Nicorandil Reduces the Basal Level of Cytosolic Free Calcium in Single Guinea Pig Ventricular Myocytes

抄録

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 nM1 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 membranepermeable 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 μM), 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 (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.