive and antitumor properties. We studied a panel of newly developed chalcone analogues (S1-S10) using MDA-MB 231 and MCF-7 ADRr breast cancer cells and the T-leukemic Jurkat cell line. Quercetin was used as the reference compound.</AbstractText>Antiproliferative activity was evaluated by cell counts performed after 72 h of exposure to the drugs. DNA analysis and redox activity were evaluated using flow cytometry. Apoptosis was assessed by morphological analysis, using YOYO-1 as DNA dye; p-glycoprotein function was ascertained by quantitating the efflux of rhodamine 123.</AbstractText>All cells were sensitive to chalcone analogues yielding IC50 in micromolar concentrations with the following order regardless of the multidrug resistance (MDR) status: S1 > S2 > quercetin. S1 and S2, the most active compounds, were selected to evaluate their effect on the cell cycle, apoptosis, redox activity, and modulation of the p-glycoprotein function. No significant perturbation in cell cycle was seen with concentration up to 1 microM after 24 h. After 72 h a slight increase in G2/M block and DNA fragmentation occurred at 10 microM. Morphological analysis of apoptosis showed that chalcone analogues induced apoptosis to a higher extent than quercetin. Redox analysis demonstrated that all substances were able to increase intracellular thiol levels, which returned to baseline value after 24 h for all drugs except quercetin. Production of reactive oxygen species was essentially unaffected by all compounds. Finally, in MDR-positive MCF-7 ADRr cells chalcone analogues were unable to modulate p-glycoprotein function while quercetin was able to.</AbstractText>Newly developed S1 and S2 chalcones have a different but higher antitumor activity than quercetin and could be considered as potential new anticancer drugs.</AbstractText> |
2,332,574 | Effects of ruminally protected choline and dietary fat on performance and blood metabolites of finishing heifers. | A 120-d finishing study utilizing 318 heifers (342 kg initial BW) was conducted to examine effects of ruminally protected choline (RPC) in diets containing graded concentrations of tallow. Heifers were blocked according to previous nutrition (full-fed or limit-fed) and allotted to 24 pens containing 11 to 15 heifers. Two pens, one within each block, were assigned to each of 12 factorially arranged treatments including dietary tallow (0, 2, or 4%) and supplemental RPC (0, 20, 40, or 60 g of product daily, estimated to supply 0, 5, 10, or 15 g/d choline postruminally). Heifers were implanted with Revalor-H and fed a finishing diet based on steam-flaked and dry-rolled corn (12.5% CP, 8% alfalfa on DM basis). Dry matter intake decreased (P < 0.10) by 5.4% when tallow was increased from 0 to 4% but was not affected by RPC. Heifers receiving 4% tallow had 7.3% lower gains than those receiving none (P < 0.10). Supplementation of RPC increased (P < 0.10) ADG, with 20 g/d resulting in an 8.6% increase. Similarly, gain efficiency improved (P < 0.10) by 7.6% with addition of 20 g/d RPC. Yield grade and kidney, pelvic, and heart fat both increased linearly (P < 0.10) with fat supplementation. The percentage of carcasses grading USDA Choice was not affected by intermediate levels of RPC but decreased with the highest level (60 g/d). Dressing percentage, hot carcass weight, marbling, and 12th-rib fat thickness were not affected significantly by either tallow or RPC. On d 90, jugular blood was collected from all heifers at 2 h postfeeding. Plasma urea and serum insulin concentrations were not affected by either tallow or RPC. Dietary tallow linearly increased (P < 0.10) NEFA, cholesterol, triglyceride, and total amino acid concentrations. Choline supplementation led to quadratic responses for total amino acids (P < 0.10), with concentrations being greatest for intermediate levels of RPC. Moderate levels of supplemental RPC improved growth performance of finishing cattle without negatively affecting carcass characteristics. Optimum performance was achieved with 20 g of product daily. |
2,332,575 | Characterization of mibefradil block of the human heart delayed rectifier hKv1.5. | The goal of this study was to analyze the effects of mibefradil on a human cardiac K(+) channel (hKv1.5) stably expressed in Chinese hamster ovary cells using the whole-cell configuration of the patch-clamp technique. Mibefradil inhibited in a concentration-dependent manner the hKv1.5 current with a K(D) value of 0.78 +/- 0.05 microM and a Hill coefficient of 0.97 +/- 0.06. Block induced by mibefradil was voltage dependent, consistent with a value of electrical distance of 0.13. The apparent association (k) and dissociation (l) rate constants measured at +50 mV were found to be 7.3 +/- 0.5 x 10(6) M(-1).s(-1) and 4.3 +/- 0.1 s(-1), respectively. Block increased rapidly between -20 and +10 mV, coincident with channel opening and suggested an open channel block mechanism, which was confirmed by a slower deactivation time course resulting in a "crossover" phenomenon when tail currents recorded under control conditions and in the presence of mibefradil were superimposed. Shifts toward negative potentials of the maximum conductance and the activation curve were observed, confirming the voltage dependence of block. Mibefradil induced a significant use-dependent block when trains of depolarization at frequencies between 0.02 and 2 Hz were applied. In the presence of mibefradil, recovery of inactivation was faster than under control conditions, suggesting that mibefradil might compete with the inactivation gate of hKv1.5. These results indicate that mibefradil blocks hKv1.5 channels in a concentration-, voltage-, time- and use-dependent manner and the concentrations needed to observe these effects are in the therapeutic range. |
