scholarly journals Cellular Mechanism of the QT Prolongation Induced by Sulpiride

2009 ◽  
Vol 28 (3) ◽  
pp. 207-212 ◽  
Author(s):  
Hyang-Ae Lee ◽  
Ki-Suk Kim ◽  
Sang-Joon Park ◽  
Eun-Joo Kim
Keyword(s):  
Action Potential ◽  
Action Potential Duration ◽  
Plasma Concentrations ◽  
Clinical Signs ◽  
Dependent Manner ◽  
Prolonged Action ◽  
Patch Clamp Technique ◽  
Concentration Dependent Manner ◽  
Severe Arrhythmia ◽  
Prolonged Action Potential Duration

In this study, the authors investigated the electrophysiological effect of sulpiride on cardiac repolarization using conventional microelectrode recording techniques in isolated canine Purkinje fibers and a whole-cell patch clamp technique in transiently transfected cells with the hERG, KCNQ1/KCNE1, KCNJ2, and SCN5A cDNA and in rat cardiac myocytes for ICa. In studies of action potential duration, 10 μM, 100 μM, 300 μM, and 1 mM sulpiride prolonged action potential duration in a concentration-dependent manner. In studies of cardiac ion channels, sulpiride did not significantly affect INa, ICa, IKs, IK1, except for IKr. Sulpiride dose-dependently decreased the hERG tail current. It is considered that the prolonged action potential duration by sulpiride was mainly the result of inhibition of the hERG channel. The data suggest that the clinical use of sulpiride is reasonable within therapeutic plasma concentrations, but all patients taking this drug should be cautiously monitored for clinical signs of long-QT syndrome and severe arrhythmia.

Effects of extracellular ATP on ICa, [Ca2+]i, and contraction in isolated ferret ventricular myocytes

1993 ◽  
Vol 264 (3) ◽  
pp. C702-C708 ◽  
Author(s):  
Y. Qu ◽  
H. M. Himmel ◽  
D. L. Campbell ◽  
H. C. Strauss
Keyword(s):  
Action Potential ◽  
Ventricular Myocytes ◽  
Ventricular Myocardium ◽  
Inhibitory Effect ◽  
Extracellular Atp ◽  
Maximal Effect ◽  
Dependent Manner ◽  
Patch Clamp Technique ◽  
Concentration Dependent Manner ◽  
The Right

The effects of extracellular ATP on the voltage-activated "L-type" Ca current (ICa), action potential, resting and transient intracellular Ca2+ levels, and cell contraction were examined in enzymatically isolated myocytes from the right ventricles of ferrets. With the use of the whole cell patch-clamp technique, extracellular ATP (10(-7) to 10(-3) M) inhibited ICa in a time- and concentration-dependent manner. ATP decreased the peak amplitude of ICa without altering the residual current at the end of 500-ms clamp steps. The concentration-response relationship for ATP inhibition of ICa was well described by a conventional Michaelis-Menten relationship with a half-maximal inhibitory concentration of 1 microM and a maximal effect of 50%. Consistent with its inhibitory effect on ICa, ATP hyperpolarized the plateau phase and shortened the action potential duration. In fura-2-loaded myocytes, extracellular ATP did not change the resting myoplasmic Ca2+ levels; however, when current was elicited under voltage-clamp conditions, ATP both decreased the myoplasmic intracellular Ca2+ transient and inhibited the degree of cell shortening. Our results suggest that ATP could be a genuine and potent extracellular modulator of cardiac function in ferret ventricular myocardium.

Molecular mechanism of doxorubicin-induced anticholinergic effect in guinea-pig atria

2000 ◽  
Vol 78 (6) ◽  
pp. 483-489 ◽  
Author(s):  
Yukio Hara ◽  
Kyosuke Temma ◽  
Zin Sekiya ◽  
Akihito Chugun ◽  
Hiroshi Kondo
Keyword(s):  
Guinea Pig ◽  
Action Potential ◽  
Acetylcholine Receptor ◽  
Action Potential Duration ◽  
Molecular Mechanisms ◽  
Muscarinic Acetylcholine Receptor ◽  
Anticholinergic Effect ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Muscarinic Acetylcholine

