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The novel [[alpha].sub.1D] [Ca.sup.2+] channel together with [[alpha].sub.1C] [Ca.sup.2+] channel contribute to the L-type [Ca.sup.2+] current ([I.sub.Ca-L]) in the mouse supraventricular tissue. However, its functional role in the heart is just emerging. We used the [[alpha].sub.1D] gene knockout (KO) mouse to investigate the electrophysiological features, the relative contribution of the [[alpha].sub.1D] [Ca.sup.2+] channel to the global [I.sub.Ca-L], the intracellular [Ca.sup.2+] transient, the [Ca.sup.2+] handling by the sarcoplasmic reticulum (SR), and the inducibility of atrial fibrillation (AF). In vivo and ex vivo ECG recordings from [[alpha].sub.1D] KO mice demonstrated significant sinus bradycardia, atrioventricular block, and vulnerability to AF. The wild-type mice showed no ECG abnormalities and no AF. Patch-clamp recordings from isolated [[alpha].sub.1D] KO atrial myocytes revealed a significant reduction of [I.sub.Ca-L] (24.5%; P < 0.05). However, there were no changes in other currents such as [I.sub.Na], [I.sub.Ca-T], [I.sub.K], [I.sub.f], and [I.sub.to] and no changes in [[alpha].sub.1C] mRNA levels of [[alpha].sub.1D] KO atria. Fura 2-loaded atrial myocytes showed reduced intracellular [Ca.sup.2+] transient (~40%; P < 0.05) and rapid caffeine application caused a 17% reduction of the SR [Ca.sup.2+] content (P < 0.05) and a 28% reduction (P < 0.05) of fractional SR [Ca.sup.2+] release in am KO atria. In conclusion, genetic deletion of [[alpha].sub.1D] [Ca.sup.2+] channel in mice results in atrial electrocardiographic abnormalities and AF vulnerability. The electrical abnormalities in the [[alpha].sub.1D] KO mice were associated with a decrease in the total [I.sub.Ca-L] density, a reduction in intracellular [Ca.sup.2+] transient, and impaired intracellular [Ca.sup.2+] handling. These findings provide new insights into the mechanism leading to atrial electrical dysfunction in the [[alpha].sub.1D] KO mice. mice; calcium transient; arrhythmia; myocyte

[[alpha].sub.1D] L-type Ca channel was assumed to be of neuroendocrine origin only: however, [[alpha].sub.1D] L-type Ca channel knockout mice exhibit sinus bradycardia and atrioventricular block, indicating a distinct role of [[alpha].sub.1D] in the heart. The presence and distribution of [[alpha].sub.1D] Ca channel in the heart and its regulation by protein kinase A (PKA) are just emerging. Our objective was to examine the localization of [[alpha].sub.1D] L-type Ca channel in rabbit and rat hearts and its modulation by PKA. Here, we show the exclusive presence of [[alpha].sub.1D] Ca channel transcript in the sinoatrial node, atrio-ventricular node, and atria but not in the ventricle by RT-PCR and the expression of [[alpha].sub.1D] Ca channel protein in atrial myocytes' sarcolemma by indirect immunostaining and Western blot. There is no significant difference in the expression level of [[alpha].sub.1D] Ca channel in the left versus right atrium. Superfusion of membrane-permeable 8-bromo-cAMP resulted in a significant increase of the peak current density of [[alpha].sub.1D] Ca current expressed in tsA201 cells. This increase was inhibited by the PKA inhibitor (PKI). Application of 8-bromo-cAMP also readily phosphorylated the [[alpha].sub.1D] Ca channel protein. The results are first to demonstrate that PKA phosphorylation of L-type Ca channel [[alpha].sub.1D]-subunit resulted in an increase of the [[alpha].sub.1D] Ca channel activity. Together with the observation that [[alpha].sub.1D] Ca channel is exclusively present in the sinoatrial node and atria, the findings suggest that [[alpha].sub.1D] Ca channel plays a unique role in the sinoatrial tissue and is a target for sympathetic control of heart rhythm. phosphorylation; protein kinase A; sinoatrial node

