Multiple modulations of action potential duration by different calcium channel blocking agents in guinea pig ventricular myocytes.
Effects of extracellular applications of different types of Ca2+ channel blocking agents (Mn2+, verapamil, and nisoldipine) on action-potential duration and membrane currents were studied by the whole-cell patch-clamp technique in guinea pig ventricular myocytes. Low concentrations of Mn2+ (1 mM) and verapamil (1 microM) prolonged action-potential duration at 90% repolarization (APD90) with a suppressed plateau phase. Increases in Mn2+ (5 mM) and verapamil (5 microM) shortened APD90 with a further depression of the plateau. Nisoldipine (0.2-1 microM) shortened APD90 without lengthening it. Applications of Mn2+ and verapamil suppressed amplitudes of the L-type Ca2+ current (ICa), the delayed outward K+ current (IK), and the inward rectifier K+ current (IK1). Furthermore, the ratios of ICa:IK inhibition were similar by low and high concentrations of Mn2+ and verapamil. Nisoldipine selectively suppressed ICa without effect on IK and IK1. A low concentration (1 mM) of Mn2+ not only decreased the peak amplitude of ICa but also delayed its decay time course, which caused an increase in late ICa amplitude at the end of a 200-ms depolarizing pulse. Both verapamil and nisoldipine suppressed peak ICa without affecting its decay. Whereas Mn2+ suppressed IBa without changing its decay time course, verapamil and nisoldipine speeded up the IBa decay with suppressed amplitude of IBa. We conclude that different types of Ca2+ channel blocking agents (Mn2+, verapamil, and nisoldipine) diversely modulate APD because of their multiple modes of actions on ICa and IK.
Zhang
S
S
Department of Cardiovascular Diseases, Medical Research Institute, Tokyo Medical and Dental University, Japan.
Sawanobori
T
T
Hirano
Y
Y
Hiraoka
M
M
D000200:Action Potentials / Q000187:drug effects* / Q000502:physiology; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D006168:Guinea Pigs; D006352:Heart Ventricles / Q000166:cytology / Q000187:drug effects*; D008345:Manganese / Q000494:pharmacology; D015737:Nisoldipine / Q000494:pharmacology; D016276:Ventricular Function; D014700:Verapamil / Q000494:pharmacology
D002121:Calcium Channel Blockers; D008345:Manganese; D015737:Nisoldipine; D014700:Verapamil; D002118:Calcium