Action of the 1,4-dihydropyridine derivative, KW-3049, on the smooth muscle membrane of the rabbit mesenteric artery

Abstract

1. The effect of 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridine-dicarboxylic acid methyl 1-(phenylmethyl)-3-piperidinyl ester hydrochloride (KW-3049) on the smooth muscle membrane of the rabbit mesenteric artery was investigated using microelectrode and single electrode voltage clamp methods. 2. In whole tissue preparations KW-3049 did not alter the resting membrane potential of the artery, but did inhibit the action potential evoked by a depolarizing current in the presence of 10 mM tetraethylammonium (TEA). 3. Using the voltage clamp technique, the effects of KW-3049 on the inward current evoked in solution containing 100 mM BaCl2 were observed. When the membrane was held at -60 mV, KW-3049 inhibited the inward current in a concentration-dependent manner. The inward current evoked by a larger depolarizing pulse was inhibited to a larger extent than that evoked by a smaller one. 4. When the membrane was held at -80 mV, the inward current evoked at test potentials of -10 and 0 mV was enhanced by low concentrations of KW-3049 (below 100 nM). 5. KW-3049 accelerated the rate of inactivation of the inward current and shifted the voltage-dependent inactivation curve to the left. 6. KW-3049 has a long-lasting inhibitory action on smooth muscle cells, since the inhibition of the inward current persisted for over 1 h after the removal of KW-3049. 7. Our results suggest that KW-3049 has a selective and long-lasting action on the Ca channels of the smooth muscle cell membrane of the rabbit mesenteric artery. This agent has both facilitatory and inhibitory actions on the Ca channel, depending on the values of the holding and command potentials.