The role of mitochondrial free radicals in the cardioprotective effect of ischemic preconditioning was examined in isolated buffer-perfused rat hearts. Infarct size in control rat hearts subjected to 30 min of regional ischemia and 120 rain of reperfusion was 32.6 [+ or -] 3.4% of the risk zone. Ischemic preconditioning (3 cycles of 5-min global ischemia/5-min reperfusion) before the same regional ischemia and reperfusion protocol significantly reduced infarct size to 2.6 [+ or -] 0.8% of the risk zone. Perfusion with menadione (3.0 [micro]M), a generator of mitochondrial free radicals, in lieu of preconditioning ischemia significantly reduced infarction to 10.9 [+ or -] 2.7%. N-2-mercaptopropionylglycine (1.0 mM), a free radical scavenger, blocked the protection of menadione, significantly increasing infarction to 23.5 [+ or -] 1.1%. Myxothiazol (0.6 [micro]M), a site III mitochondrial inhibitor, blocked the protection of menadione and significantly increased infarction to 25.2 [+ or -] 3.8%. The infarct-limiting effect of menadione was attenuated to 19.7 [+ or -] 1.5% of the risk zone by 10 [micro]M SB203580, a p38 mitogen-activated protein kinase (MAPK) inhibitor. Furthermore, menadione significantly increased p38 MAPK phosphorylation to a level 5.6-fold over basal. These results indicate that free radicals that originate within mitochondria can activate p38 MAPK and protect hearts against infarction. myocardial infarction; ischemia; mitochondria; p38 MAPK

Key points Channelopathies of autoimmune origin are novel and are associated with corrected QT (QTc) prolongation and complex ventricular arrhythmias., We have recently demonstrated that anti-SSA/Ro antibodies from patients with autoimmune diseases and with QTc prolongation on the ECG target the human ether-à-go-go-related gene (HERG) K+ channel by inhibiting the corresponding current, IKr, at the pore region., Immunization of guinea-pigs with a peptide (E-pore peptide) corresponding to the extracellular loop region connecting the S5 and S6 segments of the HERG channel induces high titres of antibodies that inhibit IKr, lengthen the action potential and cause QTc prolongation on the surface ECG. In addition, anti-SSA/Ro-positive sera from patients with connective tissue diseases showed high reactivity to the E-pore peptide., The translational impact is the development of a peptide-based approach for the diagnosis and treatment of autoimmune-associated long QT syndrome., Abstract We recently demonstrated that anti-SSA/52 kDa Ro antibodies (Abs) from patients with autoimmune diseases and corrected QT (QTc) prolongation directly target and inhibit the human ether-à-go-go-related gene (HERG) K+ channel at the extracellular pore (E-pore) region, where homology with SSA/52 kDa Ro antigen was demonstrated. We tested the hypothesis that immunization of guinea-pigs with a peptide corresponding to the E-pore region (E-pore peptide) will generate pathogenic inhibitory Abs and cause QTc prolongation. Guinea-pigs were immunized with a 31-amino-acid peptide corresponding to the E-pore region of HERG. On days 10-62 after immunization, ECGs were recorded and blood was sampled for the detection of E-pore peptide Abs. Serum samples from patients with autoimmune diseases were evaluated for reactivity to E-pore peptide by enzyme-linked immunosorbent assay (ELISA), and histology was performed on hearts using Masson's Trichrome. Inhibition of the HERG channel was assessed by electrophysiology and by computational modelling of the human ventricular action potential. The ELISA results revealed the presence of high titres of E-pore peptide Abs and significant QTc prolongation after immunization. High reactivity to E-pore peptide was found using anti-SSA/Ro Ab-positive sera from patients with QTc prolongation. Histological data showed no evidence of fibrosis in immunized hearts. Simulations of simultaneous inhibition of repolarizing currents by anti-SSA/Ro Ab-positive sera showed the predominance of the HERG channel in controlling action potential duration and the QT interval. These results are the first to demonstrate that inhibitory Abs to the HERG E-pore region induce QTc prolongation in immunized guinea-pigs by targeting the HERG channel independently from fibrosis. The reactivity of anti-SSA/Ro Ab-positive sera from patients with connective tissue diseases with the E-pore peptide opens novel pharmacotherapeutic avenues in the diagnosis and management of autoimmune-associated QTc prolongation. [ABSTRACT FROM AUTHOR]