2,332,576 | Interactions of the 5-hydroxytryptamine 3 antagonist class of antiemetic drugs with human cardiac ion channels. | Administration of the 5-hydroxytryptamine 3 receptor class of antiemetic agents has been associated with prolongation in the QRS, JT, and QT intervals of the ECG. To explore the mechanisms underlying these findings, we examined the effects of granisetron, ondansetron, dolasetron, and the active metabolite of dolasetron MDL 74,156 on the cloned human cardiac Na(+) channel hH1 and the human cardiac K(+) channel HERG and the slow delayed rectifier K(+) channel KvLQT1/minK. Using patch-clamp electrophysiology we found that all of the drugs blocked Na(+) channels in a frequency-dependent manner. At a frequency of 3 Hz, the IC(50) values for block of Na(+) current measured 2.6, 88.5, 38.0, and 8.5 microM for granisetron, ondansetron, dolasetron, and MDL 74,156, respectively. Block was relieved by strong hyperpolarizing potentials, suggesting a possible interaction with an inactivated channel state. Recovery from inactivation was impaired at -80 mV compared with -100 mV, and the fractional recovery was impaired by drug in a concentration-dependent manner. IC(50) values for block of the HERG cardiac K(+) channel measured 3.73, 0.81, 5.95, and 12.1 microM for granisetron, ondansetron, dolasetron, and MDL 74,156, respectively. Ondansetron (3 microM) also slowed decay of HERG tail currents. In contrast, none of these drugs (10 microM) produced greater than 30% block of the slow delayed rectifier K(+) channel KvLQT1/minK. We concluded that the antiemetic agents tested in this study block human cardiac Na(+) channels probably by interacting with the inactivated state. This may lead to clinically relevant Na(+) channel blockade, especially when high heart rates or depolarized/ischemic tissue is present. The submicromolar affinity of ondansetron for the HERG K(+) channel likely underlies the prolongation of cardiac repolarization reported for this drug. |
2,332,577 | Anti-SSA/Ro and anti-SSB/La autoantibodies bind the surface of apoptotic fetal cardiocytes and promote secretion of TNF-alpha by macrophages. | Despite the near universal association of congenital heart block and maternal Abs to SSA/Ro and SSB/La, the intracellular location of these Ags has made it difficult to substantiate their involvement in pathogenicity. To define whether components of the SSA/Ro-SSB/La complex, which translocate during apoptosis, are indeed accessible to extracellular Abs, two approaches were taken: immunoprecipitation of surface biotinylated proteins and scanning electron microscopy. Human fetal cardiocytes from 16-24-wk abortuses were cultured and incubated with staurosporine to induce apoptosis. Surface biotinylated 48-kDa SSB/La was reproducibly immunoprecipitated from apoptotic, but not nonapoptotic cardiocytes. Surface expression of SSA/Ro and SSB/La was further substantiated by scanning electron microscopy. Gold particles (following incubation with gold-labeled sera containing various specificities of anti-SSA/Ro-SSB/La Abs and murine mAb to SSB/La and 60-kDa SSA/Ro) were consistently observed on early and late apoptotic cardiocytes. No particles were seen after incubation with control antisera. To evaluate whether opsonized apoptotic cardiocytes promote inflammation, cells were cocultured with macrophages. Compared with nonapoptotic cardiocytes or apoptotic cardiocytes incubated with normal sera, apoptotic cardiocytes preincubated with affinity-purified Abs to SSB/La, 52-kDa SSA/Ro, or 60-kDa SSA/Ro increased the secretion of TNF-alpha from cocultured macrophages. In summary, apoptosis results in surface accessibility of all SSA/Ro-SSB/La Ags for recognition by circulating maternal Abs. It is speculated that in vivo such opsonized apoptotic cardiocytes promote an inflammatory response by resident macrophages with damage to surrounding conducting tissue. |
2,332,578 | Tyrosine kinase signaling in action potential shortening and expression of HSP72 in late preconditioning. | We investigated the role of tyrosine kinase (TK) signaling in the opening of the ATP-sensitive K(+) (K(ATP)) channel and 72-kDa heat shock protein (HSP72) expression during late preconditioning. Rabbits were subjected to surgical operation (sham) or were preconditioned (PC) with four cycles of 5 min of ischemia and 10 min of reperfusion. Twenty-four hours later, animals were subjected to 30 min of ischemia and 180 min of reperfusion. Genistein (1 mg/kg ip) was used to block the receptor TK. Six groups were studied: control, sham, genistein-sham, PC, genistein-PC, and vehicle-PC group (1% dimethyl sulfoxide). Genistein or vehicle was given 30 min before the surgical procedure. Genistein pretreatment decreased the expression of HSP72 in PC hearts and suppressed action potential duration shortening during ischemia in sham and PC groups. Infarct size (%risk area) was reduced in the PC (11.6 +/- 1.0%) and vehicle-PC (19.3 +/- 2.0%) compared with the control (40.0 +/- 3.8%) or sham (46.0 +/- 2.0%) groups (P < 0.05). Genistein pretreatment increased infarct size to 46.4 +/- 4.1% in the PC hearts. We conclude that TK signaling is involved in K(ATP) channel opening and HSP72 expression during late PC. |
