Voltage- and use-dependent block of the inward calcium current by MCI-176, a new non-dihydropyridine calcium antagonist, in canine ventricular muscles and single ventricular cells of the guinea-pig.

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Effects of MCI-176, 2-(2, 5-dimethoxyphenylmethyl)-3-(2-dimethyl-aminoethyl)-6-isopropoxy-4(3H)-quinazolinone hydrochloride, on action potentials of canine ventricular muscles and on membrane currents of single ventricular cells of the guinea-pig heart were studied with the microelectrode and the patchclamp ("whole-cell recording") methods. In canine ventricular trabeculae, MCI-176 (10-5-10-4 M) decreased the plateau potential, the action potential duration at 30%-repolarization and the maximum rate of rise of the action potential; and it also decreased the amplitude and the duration of the slow response action potential in a concentration-dependent manner. Those effects were much more apparent at higher stimulus frequency. Under voltage clamp condition of single ventricular cells of the guinea-pig heart, MCI-176 (3×10-5 M) decreased the inward calcium current (ICa) by 25-30% when the membrane potential was held at the resting membrane potential, and the drug abolished it when the membrane potential was held at -30 mV. MCI-176 added at rest decreased ICa ("Initial block") and reduced it further with repetitive depolarizations in a beat-to-beat fashion. MCI-176 facilitated the reduction of ICa by increasing the clamp pulse frequency. These results indicate that MCI-176 decreases ICa of mammalian ventricular muscles in a voltage- and use-dependent manner.
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