Background: In patients with autoimmune disease, anti-Ro/SSA antibodies (anti-Ro/SSA) are responsible for a novel autoimmune-associated long-QT syndrome by targeting the hERG potassium channel and inhibiting the related current (IKr). Because anti-Ro/SSA are also present in a significant proportion of healthy subjects and may be associated with torsades de pointes (TdP) arrhythmia, we tested the hypothesis that anti-Ro/SSA may represent a silent risk factor in patients developing TdP. Methods and Results: Twenty-five consecutive patients who experienced TdP were prospectively collected independent of ongoing therapies and concomitant diseases. Anti-Ro/SSA were detected by fluoroenzyme immunoassay, immuno-Western blotting, and line-blot immunoassay. Purified IgGs from anti-Ro/SSA-positive and anti-Ro/SSA-negative patients were tested on IKr using HEK293 cells stably expressing the hERG channel. As expected, in TdP patients, many known corrected QT interval-prolonging risk factors were simultaneously present, including hypokalemia that was the most common (52%). Anti-Ro/SSA were present in 60% of the subjects, mostly the anti-Ro/SSA-52-kD subtype detected by immuno-Western blotting only. A history of autoimmune disease was found in only 2 of anti-Ro/SSA-positive patients. Experimental data demonstrated that purified anti-Ro/SSA-positive IgGs significantly inhibited IKr and cross reacted with hERG-channel proteins. Moreover, anti-Ro/SSA-positive sera exhibited high reactivity with a peptide corresponding to the hERG-channel pore-forming region. Conclusions: Anti-Ro/SSA may represent a clinically silent novel risk factor for TdP development via an autoimmune-mediated electrophysiological interference with the hERG channel. We propose that TdP patients may benefit from specific anti-Ro/SSA testing even in the absence of autoimmune diseases as immunomodulating therapies may be effective in shortening corrected QT interval and reducing TdP recurrence risk. [ABSTRACT FROM AUTHOR]

Background--Emerging clinical evidence demonstrates high prevalence of QTc prolongation and complex ventricular arrhythmias in patients with anti-Ro antibody (anti-Ro Ab)-positive autoimmune diseases. We tested the hypothesis that anti-Ro Abs target the HERG (human ether-a-go-go-related gene) K+ channel, which conducts the rapidly activating delayed K+ current, IKr, thereby causing delayed repolarization seen as QT interval prolongation on the ECG. Methods and Results--Anti-Ro Ab-positive sera, purified IgG, and affinity-purified anti-52kDa Ro Abs from patients with autoimmune diseases and QTc prolongation were tested on IKr using HEK293 cells expressing HERG channel and native cardiac myocytes. Electrophysiological and biochemical data demonstrate that anti-Ro Abs inhibit IKr to prolong action potential duration by directly binding to the HERG channel protein. The 52-kDa Ro antigen-immunized guinea pigs showed QTc prolongation on ECG after developing high titers of anti-Ro Abs, which inhibited native IKr and crossreacted with guinea pig ERG channel. Conclusions--The data establish that anti-Ro Abs from patients with autoimmune diseases inhibit IKr by cross-reacting with the HERG channel likely at the pore region where homology between anti-52-kDa Ro antigen and HERG channel is present. The animal model of autoimmune-associated QTc prolongation is the first to provide strong evidence for a pathogenic role of anti-Ro Abs in the development of QTc prolongation. It is proposed that adult patients with anti-Ro Abs may benefit from routine ECG screening and that those with QTc prolongation should receive counseling about drugs that may increase the risk for life-threatening arrhythmias. [ABSTRACT FROM AUTHOR]

