Sensitivity and Specificity of the In Vitro Guinea Pig Papillary Muscle Action Potential Duration for the Assessment of Drug-Induced Torsades De Pointes Liability in Humans

2015 ◽  
pp. 205-219
Author(s):  
Joffrey Ducroq
Keyword(s):  
Guinea Pig ◽  
Action Potential ◽  
Sensitivity And Specificity ◽  
Papillary Muscle ◽  
Action Potential Duration ◽  
Torsades De Pointes ◽  
Muscle Action ◽  
Drug Induced ◽  
Muscle Action Potential

Diazepam reduces action potential duration in guinea-pig papillary muscle by a cAMP-dependent mechanism

Life Sciences ◽  
1999 ◽  
Vol 64 (25) ◽  
pp. 2383-2389 ◽  
Author(s):  
J.J. Janvier ◽  
J. García-Estan˜ ◽  
J. Hernández
Keyword(s):  
Guinea Pig ◽  
Action Potential ◽  
Papillary Muscle ◽  
Action Potential Duration ◽  
Dependent Mechanism

Effect of Clebopride, Antidopaminergic Gastrointestinal Prokinetics, on Cardiac Repolarization

2007 ◽  
Vol 26 (1) ◽  
pp. 25-31 ◽  
Author(s):  
Ki-Suk Kim ◽  
Won-Ho Shin ◽  
Sang-joon Park ◽  
Eun-Joo Kim
Keyword(s):  
Action Potential ◽  
Action Potential Duration ◽  
Chinese Hamster ◽  
Torsades De Pointes ◽  
Threshold Concentration ◽  
Drug Induced ◽  
Whole Cell Patch Clamp ◽  
Phase 0 ◽  
Prokinetic Drug ◽  
Channel Currents

The inhibition of the potassium current IKr and QT prolongation has been known to be associated with drug-induced torsades de pointes arrhythmias (TdP) and sudden cardiac death. In this study, the authors investigated the cardiac electrophysiological effects of clebopride, a class of antidopaminergic gastrointestinal prokinetic, that has been reported to prolong the QT interval by using the conventional microelectrode recording techniques in isolated rabbit Purkinje fiber and whole-cell patch clamp techniques in human ether-à-go-go-related gene (hERG)-stably transfected Chinese hamster ovarian (CHO) cells. Clebopride at 10 μM significantly decreased the Vmax of phase 0 depolarization ( p < .05) and significantly prolonged the action potential duration at 90% repolarization (APD90) ( p < .01), whereas the action potential duration at 50% repolarization (APD50) was not prolonged. For hERG potassium channel currents, the IC50 value was 0.62 ± 0.30 μM. Clebopride was found to have no effect on sodium channel currents. When these results were compared with Cmax (1.02 nM) of clinical dosage (1 mg, [p.o.]), it can be suggested that clebopride is safe at the clinical dosage of 1 mg from the electrophysiological aspect. These findings indicate that clebopride, an antidopaminergic gastrointestinal prokinetic drug, may provide a sufficient “safety factor” in terms of the electrophysiological threshold concentration. But, in a supratherapeutic concentration that might possibly be encountered during overdose or impaired metabolism, clebopride may have torsadogenic potency.

scholarly journals Myocardial Depressant Effects of Sevoflurane

1996 ◽  
Vol 84 (5) ◽  
pp. 1166-1176 ◽  
Author(s):  
Wyun Kon Park ◽  
Joseph J. Pancrazio ◽  
Chang Kook Suh ◽  
Carl III Lynch
Keyword(s):  
Sarcoplasmic Reticulum ◽  
Guinea Pig ◽  
Action Potential ◽  
Papillary Muscle ◽  
Action Potential Duration ◽  
Action Potentials ◽  
Peak Force ◽  
Rapid Cooling ◽  
K Current ◽  
Slow Action Potentials

Background The effects of anesthetic concentrations of sevoflurane were studied in isolated myocardial tissue to delineate the mechanisms by which cardiac function is altered. Methods Isometric force of isolated guinea pig ventricular papillary muscle was studied at 37 degrees C in normal and 26 mM K+ Tyrode's solution at various stimulation rates. Normal and slow action potentials were evaluated using conventional microelectrodes. Effects of sevoflurane on sarcoplasmic reticulum function in situ were also evaluated by its effect on rapid cooling contractures, which are known to activate Ca2+ release from the sarcoplasmic reticulum, and on concentrations of rat papillary muscle. Finally, Ca2+ and K+ currents of isolated guinea pig ventricular myocytes were examined using the whole-cell patch clamp technique. Results Sevoflurane equivalent to 1.4% and 2.8% depressed guinea pig myocardial contractions to approximately 85 and approximately 65% of control, respectively, although the maximum rate of force development at 2 or 3 Hz and force in rat myocardium after rest showed less depression. In the partially depolarized, beta-adrenergically stimulated myocardium, sevoflurane selectively depressed late peak force without changing early peak force, whereas it virtually abolished rapid cooling contractures. Sevoflurane did not alter the peak amplitude or maximum depolarization rate of normal and slow action potentials, but action potential duration was significantly prolonged. In isolated guinea pig myocytes at room temperature, 0.7 mM sevoflurane (equivalent to 3.4%) depressed peak Ca2+ current by approximately 25% and increased the apparent rate of inactivation. The delayed outward K+ current was markedly depressed, but the inwardly rectifying K+ current was only slightly affected by 0.35 mM sevoflurane. Conclusions These results suggest that the direct myocardial depressant effects of sevoflurane are similar to those previously described for isoflurane. The rapid initial release of Ca2+ from the sarcoplasmic reticulum is not markedly decreased, although certain release pathway, specifically those induced by rapid cooling, appear to be depressed. Contractile depression may be partly related to the depression of Ca2+ influx through the cardiac membrane. The major electrophysiologic effect of sevoflurane seems to be a depression of the delayed outward K+ current, which appears to underlie the increased action potential duration.

Age-Related Change in Peripheral Nerve Conduction: Compound Muscle Action Potential Duration and Dispersion

Gerontology ◽  
1999 ◽  
Vol 45 (3) ◽  
pp. 168-173 ◽  
Author(s):  
Katsumi Kurokawa ◽  
Yasuyo Mimori ◽  
Eiji Tanaka ◽  
Tatsuo Kohriyama ◽  
Shigenobu Nakamura
Keyword(s):  
Action Potential ◽  
Peripheral Nerve ◽  
Nerve Conduction ◽  
Action Potential Duration ◽  
Compound Muscle Action Potential ◽  
Muscle Action ◽  
Age Related ◽  
Muscle Action Potential
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