The molecular mechanisms of anticholinergic actions of doxorubicin were examined by electrophysiological methods in atria and myocytes isolated from guinea-pig heart. A direct anticholinergic action of doxorubicin was confirmed with antagonistic action on carbachol-induced negative inotropic effect in atria. Both carbachol and adenosine produced shortening of action potential duration in atria measured by a microelectrode method. Doxorubicin (10-100 µM) inhibited the carbachol-induced action potential shortening in a concentration-dependent manner. However, doxorubicin did not antagonize the shortening elicited by adenosine. The whole-cell voltage clamp technique was performed to induce the muscarinic acetylcholine-receptor-operated K+ current (IK.ACh) in atrial myocytes loaded with GTP or GTPgammaS, a nonhydrolysable analogue of GTP. Doxorubicin (1-100 µM) suppressed carbachol-induced IK.ACh in a concentration-dependent manner (IC50 = 5.6 µM). In contrast, doxorubicin (10 and 100 µM) suppressed neither adenosine-induced IK.ACh nor GTPgammaS-induced IK.ACh. These results indicate that doxorubicin produces a direct anticholinergic effect through the muscarinic receptors in atrial myocytes.Key words: action potential duration, anticholinergic action, atrial cell, doxorubicin, the muscarinic acetylcholine-receptor-operated K+ current.

Blockade of Myocardial ATP-sensitive Potassium Channels by Ketamine 

1997 ◽  
Vol 87 (1) ◽  
pp. 68-74 ◽  
Author(s):  
Seong-Hoon Ko ◽  
Sang-Kyi Lee ◽  
Young-Jin Han ◽  
Huhn Choe ◽  
Yong-Geun Kwak ◽  
...  
Keyword(s):  
Action Potential ◽  
Action Potential Duration ◽  
Katp Channel ◽  
Ventricular Myocytes ◽  
Katp Channels ◽  
Dependent Manner ◽  
Channel Activity ◽  
Concentration Dependent Manner ◽  
Channel Currents ◽  
Inside Out

Background The adenosine triphosphate (ATP)-sensitive potassium (KATP) channel underlies the increase in potassium permeability during hypoxia and ischemia. The increased outward potassium current during ischemia may be an endogenous cardioprotective mechanism. This study was designed to determine the effects of ketamine on KATP channel in rat hearts. Methods Inside-out and cell-attached configurations of patch-clamp techniques and 3 M potassium chloride-filled conventional microelectrodes were used to investigate the effect of ketamine on KATP channel currents in single rat ventricular myocytes and on the action potential duration of rat papillary muscles, respectively. Results Ketamine inhibited KATP channel activity in rat ventricular myocytes in a concentration-dependent manner. In the inside-out patches, the concentration of ketamine for half-maximal inhibition and the Hill coefficient were 62.9 microM and 0.54, respectively. In a concentration-dependent manner, ketamine inhibited pinacidil- and 2,4-dinitrophenol-activated KATP channels in cell-attached patches. The application of ketamine to the intracellular side of membrane patches did not affect the conduction of single-channel currents of KATP channels. Ketamine increased the action potential duration, which was then shortened by pinacidil in a concentration-dependent manner. Conclusions Ketamine inhibited KATP channel activity in a concentration-dependent manner. These results suggest that ketamine may attenuate the cardioprotective effects of the KATP channel during ischemia and reperfusion in the rat myocardium.

scholarly journals Human Cardiac Mesenchymal Stem Cells Remodel in Disease and Can Regulate Arrhythmia Substrates

2020 ◽  
Vol 13 (10) ◽  
Author(s):  
Prasongchai Sattayaprasert ◽  
Sunil K. Vasireddi ◽  
Emre Bektik ◽  
Oju Jeon ◽  
Mohammad Hajjiri ◽  
...  
Keyword(s):  
Stem Cells ◽  
Action Potential ◽  
Induced Pluripotent Stem Cells ◽  
Cardiac Myocytes ◽  
Pluripotent Stem Cells ◽  
Action Potential Duration ◽  
Calcium Release ◽  
Prolonged Action ◽  
Induced Pluripotent ◽  
Prolonged Action Potential Duration