2,332,579 | Distinct patterns of cytokine gene suppression by the equivalent effective doses of cyclosporine and tacrolimus in rat heart allografts. | In vitro studies of the mode of action of cyclosporine (CsA) and tacrolimus have indicated that both drugs produce immunosuppression by a quite similar cellular and molecular mechanism to block T cell receptor emanated transcriptional activation of interleukin(IL)-2 and other cytokine genes. Herein, we show that there are distinct patterns of cytokine gene expression in rat heart allografts under equivalent effective doses ("optimal dose") of CsA and tacrolimus. The optimal doses of CsA (10 mg/kg/day) and tacrolimus (3.2 mg/kg/day), which induce similar mean graft survival time (MST), were administered in LEW recipients with ACI heart grafts from day 0 after grafting until sacrifice. Heart grafts were harvested at days 3, 5, and 7. The expression of various cell surface markers, cytokines, and cytotoxic factors was determined by immunohistology and reverse transcriptase-polymerase chain reaction (RFT-PCR). Cell populations that stained positively in the heart tissues of allograft control increased through day 7 for CD4+ and CD8+ T lymphocytes, NKR-Pla+ natural killer (NK) cells, and ED2+ macrophages. CsA and tacrolimus have comparable activity to block these cell local infiltrations. The mRNA levels of the majority of the factors were dramatically up-regulated in the allografts over time, peaking at day 5. The optimal doses of CsA and tacrolimus had similar inhibitory effects on Th1 type cytokine IL-2 and interferon [INF]-gamma), inflammatory cytokine (IL-1beta and tumor necrosis factor [TNF]-alpha), and cytotoxic factor (granzyme B and perforin) mRNA expression. However, the drugs had different effect on Th2 type cytokines (IL-4 and IL-10). Whereas IL-4 expression was not affected by tacrolimus and was enhanced by CsA, IL-10 expression was more significantly suppressed by tacrolimus than CsA. Differences in the suppression of Th2 type cytokine gene expression indicate that the in vivo molecular networks by which CsA and tacrolimus exert their full immunosuppressive activity are not necessarily the same. |
2,332,580 | Mechanisms of ischemic preconditioning in skeletal muscle. | Ischemic preconditioning (IP) (one or more cycles each consisting of a short period of ischemia and a short period of reperfusion, before the sustained ischemia) reduces ischemia-related organ damage in heart and skeletal muscle but the underlying mechanisms are not clear. This study was intended to assess the possible involvement of K(ATP) channels and of adenosine receptors in IP of skeletal muscle in a rat model of skeletal muscle ischemia.</AbstractText>Groups of 8-15 rats were given the following in vivo treatments: ischemia-reperfusion (I-R: 2.5 h tourniquet-induced ischemia of the right hindlimb, then 2 h reperfusion); IP (three cycles of 5 min ischemia, then 5 min reperfusion) before I-R; cromakalim and I-R; glibenclamide, cromakalim, and I-R; glibenclamide, IP, and I-R; [R]-N(6)-[1-methyl-2-phenylethyl]adenosine (R-PIA) and I-R; adenosine and I-R; and glibenclamide, IP, and I-R. Parameters of muscle function (postischemic maximal force, performance, contraction index, and force after 1 min of stimulation) were then assessed in vitro in the extensor digitorum longus muscle.</AbstractText>Pretreatment with either IP or the K(ATP) channel opener cromakalim significantly improved postischemic muscle function. The protective effect of cromakalim was not seen when the K(ATP) channel blocker glibenclamide was added. Glibenclamide, however, did not block IP-induced protection. Pretreatment with the adenosine A(1) receptor agonist 8-(p-sulfophenyl)-theophyllin (8-SPT) or with adenosine did not improve postischemic muscle function. The adenosine receptor agonist did not block IP-induced protection against ischemic damage.</AbstractText>The results show significant improvements in postischemic skeletal muscle function after IP or cromakalim pretreatment but they do not support a role for K(ATP) channels or for adenosine receptors in IP of skeletal muscle.</AbstractText>Copyright 2000 Academic Press.</CopyrightInformation> |
2,332,581 | Specific subnuclei of the nucleus tractus solitarius play a role in determining the duration of inspiration in the rat. | Our previous data obtained in the cat suggest that the neurons of the ventrolateral subnucleus of the tractus solitarius (vlNTS) act as an inspiratory off-switch and terminate the inspiratory phase of the respiratory cycle (Berger et al., Eur. J. Pharmacol. 277 (1995) 195-208; Gillis et al., Neurosci. Abstr. 23 (1997) 725). The purpose of the present study was to determine whether inhibition of the region of the vlNTS of the rat using drugs that hyperpolarize, disfacilitate or block both axonal conduction and action potential generation would alter the inspiratory phase of the respiratory cycle. Experiments were conducted in anesthetized, vagotomized and spontaneously breathing rats while monitoring diaphragmatic electromyogram activity. Vagus nerves were sectioned in order to rule out prolongation of inspiration evoked by microinjection of agents into the vlNTS which block excitatory drive from lung afferent inputs. Bilateral microinjection of the inhibitory amino acid gamma-aminobutyric acid (GABA) 25 nmol/45 nl produced an immediate prolongation of inspiratory duration (484+/-18 to 1291+/-84 ms) and an apneustic pattern of breathing. Other effects observed were a significant shortening of expiratory duration (778+/-36 to 432+/-38 ms), rise in blood pressure (83+/-4 to 108+/-6 mmHg) and a small but significant increase in heart rate (439+/-17 to 452+/-18 beats/min). Bilateral microinjection of the ionotropic glutamate receptor antagonist kynurenic acid (1 nmol) and the Na(+) channel blocker tetrodotoxin (10 pmol) into the region of the vlNTS consistently produced a similar prolongation of inspiratory duration and an apneustic pattern of breathing. These results support the hypothesis that neurons in the region of the vlNTS promote the transition from inspiration to expiration and function as part of the 'Inspiratory Off Switch'. |