Mancarella S, Yue Y, Karnabi E, Qu Y, El-Sherif N, Boutjdir M. Impaired Ca[sup2+] homeostasis is associated with atrial fibrillation in the α1D L-type Ca[sup2+] channel KU mouse. Am J Physiol Heart Circ Physiol 295: H2017-H2024, 2008. First published September 12, 2008; doi: 10.1152/ajpheart.00537.2008.-The novel α1D Ca[sup2+] channel together with α1D Ca[sup2+] channel contribute to the L-type Ca[sup2+] current (I[subCa-L]) in the mouse supraventricular tissue. However, its functional role in the heart is just emerging. We used the α1D gene knockout (KO) mouse to investigate the electrophysiological features, the relative contribution of the α1D Ca[sup2+] channel to the global I[subCa-L], the intracellular Ca[sup2+] transient, the Ca[sup2+] handling by the sarcoplasmic reticulum (SR), and the inducibility of atrial fibrillation (AF). In vivo and ex vivo ECG recordings from α1D KO mice demonstrated significant sinus bradycardia, atrioventricular block, and vulnerability to AF. The wild-type mice showed no ECG abnormalities and no AF. Patch-clamp recordings from isolated α1D KO atrial myocytes revealed a significant reduction of I[subCa-L] (24.5%; P < 0.05). However, there were no changes in other currents such as I[subNa], I[subCa-T], I[subK], If, and I[subf] and no changes in α[subIC] mRNA levels of α1D KO atria. Fura 2-loaded atrial myocytes showed reduced intracellular Ca[sup2+] transient (-40%; P < 0.05) and rapid caffeine application caused a 17% reduction of the SR Ca[sup2+] content (P < 0.05) and a 28% reduction (P < 0.05) of fractional SR Ca[sup2+] release in α1D KO atria. In conclusion, genetic deletion of α1D Ca[sup2+] channel in mice results in atrial electrocardiographic abnormalities and AF vulnerability. The electrical abnormalities in the α1D KO mice were associated with a decrease in the total I[subCa-L] density, a reduction in intracellular Ca[sup2+] transient, and impaired intracellular Ca[sup2+] handling. These findings provide new insights into the mechanism leading to atrial electrical dysfunction in the α1D KO mice. [ABSTRACT FROM AUTHOR]

Abstract: Purpose: Ischemic heart disease carries an increased risk of malignant ventricular tachycardia (VT), fibrillation (VF), and sudden cardiac death. Protein kinase C (PKC) epsilon activation has been shown to improve the hemodynamics in hearts subjected to ischemia/reperfusion. However, very little is known about the role of epsilon PKC in reperfusion arrhythmias. Here we show that epsilon PKC activation is anti-arrhythmic and its inhibition is pro-arrhythmic. Method: Langendorff-perfused isolated hearts from εPKC agonist (εPKC activation), antagonist (εPKC inhibition) transgenic (TG), and wild-type control mice were subjected to 30min stabilization period, 10min global ischemia, and 30min reperfusion. Action potentials (APs) and calcium transients (CaiT) were recorded simultaneously at 37°C using optical mapping techniques. The incidence of VT and VF was assessed during reperfusion. Results: No VT/VF was seen in any group during the stabilization period in which hearts were perfused with Tyrode’s solution. Upon reperfusion, 3 out of the 16 (19%) wild-type mice developed VT but no VF. In εPKC antagonist group, in which εPKC activity was downregulated, 10 out of 13 (76.9%) TG mice developed VT, of which six (46.2%) degenerated into sustained VF upon reperfusion. Interestingly, in εPKC agonist mice, in which the activity of εPKC was upregulated, no VF was observed and only 1 out of 12 mice showed only transient VT during reperfusion. During ischemia and reperfusion, CaiT decay was exceedingly slower in the antagonist mice compared to the other two groups. Conclusion: Moderate in vivo activation of εPKC exerts beneficial antiarrhythmic effect vis-a-vis the lethal reperfusion arrhythmias. Abnormal CaiT decay may, in part, contribute to the high incidence of reperfusion arrhythmias in the antagonist mice. These findings have important implications for the development of PKC isozyme targeted therapeutics and subsequently for the treatment of ischemic heart diseases. [Copyright &y& Elsevier]

It is well established that β-adrenoceptor stimulation activates PKA and α1-adrenoceptor stimulation activates PKC. In normal ventricular myocytes, acute activation of α1-adrenoceptors inhibits β-adrenoceptor stimulated L-type Ca current (ICa-L) and direct activation of &epsiv;PKC leads to ICa-L inhibition. Because increased PKC activity has been observed chronically in in vivo setting such as failing human heart, we hypothesized that chronic in vivo activation of &epsiv;PKC alters ICa-L and its response to adrenergic stimulation. Therefore, we investigated the interaction between β- and α1-adrenoceptors vis-a&grave;-vis ICa-L in myocytes from transgenic mice (TG) with cardiac specific constitutive activation of &epsiv;PKC (&epsiv;PKC agonist). Whole-cell ICa-L was recorded from &epsiv;PKC agonist TG mice and age-matched non-TG (NTG) littermates under: (1) basal condition, (2) β-adrenoceptor agonist, isoproterenol (ISO), and (3) ISO plus α1-adrenoceptor agonist, methoxamine. The present results are the first to demonstrate that chronic in vivo activation of &epsiv;PKC leads to reduced basal ICa-L density. β-adrenoceptor activation of ICa-L is blunted in &epsiv;PKC agonist TG mice. α-adrenoceptor cross-talk with β-adrenoceptor signaling pathways vis-a&grave;-vis L-type Ca channels is impaired in &epsiv;PKC agonist TG mice. The diminished response to ISO and methoxamine suggests a protective feedback regulatory mechanism in &epsiv;PKC agonist TG mice and could be vital in the settings of excessive release of catecholamines during heart failure. [Copyright &y& Elsevier]

