DIFFERENTIAL POTENTIATION BY DEPOLARIZATION OF THE EFFECTS OF CALCIUM-ANTAGONISTS ON CONTRACTION AND CA2-PIG HEART( CURRENT IN GUINEA)

1 The effects of elevation of extracellular K+ concentration ([K+](o)) on the negative inotropic potencies of three representative calcium a ntagonists, diltiazem, verapamil and nifedipine, were investigated in guinea-pig papillary muscle preparations. 2 The negative inotropic eff ect 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 memb rane 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 inotropi c effects, the blocking actions of the three calcium antagonists on th e L-type Ca2+ channel current (I-Ca(L)) were compared at the holding p otentials of - 80 mV and - 60 mV by the whole-cell patch-clamp techniq ue. 5 The use-dependent blocking effect of diltiazem on I-Ca(L) was en hanced 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 depolarizati on. 6 The differential effects of the [K+](o) elevation on the negativ e inotropic potencies of the three calcium antagonists are explained b y the differences in voltage-dependency of their use-dependent blockin g effects on I-Ca(L). 7 The properties of diltiazem and verapamil obse rved in this study may contribute to their protective effects on the i schaemic myocardium, without affecting the normal myocardium.