Background: The mesenchymal stem cell (MSC), known to remodel in disease and have an extensive secretome, has recently been isolated from the human heart. However, the effects of normal and diseased cardiac MSCs on myocyte electrophysiology remain unclear. We hypothesize that in disease the inflammatory secretome of cardiac human MSCs (hMSCs) remodels and can regulate arrhythmia substrates. Methods: hMSCs were isolated from patients with or without heart failure from tissue attached to extracted device leads and from samples taken from explanted/donor hearts. Failing hMSCs or nonfailing hMSCs were cocultured with normal human cardiac myocytes derived from induced pluripotent stem cells. Using fluorescent indicators, action potential duration, Ca2+ alternans, and spontaneous calcium release (SCR) incidence were determined. Results: Failing and nonfailing hMSCs from both sources exhibited similar trilineage differentiation potential and cell surface marker expression as bone marrow hMSCs. Compared with nonfailing hMSCs, failing hMSCs prolonged action potential duration by 24% ( P <0.001, n=15), increased Ca2+ alternans by 300% ( P <0.001, n=18), and promoted spontaneous calcium release activity (n=14, P <0.013) in human cardiac myocytes derived from induced pluripotent stem cells. Failing hMSCs exhibited increased secretion of inflammatory cytokines IL (interleukin)-1β (98%, P <0.0001) and IL-6 (460%, P <0.02) compared with nonfailing hMSCs. IL-1β or IL-6 in the absence of hMSCs prolonged action potential duration but only IL-6 increased Ca2+ alternans and promoted spontaneous calcium release activity in human cardiac myocytes derived from induced pluripotent stem cells, replicating the effects of failing hMSCs. In contrast, nonfailing hMSCs prevented Ca2+ alternans in human cardiac myocytes derived from induced pluripotent stem cells during oxidative stress. Finally, nonfailing hMSCs exhibited >25× higher secretion of IGF (insulin-like growth factor)-1 compared with failing hMSCs. Importantly, IGF-1 supplementation or anti–IL-6 treatment rescued the arrhythmia substrates induced by failing hMSCs. Conclusions: We identified device leads as a novel source of cardiac hMSCs. Our findings show that cardiac hMSCs can regulate arrhythmia substrates by remodeling their secretome in disease. Importantly, therapy inhibiting (anti–IL-6) or mimicking (IGF-1) the cardiac hMSC secretome can rescue arrhythmia substrates.

scholarly journals Comparative Analysis of Genetic Variations in the Nav1.5 Sodium Channel Subunits that Underlie Brugada Syndrome Using Patient-Specific iPSC-CMs

2020 ◽  
Author(s):  
Yue Zhu ◽  
Linlin Wang ◽  
Chang Cui ◽  
Shaojie Chen ◽  
Hongwu Chen ◽  
...  
Keyword(s):  
Action Potential ◽  
Brugada Syndrome ◽  
Action Potential Duration ◽  
Sodium Current ◽  
Genetic Variations ◽  
Patient Specific ◽  
Control Group ◽  
Prolonged Action ◽  
Ips Cell ◽  
Prolonged Action Potential Duration

Abstract Background: Brugada syndrome (BrS) is an autosomal dominant disorder that causes a high predisposition to sudden cardiac death. Several genes have been reported to be associated with BrS. Considering that the heterogeneity in clinical manifestations may result from genetic variations, the application of patient-specific induced pluripotent stem (iPS) cell-derived cardiomyocytes (CMs) may help to reveal cell phenotype characteristics resulting from different genetic backgrounds. The present study was to compare the structural and electrophysiological characteristics of sodium channel subunits with different genetic variations and evaluate the safety of quinidine for use with BrS patient-specific iPSC-derived cardiomyocytes.Methods: Two BrS patient-specific iPS cell lines were constructed that carried missense mutations in SCN5A and SCN1B. One iPS cell line from a healthy volunteer was used as a control. The differentiated cardiomyocytes from the three groups were evaluated by flow cytometry, immunofluorescence staining, electron microscopy, as well as calcium transient and patch clamp analyses to assess different pathological phenotypes. Finally, we evaluated the drug responses to varying concentrations of quinidine by measuring the action potential.Results: Compared to the control group, BrS-CMs showed a significant reduction in sodium current, prolonged action potential duration and varying degrees of decreased Vmax, but no structural difference was observed. After applying different concentrations of quinidine, the disease-specific groups and the control group had a downward trend in maximal upstroke velocity, resting membrane potential and action potential amplitude, and exhibited prolonged action potential duration without increasing incidence of arrhythmic events.Conclusion: Both patient-specific iPSC-CMs recapitulated the BrS phenotype at the cellular level. Although the SCN5A variation led to a markedly lower sodium current than what was observed with the SCN1B variation, their responses to quinidine were quite similar. The present study provides an advantageous platform for exploring disease mechanisms and evaluating drug safety in vitro.

Sign in / Sign up

Export Citation Format

Share Document