2,332,582 | Epidural fentanyl-bupivacaine compared with clonidine-bupivacaine for analgesia in labour. | Alpha-adrenergic agonists produce pain relief through an opioid independent mechanism and may be alternatives to opioids for combination with local anaesthetics for analgesia during labour. We studied 41 pregnant women. Epidural block was performed with 75 microg clonidine (n = 20) or 50 microg fentanyl (n = 21) combined with 0.125% bupivacaine (10 mL). Maternal vital parameters were measured. Analgesia was evaluated using a visual analogue scale (VAS); sedation was scored using a five-point scale. There were no differences in maternal vital parameters, fetal heart rate (FHR) or Apgar scores between the groups. Analgesia lasted longer in the bupivacaine-clonidine group (139.4 +/- 31 min) compared with the bupivacaine-fentanyl group (127.9 +/- 48 min) (P = 0.42). Additional analgesic requirement was more often in the fentanyl-bupivacaine group and total bupivacaine requirement was less in the clonidine-bupivacaine group (22.5 +/- 12.5 mg vs. 30.9 +/- 12.8 mg) (P = 0.04). This small study confirms that this combination of bupivacaine and clonidine provides satisfactory analgesia for first-stage labour, and of longer duration than bupivacaine-fentanyl. |
2,332,583 | Substance P preferentially inhibits large conductance nicotinic ACh receptor channels in rat intracardiac ganglion neurons. | The effects of substance P (SP) on nicotinic acetylcholine (ACh)-evoked currents were investigated in parasympathetic neurons dissociated from neonatal rat intracardiac ganglia using standard whole cell, perforated patch, and outside-out recording configurations of the patch-clamp technique. Focal application of SP onto the soma reversibly decreased the peak amplitude of the ACh-evoked current with half-maximal inhibition occurring at 45 microM and complete block at 300 microM SP. Whole cell current-voltage (I-V) relationships obtained in the absence and presence of SP indicate that the block of ACh-evoked currents by SP is voltage independent. The rate of decay of ACh-evoked currents was increased sixfold in the presence of SP (100 microM), suggesting that SP may increase the rate of receptor desensitization. SP-induced inhibition of ACh-evoked currents was observed following cell dialysis and in the presence of either 1 mM 8-Br-cAMP, a membrane-permeant cAMP analogue, 5 microM H-7, a protein kinase C inhibitor, or 2 mM intracellular AMP-PNP, a nonhydrolyzable ATP analogue. These data suggest that a diffusible cytosolic second messenger is unlikely to mediate SP inhibition of neuronal nicotinic ACh receptor (nAChR) channels. Activation of nAChR channels in outside-out membrane patches by either ACh (3 microM) or cytisine (3 microM) indicates the presence of at least three distinct conductances (20, 35, and 47 pS) in rat intracardiac neurons. In the presence of 3 microM SP, the large conductance nAChR channels are preferentially inhibited. The open probabilities of the large conductance classes activated by either ACh or cytisine were reversibly decreased by 10- to 30-fold in the presence of SP. The single-channel conductances were unchanged, and mean apparent channel open times for the large conductance nAChR channels only were slightly decreased by SP. Given that individual parasympathetic neurons of rat intracardiac ganglia express a heterogeneous population of nAChR subunits represented by the different conductance levels, SP appears to preferentially inhibit those combinations of nAChR subunits that form the large conductance nAChR channels. Since ACh is the principal neurotransmitter of extrinsic (vagal) innervation of the mammalian heart, SP may play an important role in modulating autonomic control of the heart. |
2,332,584 | Block of human heart hH1 sodium channels by the enantiomers of bupivacaine. | S(-)-bupivacaine reportedly exhibits lower cardiotoxicity but similar local anesthetic potency compared with R(+)-bupivacaine. The bupivacaine binding site in human heart (hH1) Na+ channels has not been studied to date. The authors investigated the interaction of bupivacaine enantiomers with hH1 Na+ channels, assessed the contribution of putatively relevant residues to binding, and compared the intrinsic affinities to another isoform, the rat skeletal muscle (mu1) Na+ channel.</AbstractText>Human heart and mu1 Na+ channel alpha subunits were transiently expressed in HEK293t cells and investigated during whole cell voltage-clamp conditions. Using site-directed mutagenesis, the authors created point mutations at positions hH1-F1760, hH1-N1765, hH1-Y1767, and hH1-N406 by introducing the positively charged lysine (K) or the negatively charged aspartic acid (D) and studied their influence on state-dependent block by bupivacaine enantiomers.</AbstractText>Inactivated hH1 Na+ channels displayed a weak stereoselectivity with a stereopotency ratio (+/-) of 1.5. In mutations hH1-F1760K and hH1-N1765K, bupivacaine affinity of inactivated channels was reduced by approximately 20- to 40-fold, in mutation hH1-N406K by approximately sevenfold, and in mutations hH1-Y1767K and hH1-Y1767D by approximately twofold to threefold. Changes in recovery of inactivated mutant channels from block paralleled those of inactivated channel affinity. Inactivated hH1 Na+ channels exhibited a slightly higher intrinsic affinity than mu1 Na+ channels.</AbstractText>Differences in bupivacaine stereoselectivity and intrinsic affinity between hH1 and mu1 Na+ channels are small and most likely of minor clinical relevance. Amino acid residues in positions hH1-F1760, hH1-N1765, and hH1-N406 may contribute to binding of bupivacaine enantiomers in hH1 Na+ channels, whereas the role of hH1-Y1767 remains unclear.</AbstractText> |