Objectives: Ischemic preconditioning (PC) reduces myocardial infarction by a mechanism that involves opening of mitochondrial ATP-dependent potassium channels (mKATP), reactive oxygen species (ROS), and possibly activation of p38 mitogen-activated protein kinase (p38 MAPK). The actual order of these steps, however, is a matter of current debate. This study examined whether protection afforded by menadione, which protects by causing mitochondria to produce ROS, requires mKATP opening. In addition, we tested whether protection from anisomycin, a p38 MAPK activator, is dependent on ROS production. Methods and Results: Isolated, buffer-perfused rat hearts were pretreated with menadione, and infarction was assessed after 30 min of regional ischemia and 120 min of reperfusion. Menadione reduced infarction in a dose-dependent manner with an EC50 of 270 nM. Menadione’s infarct-limiting effect was insensitive to 200 μM 5-hydroxydecanoate (5HD), an mKATP channel blocker, whereas protection by diazoxide and PC were blocked by 5HD. Anisomycin caused hearts to resist infarction and this protective effect was abrogated by SB203580, a p38 MAPK inhibitor, and 2-mercaptopropionylglycine (MPG), a free radical scavenger. Conclusions: These results indicate that mKATP opening occurs upstream of mitochondrial ROS generation in the protective pathway. Furthermore, protection afforded by anisomycin was p38 MAPK- and ROS-dependent. [Copyright &y& Elsevier]

Abstract: Pervious biochemical and hemodynamic studies have highlighted the important role of εPKC in cardioprotection during ischemic preconditioning. However, little is known about the electrophysiological consequences of εPKC modulation in ischemic hearts. Membrane permeable peptide εPKC selective activator and inhibitor were used to investigate the role of εPKC modulation in reperfusion arrhythmias. Methods: Protein transduction domain from HIV-TAT was used as a carrier for peptide delivery into intact Langendorff perfused guinea pig hearts. Action potentials were imaged and mapped (124 sites) using optical techniques and surface ECG was continuously recorded. Hearts were exposed to 30min stabilization period, 15min of no-flow ischemia, followed by 20min reperfusion. Peptides (0.5μM) were infused as follows: (a) control (vehicle-TAT peptide; TAT-scrambled ψεRACK peptide); (b) εPKC agonist (TAT-ψεRACK); (c) εPKC antagonist (TAT-εV1). Results: Hearts treated with εPKC agonist ψεRACK had reduced incidence of ventricular tachycardia (VT, 64%) and fibrillation (VF, 50%) compared to control (VT, 80%, P <0.05) and (VF, 70%, P <0.05). However, the highest incidence of VT (100%, P <0.05) and VF (80%) occurred in hearts treated with εPKC antagonist peptide εV1 compared to control and to εPKC agonist ψεRACK. Interestingly, at 20min reperfusion, 100% of hearts treated with εPKC agonist ψεRACK exhibited complete recovery of action potentials compared to 40% (P <0.05) of hearts treated with εPKC antagonist peptide, εV1 and 65% (P <0.5) of hearts in control. At 20min reperfusion, maps of action potential duration from εPKC agonist ψεRACK showed minimal dispersion (48.2±9ms) compared to exacerbated dispersion (115.4±42ms, P <0.05) in εPKC antagonist and control (67±20ms, P <0.05). VT/VF and dispersion from hearts treated with scrambled agonist or antagonist peptides were similar to control. Conclusion: The results demonstrate that εPKC activation by ψεRACK peptide protects intact hearts from reperfusion arrhythmias and affords better recovery. On the other hand, inhibition of εPKC increased the incidence of arrhythmias and worsened recovery compared to controls. The results carry significant therapeutic implications for the treatment of acute ischemic heart disease by preconditioning-mimicking agents. [Copyright &y& Elsevier]

