Mechanisms of the Inhibitory Action of Semotiadil Fumarate, a Novel Ca Antagonist, on the Voltage-Dependent Ca Current in Smooth Muscle Cells of the Rabbit Portal Vein

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Abstract
Effects of semotiadil on the voltage-dependent Ca current (ICa) were investigated in dispersed smooth muscle cells of the rabbit portal vein. At a holding potential of -100 mV, semotiadil (> or = 0.1 microM; dissolved in dimethylsulphoxide, DMSO) inhibited the ICa in a concentration-dependent manner (IC50 = 2.0 microM, Hill's coefficient = 1.0). At a holding potential of -80 mV or -60 mV, the concentration-inhibition curve observed in the presence of semotiadil was shifted to the left compared with that observed at -100 mV; and semotiadil shifted the voltage-dependent inactivation curve to the left. The curve for the decay of ICa was fitted with two time constants. Semotiadil (< 1 microM) reduced the slow but not the fast time constant. The curve for the recovery from ICa inactivation also consisted of two time constants, and semotiadil (1 microM) prolonged the slow recovery. Semotiadil dissolved in deionized water more potently inhibited ICa than semotiadil dissolved in DMSO. At pH 10.0, semotiadil did not modify the voltage-dependent inactivation curve. However, recovery from the inactivation was much faster at pH 10.0 than at pH 7.3. These results indicate that the voltage-dependent inhibition of ICa by semotiadil may be due to binding of the ionized drug during the inactivated state and also inhibition of the transition from the inactivated to the resting state. Long-lasting inhibition of ICa after removal of semotiadil may be due to tight binding of semotiadil on the channel through a hydrophobic site.

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