2,332,585 | Effects of butorphanol and carprofen on the minimal alveolar concentration of isoflurane in dogs. | To evaluate the effects of butorphanol and carprofen, alone and in combination, on the minimal alveolar concentration (MAC) of isoflurane in dogs.</AbstractText>Randomized complete-block crossover study.</AbstractText>6 healthy adult dogs.</AbstractText>Minimal alveolar concentration of isoflurane was determined following administration of carprofen alone, butorphanol alone, carprofen and butorphanol, and neither drug (control). Anesthesia was induced with isoflurane in oxygen, and MAC was determined by use of a tail clamp method. Three hours prior to induction of anesthesia, dogs were fed a small amount of canned food without any drugs (control) or with carprofen (2.2 mg/kg of body weight [1 mg/lb]). Following initial determination of MAC, butorphanol (0.4 mg/kg [0.18 mg/lb], i.v.) was administered, and MAC was determined again. Heart rate, respiratory rate, indirect arterial blood pressure, endtidal partial pressure of CO2, and saturation of hemoglobin with oxygen were recorded at the time MAC was determined.</AbstractText>Mean +/- SD MAC of isoflurane following administration of butorphanol alone (1.03 +/- 0.22%) or carprofen and butorphanol (0.90 +/- 0.21%) were significantly less than the control MAC (1.28 +/- 0.14%), but MAC after administration of carprofen alone (1.20 +/- 0.13%) was not significantly different from the control value. The effects of carprofen and butorphanol on the MAC of isoflurane were additive. There were not any significant differences among treatments in regard to cardiorespiratory data.</AbstractText>Results suggest that administration of butorphanol alone or in combination with carprofen significantly reduces the MAC of isoflurane in dogs; however, the effects of butorphanol and carprofen are additive, not synergistic.</AbstractText> |
2,332,586 | Significance of autoantibodies in neonatal lupus erythematosus. | Autoantibodies produced by the mother and transported into the fetal circulation are of significant importance in the diagnosis of neonatal lupus syndromes. These humoral autoimmune findings provide an unique opportunity to assess the pathogenic role of autoantibodies against the Ro(SS-A)/La(SS-B) complex, most notably for congenital heart block. Current knowledge about the involved autoantibody-autoantigen systems, including recent therapeutic concepts of these autoimmune syndromes, is summarized. |
2,332,587 | Polymorphism of class A scavenger receptors in C57BL/6 mice. | Scavenger receptors class A (SR-A) have been hypothesized to regulate the development of atherosclerotic lesions through recognition of modified low density lipoprotein (LDL) and macrophage adhesion to substrata. Supporting data have been collected from studies using the monoclonal antibody 2F8, an antibody developed from the BALB/c strain-derived macrophage cell line, RAW.264. Although 2F8 immunostained both cultured peritoneal macrophages (MPM) and thymic macrophages from Swiss, BALB/c, and DBA/2 mice, no immunostaining was detected in cells and tissues from C57BL/6 mice, one of the most commonly used atherosclerosis-susceptible mouse strains. Similarly, 2F8 detected SR-A protein in MPM by Western blotting in all strains except C57BL/6. However, a guinea pig antiserum developed to a fusion protein of the extracellular SR-A domain detected appropriately sized bands in all strains. Incubation with 2F8 antagonized acetylated low-density lipoprotein (AcLDL)-induced cholesterol esterification in MPM from BALB/c, Swiss, and DBA/2 strains but had no effect on MPM from C57BL/6 mice. Sequencing of SR-A cDNA from C57BL/6 mice demonstrated complete identity with published sequence in the collagen-like domain. However, four single-residue substitutions were noted in the alpha-helical coiled-coil domain. Site-directed mutagenesis demonstrated that a single substitution (L168S) in this domain accounted for the loss of 2F8 immunoreactivity. Differing reactivities toward a commonly used monoclonal antibody were used to identify polymorphism of SR-A in C57BL/6 mice. |
2,332,588 | Fetal pulse oximetry: an adjunct to electronic fetal heart rate monitoring. | Electronic fetal heart rate monitoring is routinely used as an indirect measure of fetal oxygenation, yet its value continues to be questioned. With a nonreassuring fetal heart rate pattern, the clinician often needs additional information about fetal oxygen status. Fetal pulse oximetry is a new fetal assessment technology. After consideration of the results of a multicenter randomized, controlled, clinical trial on fetal pulse oximetry in the United States, the U.S. Food and Drug Administration approved the technology for clinical use on May 12, 2000. The results of this trial are anticipated to be published in late 2000. |
2,332,589 | Hemodynamic effects of MF 10058, a new cardioselective muscarinic M(2) receptor antagonist, in conscious dogs. | The 5-¿4-[4-(diethylamino)butyl]-1-piperidinyl¿acetyl-5H-dibenz[b, f]-azepine (MF 10058) is a new potent and selective muscarinic M(2) receptor antagonist. The hemodynamic effects of MF 10058 were investigated in conscious freely moving dogs. Placebo and three doses of MF 10058 (2, 4 and 8 mg/kg) were orally administered according to a randomised four-way crossover design. Heart rate, cardiac conduction times, systolic and diastolic blood pressure were telemetrically recorded for 12-24 h after dosing. After placebo administration, a consistent reduction over time in heart rate was observed during the night-time period (-15%, P=0.019). MF 10058 administration antagonised the nocturnal bradycardia and shortened QT interval. The effect of the drug reached statistically significance, compared to placebo, with the highest dose of 8 mg/kg (+19% on heart rate, P=0.013; -4% on QT interval, P=0.049). The effect on heart rate lasted for the entire 24-h observation period (+16%, P=0.030). Nocturnal systolic and diastolic blood pressure were not significantly affected by MF 10058. No other signs of peripheral or central cholinergic block were observed at any dose. The results of this study demonstrated that oral administration of MF 10058 produces long-lasting hemodynamic effects in the conscious dog. The drug has a therapeutic potential for the treatment of bradycardic disorders. |
