Selective and long-lasting inhibitory actions of the dihydropyridine derivative, CV-4093, on calcium currents in smooth muscle cells of the rabbit pulmonary artery

Abstract

Effects of CV-4093, a newly synthesized dihydropiridine type of Ca antagonist, on membrane currents in enzymatically dispersed single smooth muscle cells of the rabbit main pulmonary artery were investigated using the single electrode voltage clamp method. Three types of membrane currents were evident, i.e., Ca and Na inward and K outward currents. CV-4093 potently inhibited the Ca inward current, as compared to findings with other currents. When the potential was at -60 mV, CV-4093 consistently inhibited the Ca current evoked by depolarization to 0 mV. However, a low concentration of CV-4093 (1-3 nM) enhanced the Ca current evoked by the depolarizing pulse of -20 mV, when the membrane potential was held at -80 mV. Inhibition of the Ca current induced by CV-4093 developed slowly and over 10 min was required to reach the maximum inhibition. Changes in the frequency of the depolarizing pulse did not modify the rate of inhibition induced by CV-4093. The inhibition was not restored by washout of the drug for over 40 min, and hyperpolarizations of the membrane did not accelerate the recovery. The IC50 of CV-4093 obtained for the K outward current was 3000 times larger than that obtained for the Ca inward current. CV-4093 apparently has highly selective and long-lasting inhibitory actions on the Ca current in smooth muscle cells of the rabbit main pulmonary artery.