Nicorandil reduces the basal level of cytosolic free calcium in single guinea pig ventricular myocytes.
Using fluorescent Ca2+ indicator fura-2 and whole-cell patch-clamp techniques, we examined the effect of 2-nicotinamidoethyl nitrate (nicorandil) on the intracellular free Ca2+ concentration ([Ca2+]i) and electrical properties in single guinea pig ventricular myocytes. Nicorandil (10 nM approximately 1 mM) reduced the resting level [Ca2+]i monitored as fura-2 fluorescence ratio in a concentration-dependent manner. Dibutyryl guanosine 3':5'-cyclic monophosphate (cyclic GMP), a membrane permeable cyclic GMP analogue, mimicked the nicorandil action. Neither application of caffeine (10 mM) nor deprivation of extracellular Na+ ions could prevent the nicorandil action on [Ca2+]i. In contrast, the nicorandil effect was virtually blocked by sodium orthovanadate (40 microM), a Ca2+ pumping ATPase inhibitor. During electrophysiological experiments, nicorandil shortened action potential durations (205 +/- 80 ms to 153 +/- 76 ms) by increasing a glibenclamide-sensitive outward K+ conductance. However, the drug produced little hyperpolarization (approximately 2 mV) because the resting potential of ventricular myocytes was close to the K+ equilibrium potential. The involvement of voltage-dependent Ca-channel current and Na-Ca exchanger was considered to be minimal under physiological conditions. It is thus concluded that nicorandil decreases basal [Ca2+]i via cyclic GMP-mediated activation of the plasma membrane Ca2+ pump in guinea pig ventricular myocytes.
Horie
M
M
Department of Molecular Diagnostics, Kyoto University, Faculty of Medicine, Japan.
Suzuki
H
H
Hayashi
S
S
Zang
W J
WJ
Komori
M
M
Okada
Y
Y
Fujita
J
J
Kawai
C
C
D000818:Animals; D001481:Basal Metabolism / Q000187:drug effects*; D002118:Calcium / Q000378:metabolism*; D000252:Calcium-Transporting ATPases / Q000502:physiology; D006152:Cyclic GMP / Q000502:physiology; D003600:Cytosol / Q000378:metabolism*; D005260:Female; D016257:Fura-2; D006168:Guinea Pigs; D006352:Heart Ventricles / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D066298:In Vitro Techniques; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D020108:Nicorandil; D012508:Sarcolemma / Q000502:physiology; D014665:Vasodilator Agents / Q000494:pharmacology*
D014665:Vasodilator Agents; D009536:Niacinamide; D020108:Nicorandil; D000252:Calcium-Transporting ATPases; D006152:Cyclic GMP; D002118:Calcium; D016257:Fura-2