2,332,590 | Anti-CD4 induced rat heart tolerance: no presence of primed T cells and regulatory mechanisms for cytotoxic T cells. | Treatment with anti-CD4 monoclonal antibody (mAb) (OX38) induces heart, but not skin graft tolerance in WF (RT1u) to Lewis (RT1l) rat strain combinations. We examined differences in cellular responses between heart-bearing and skin-rejected hosts that were both treated with anti-CD4 mAb. In the tolerant LEW rats bearing WF heart transplants, the secondary WF heart but not skin grafts were accepted. On the other hand, in anti-CD4 treated WF skin-rejected hosts, both secondary WF heart and skin grafts were rapidly rejected. Spleen cells from anti-CD4 treated WF skin-rejected LEW rats but not from WF heart-bearing LEW rats received the same treatment generated CTL after in vitro stimulation with paraformaldehyde (PFA) treated donor WF stimulator spleen cells. Adoptive transfer of spleen cells from WF skin-rejected LEW rats with or without anti-CD4 therapy into the tolerant LEW rats at the secondary WF heart transplantation blocked the secondary heart graft acceptance. However, transfer of spleen cells from WF heart-rejected rats without immunosuppression failed to block acceptance of the secondary heart graft. Our results indicated the lack of primed T cells and presence of regulatory mechanisms for tissue specific T cells in anti-CD4 treated heart bearing hosts. |
2,332,591 | Tissue-specific effects of sulfonylureas: lessons from studies of cloned K(ATP) channels. | Sulfonylureas stimulate insulin secretion in type-2 diabetic patients by blocking ATP-sensitive (K(ATP)) potassium channels in the pancreatic beta-cell membrane. This effect is mediated by the binding of the drug to the sulfonylurea receptor (SUR) subunit of the channel. K(ATP) channels are also present in other tissues, but often contain different types of SUR subunits (e.g., SUR1 in beta-cells, SUR2A in heart, SUR2B in smooth muscle). The sensitivity of these different types of K(ATP) channels to sulfonylureas is variable: gliclazide and tolbutamide block the beta-cell, but not the cardiac or smooth muscle, types of K(ATP) channel. In contrast, glibenclamide blocks all three types of channel with similar affinity. The reversibility of the drugs also varies, with tolbutamide and gliclazide being reversible on all three types of K(ATP) channel, while glibenclamide is reversible on cardiac, but not beta-cell, K(ATP) channels. This review summarizes current knowledge of how sulfonylureas act on the different types of K(ATP) channel found in beta-cells and in extrapancreatic tissues, and discusses the implications of these findings for their use as therapeutic agents. |
2,332,592 | Recovery profiles and costs of anesthesia for outpatient unilateral inguinal herniorrhaphy. | The use of an ilioinguinal-hypogastric nerve block (IHNB) as part of a monitored anesthesia care (MAC) technique has been associated with a rapid recovery profile for outpatients undergoing inguinal herniorrhaphy procedures. This study was designed to compare the cost-effectiveness of an IHNB-MAC technique with standardized general and spinal anesthetics techniques for inguinal herniorrhaphy in the ambulatory setting. We randomly assigned 81 consenting outpatients to receive IHNB-MAC, general anesthesia, or spinal anesthesia. We evaluated recovery times, 24-h postoperative side effects and associated incremental costs. Compared with general and spinal anesthesia, patients receiving IHNB-MAC had the shortest time-to-home readiness (133+/-68 min vs. 171+/-40 and 280+/-83 min), lowest pain score at discharge (15+/-14 mm vs. 39+/-28 and 34+/-32 mm), and highest satisfaction at 24-h follow-up (75% vs. 36% and 64%). The total anesthetic costs were also the least in the IHNB-MAC group ($132.73+/-33.80 vs. $172.67+/-29.82 and $164.97+/-31.03). We concluded that IHNB-MAC is the most cost-effective anesthetic technique for outpatients undergoing unilateral inguinal herniorrhaphy with respect to speed of recovery, patient comfort, and associated incremental costs. |
2,332,593 | Prolonged cardiotoxicity from poison lilly (Veratrum viride). | A 51-y-o otherwise healthy male presented to the emergency department 45 min after ingesting a soup made with boiled "leeks". Physical examination was significant for severe vomiting depressed mental status, and sluggishly reactive 2-3 mm pupils. Heart rate was 30 bpm and bp was 40/p mmHg requiring atropine and fluid resuscitation. After 60 min substernal chest pressure was noted and an ECG showed new V2-V6 ST segment depression. Recurrent hypotension required the use ofa dopamine infusion. At this time, the regional poison control center botanist identified a sample of the ingested material as Veratrum viride. The patient improved slowly over the next 24 hours, although bradycardia and heart block persisted for approximately 48 hours. |
