Differential potentiation by depolarization of the effects of calcium antagonists on contraction and Ca2+ current in guinea-pig heart.

1. The effects of elevation of extracellular K+ concentration ([K+]o) on the negative inotropic potencies of three representative calcium antagonists, diltiazem, verapamil and nifedipine, were investigated in guinea-pig papillary muscle preparations. 2. The negative inotropic effect of diltiazem was potentiated 110 fold when [K+]o was raised from 2.7 mM to 12.7 mM. The effect of verapamil was also potentiated to a lesser extent, but that of nifedipine was not affected. 3. Resting membrane potentials in ventricular muscles were about -80 mV and -60 mV in 2.7 mM K+ and 12.7 mM K+, respectively. 4. To clarify the mechanism responsible for the differential potentiation of the negative inotropic effects, the blocking actions of the three calcium antagonists on the L-type Ca2+ channel current (ICa(L)) were compared at the holding potentials of -80 mV and -60 mV by the whole-cell patch-clamp technique. 5. The use-dependent blocking effect of diltiazem on ICa(L) was enhanced markedly by the change in the holding potential from -80 mV to -60 mV. The effect of verapamil was also enhanced to a lesser extent but that of nifedipine was not affected in this range of depolarization. 6. The differential effects of the [K+]o elevation on the negative inotropic potencies of the three calcium antagonists are explained by the differences in voltage-dependency of their use-dependent blocking effects on ICa(L). 7. The properties of diltiazem and verapamil observed in this study may contribute to their protective effects on the ischaemic myocardium, without affecting the normal myocardium.