Abstract: Congenital heart block (CHB) is an autoimmune disease associated with autoantibodies against intracellular ribonucleoproteins SSB/La and SSA/Ro. The hallmark of CHB is complete atrioventricular block. We have recently established that anti-SSA/Ro -SSB/La autoantibodies inhibit α1D L-type Ca current, ICa-L, and cross-react with the α1D Ca channel protein. This study aims at identifying the possible binding sites on α1D protein for autoantibodies from sera of mothers with CHB children. GST fusion proteins of the extracellular regions between the transmembrane segments (S5–S6) of each of the four α1D Ca channel protein domains I–IV were prepared and tested for reactivity with sera from mothers with CHB children and controls using ELISA. Sera containing anti-Ro/La autoantibodies from 118 mothers with CHB children and from 15 mothers with anti-Ro/La autoantibodies but have healthy children, and from 28 healthy mothers without anti-Ro/La autoantibodies and healthy children were evaluated. Seventeen of 118 (14.4%) sera from mothers with CHB children reacted with the extracellular loop of domain I S5–S6 region (E1). In contrast, only 2 of 28 (7%) of sera from healthy mothers (−anti-Ro/La) and healthy children reacted with E1 loop and none (0 of 15) of sera from healthy mothers (+anti-Ro/La) and healthy children reacted with the E1 loop. Preincubation of E1 loop with the positive sera decreased the O.D reading establishing the specificity of the response. Electrophysiological characterization of the ELISA positive sera and purified IgG showed inhibition (44.1% and 49.8%, respectively) of the α1D ICa-L expressed in tsA201 cells. The inhibition was abolished when the sera were pre-incubated with E1 fusion protein. The results identified the extracellular loop of domain I S5–S6 of L-type Ca channel α1D subunit as a target for autoantibodies from a subset of mothers with CHB children. This novel finding provides insights into the potential development of therapeutic peptides that could bind to the pathogenic antibodies and prevent CHB. [Copyright &y& Elsevier]

Abstract: Cav1.2 (α1C) and Cav1.3 (α1D) L-type Ca channels are co-expressed in the heart. To date, there are no pharmacological or biophysical tools to separate α1D from α1C Ca currents (ICa-L) in cardiomyocytes. Here, we established a physiological model to study α1D ICa-L in native myocytes using RNA interference. Transfection of rat neonatal cardiomyocytes (RNC) with α1C specific siRNA resulted in low silencing efficiency (50–60%) at the mRNA and protein levels. The use of lentivirus shRNA resulted in 100% transfection efficiency and 92% silencing of the α1C gene by real-time PCR and Western blot. Electrophysiological experiments showed that the total ICa-L was similarly reduced by 80% in lentivirus transfected cells. Both biochemical and functional data demonstrated high transfection and silencing efficiency in the cardiomyocytes using lentiviral shRNA. This novel approach allows for the assessments of the roles of α1C and α1D Ca channels in native myocytes and could be used to examine their roles in physiological and pathological settings. [Copyright &y& Elsevier]

It was recently reported that sera from patients with systemic lupus erythematosus contain antibodies reactive with the second extracellular loop of the serotoninergic 5-HT4 receptor expressed in the human heart. This antibody response was associated with antibodies to 52 kD SSA/Ro, a reactivity prevalent in mothers of children with congenital heart block (CHB). The current study was undertaken to determine whether the 5-HT4 receptor is a target of the immune response in these mothers. Initial experiments demonstrated mRNA expression of the 5-HT4 receptor in the human foetal atrium. Electrophysiologic studies established that human foetal atrial cells express functional 5-HT4 receptors. Sera from 116 mothers enrolled in the Research Registry for Neonatal Lupus, whose children have CHB, were evaluated. Ninety-nine (85%) of these maternal sera contained antibodies to SSA/Ro, 84% of which were reactive with the 52 kD SSA/Ro component by immunoblot. None of the 116 sera were reactive with the peptide spanning aa165–185 of the serotoninergic receptor. Rabbit antisera which recognized this peptide did not react with 52 kD SSA/Ro or peptide aa365–382 in the C terminus. Although 5-HT4 receptors are present and functional in the human foetal heart, maternal antibodies to the 5-HT4 receptor are not associated with the development of CHB. [Copyright &y& Elsevier]

Examines the ionic basis of the abnormal electrophysiological character of myocytes from the right ventricle of chronic hypoxic guinea pigs. Effect of chronic hypoxia; Role of attenuatement of the outward potassium in the prolongation of the action potential duration; Influence of metabolic changes on phospholyration and dephosphorylation.