2,332,594 | Replication-defective mutants of mouse cytomegalovirus protect against wild-type virus challenge. | Five temperature-sensitive mutants (tsm9, tsm13, tsm20, tsm22, tsm30) of murine cytomegalovirus have been shown previously not to produce infectious virus in mice. In the present study, the stage at which these mutants are blocked in their replication in vitro was examined by transcriptional analysis of 4 temporally regulated marker genes (IE-1, E-1, gB and gH) using a semi-quantitative reverse transcription polymerase chain reaction (RT-PCR) coupled with an electron microscopic analysis of infected cells incubated at permissive (33 degrees C) and non-permissive (39 and/or 40 degrees C) temperatures. Replication of tsm13 appeared to be blocked at a late phase of replication after capsid formation while the block appeared to be as early as the immediate-early phase in tsm22- infected cells. In contrast, mutants tsm9, tsm20 and tsm30 were blocked at a maturation step, probably of capsid formation, as gene transcription of all 4 marker genes occurred, albeit at reduced level, at 39 and 40 degrees C but no capsids or virions were produced at 40 degrees C. Replication and transcription of mutants tsm13, tsm20 and tsm30 were also examined in infected mice. Mutant tsm13 showed no gene expression or infectious virus while mutants tsm20 and tsm30 produced no infectious virus from days 3-60 post infection, except unusually for a low titre of tsm30 (2.3 x 10(3) pfu/ml) in salivary glands 21 days post infection. Gene transcription of all 4 marker genes was observed in one or more tissues (salivary glands, spleen, kidneys, liver, thymus, heart, lungs) at one or more time points (3, 7, 10, 14, 21 days post-infection) with both mutants. Mice became infected latently with tsm20 but not tsm30, and mice previously infected with tsm20 or tsm30 were protected against a sub-lethal challenge with virulent parental virus; tsm30 also protected against a lethal challenge. This suggests that these two mutants may be good model vaccines for further studies on the mechanism of protection induced and for identification of the ts genes. |
2,332,595 | The polysaccharide fucoidan inhibits microvascular thrombus formation independently from P- and L-selectin function in vivo. | Adhesion molecules of the selectin family (mainly P- and L-selectin) have been suggested to mediate interactions between platelets, leukocytes and endothelial cells in thrombus formation. The polysaccharide fucoidan has anticoagulative properties, but is also able to bind and block the function of the selectins. Here, we investigated in vivo (i) if fucoidan can prevent microvascular thrombus formation, and (ii) whether this is potentially mediated by the inhibition of P-and/or L-selectin.</AbstractText>For this purpose, we used intravital microscopy in the mouse cremaster microcirculation in which thrombosis was induced photochemically by light exposure to individual arterioles and venules after intravenous (i.v.) injection of FITC-dextran.</AbstractText>We found that intravenous administration of fucoidan significantly prolonged the time required for complete occlusion in arterioles and venules by almost seven- and nine-fold, respectively. In contrast, treatment with monoclonal antibodies against P- and L-selectin had no effect on the development of microvascular thrombosis. Fucoidan and also the anti-P-selectin antibody completely inhibited baseline venular leukocyte rolling in the cremaster muscle, indicating that these treatment regimes abolished P-selectin function. Importantly, fucoidan and the anti-P-selectin antibody had no effect on systemic platelet and leukocyte counts. On the other hand, we found that fucoidan treatment significantly altered coagulation parameters, including prothrombin time (Quick percentage), activated partial thromboplastin time (APTT) and thrombin clotting time (TCT), which may explain the potent in vivo anticoagulative effect of fucoidan observed here.</AbstractText>Taken together, our novel findings suggest that fucoidan effectively prevents microvascular thrombus formation induced by endothelial damage in arterioles and venules in vivo. This protective effect of fucoidan is not attributable to inhibition of P- and L-selectin function but may instead be related to the anticoagulative capacity of fucoidan.</AbstractText> |
2,332,596 | Oxidative stress and apoptosis. | Apoptosis or programmed cell death, is essential for the normal functioning and survival of most multi-cellular organisms. The morphological and biochemical characteristics of apoptosis, however, are highly conserved during the evolution. It is currently believed that apoptosis can be divided into at least three functionally distinct phases, i.e. induction, effector and execution phase. Recent studies have demonstrated that reactive oxygen species (ROS) and the resulting oxidative stress play a pivotal role in apoptosis. Antioxidants and thiol reductants, such as N-acetylcysteine, and overexpression of manganese superoxide (MnSOD) can block or delay apoptosis. Bcl-2, an endogenously produced protein, has been shown to prevent cells from dying of apoptosis apparently by an antioxidative mechanism. Taken together ROS, and the resulting cellular redox change, can be part of signal transduction pathway during apoptosis. It is now established that mitochondria play a prominent role in apoptosis. During mitochondrial dysfunction, several essential players of apoptosis, including pro-caspases, cytochrome C, apoptosis-inducing factor (AIF), and apoptotic protease-activating factor-1 (APAF-1) are released into the cytosol. The multimeric complex formation of cytochrome C, APAF-1 and caspase 9 activates downstream caspases leading to apoptotic cell death. All the three functional phases of apoptosis are under the influence of regulatory controls. Thus, increasing evidences provide support that oxidative stress and apoptosis are closely linked physiological phenomena and are implicated in pathophysiology of some of the chronic diseases including AIDS, autoimmunity, cancer, diabetes mellitus, Alzheimer's and Parkinson's and ischemia of heart and brain. |
2,332,597 | Effects of halothane on the transient outward K(+) current in rat ventricular myocytes. | 1. Halothane has been shown to affect several membrane currents in cardiac tissue including the L-type calcium current (I(Ca)), sodium current and a variety of potassium currents. However, little is known about the effects of halothane on the transient outward K(+) current (I(to)). 2. Single ventricular myocytes from rat hearts were voltage clamped using the whole cell patch configuration and an EGTA-containing pipette solution to record the Ca(2+)-independent, 4-aminopyridine sensitive component of I(to). 300 microM Cd(2+) or 10 microM nifedipine was used to block I(Ca). 3. At +80 mV, I(to) (peak current minus current at the end of the pulse) was 1.8+/-0.2 nA under control conditions which was reduced to 1.3+/-0.2 nA by 1 mM halothane (P:<0.001, mean+/-s.e.mean, n=9). The inhibition of I(to) by halothane was concentration-dependent (K(0.5), 1.1+/-0.2 mM). 4. One mM halothane led to a 16 mV shift in the steady-state inactivation curve towards negative membrane potentials (P:=0.005, n=8) but had no significant effect on the activation-voltage relationship (P:=0. 724). One mM halothane also increased the rate of inactivation of I(to); the dominant time constant of inactivation was reduced from 14+/-1 to 9+/-1 ms (P:=0.017, mean+/-s.e.mean, n=6). 5. These data show that halothane reduced I(to); 0.3 mM, close to the MAC(50) value for halothane, inhibited the current by 15% and as such, the inhibition of I(to) will be relevant to the clinical situation. Halothane induced a shift in the steady-state inactivation curve and accelerated the inactivation process of I(to) which could be responsible for its inhibitory effect. 6. Due to the differential transmural expression of I(to) in ventricular tissue, inhibition of I(to) would reduce the transmural dispersion of refractoriness which could contribute to the arrhythmogenic properties of halothane. |
2,332,598 | Transcriptional regulation of the CLC-K1 promoter by myc-associated zinc finger protein and kidney-enriched Krüppel-like factor, a novel zinc finger repressor. | The expression of CLC-K1 and CLC-K2, two kidney-specific CLC chloride channels, is transcriptionally regulated on a tissue-specific basis. Previous studies have shown that a GA element near their transcriptional start sites is important for basal and cell-specific activities of the CLC-K1 and CLC-K2 gene promoters. To identify the GA-binding proteins, the human kidney cDNA library was screened by a yeast one-hybrid system. A novel member of the Cys2-His2 zinc finger gene designated KKLF (for "kidney-enriched Krüppel-like factor") and the previously isolated MAZ (for "myc-associated zinc finger protein") were cloned. KKLF was found to be abundantly expressed in the liver, kidneys, heart, and skeletal muscle, and immunohistochemistry revealed the nuclear localization of KKLF protein in interstitial cells in heart and skeletal muscle, stellate cells, and fibroblasts in the liver. In the kidneys, KKLF protein was localized in interstitial cells, mesangial cells, and nephron segments, where CLC-K1 and CLC-K2 were not expressed. A gel mobility shift assay revealed sequence-specific binding of recombinant KKLF and MAZ proteins to the CLC-K1 GA element, and the fine-mutation assay clarified that the consensus sequence for the KKLF binding site was GGGGNGGNG. In a transient-transfection experiment, MAZ had a strong activating effect on transcription of the CLC-K1-luciferase reporter gene. On the other hand, KKLF coexpression with MAZ appeared to block the activating effect of MAZ. These results suggest that a novel set of zinc finger proteins may help regulate the strict tissue- and nephron segment-specific expression of the CLC-K1 and CLC-K2 channel genes through their GA cis element. |
2,332,599 | Mechanisms behind and treatment of sudden, unexpected circulatory collapse during central neuraxis blockade. | Judging from the number of cases reported in the literature, severe bradycardia and/or asystole in association with central neuraxis blockade fortunately seems a rare complication. However, short periods of extreme bradycardia may go unnoticed and manifest cases, especially when outcome is favourable, may go unreported, and thus the real incidence may be much higher. Although the decrease in systemic blood pressure as a result of central neuraxis blockade is caused by various mechanisms, the most important factor causing severe hypotension, bradycardia and circulatory collapse is decreased venous return, and both prevention and treatment are aimed at preserving or restoring adequate venous return to the heart. Correction of preoperative hypovolaemia, limiting the extent of sensory blockade and positioning the patient so that gravity promotes venous return are the most significant preventive measures. Although a widespread custom, controversy exists regarding the efficacy of a preload; for certain categories of patients intravenous volume loading may be deleterious, and rather than a routine measure, the decision to administer a preload should be based on the clinical situation and the condition of the individual patient. For the treatment of mild bradycardia, anticholinergic drugs are the first choice. Hypotension may be treated by promoting venous return using gravity, by intravenous fluid infusion, by intravenous administration of sympathomimetic drugs, or by a combination of all three measures. In the event of sudden circulatory collapse, the first therapeutic measure that is usually immediately effective is elevation of the legs, thus promoting venous return. |
Subsets and Splits
No community queries yet
The top public SQL queries from the community will appear here once available.