Potentiation of cardiodepressive action among calcium antagonists from different classes: evidence for a mechanism at the single calcium channel level

Abstract

The ability of calcium antagonists and antiarrhythmic agents to potentiate the negative inotropic effects of calcium antagonists was investigated in guinea-pig left atria. The potency of nitrendipine was enhanced by several amphiphilic agents by one order of magnitude or more (by pretreatment with quinidine or bepridil). The effect of preincubation with bepridil was investigated for a larger number of dihydropyridines. Only some of them were potentiated like nitrendipine. There was no potentiation between any two members of the same chemical group, i.e. between two dihydropyridines or two catamphiphilic calcium antagonists. The interaction between bepridil and nitrendipine was studied in more detail. In atria, its extent was influenced by several conditions, such as the stimulus frequency, the incubation temperature, or the extracellular K+ concentration. In measurements of whole-cell calcium currents in guinea-pig myocytes, the interaction was found to take place in a quantitatively similar manner. At the single channel level, an enhancement of the effects could also be demonstrated. It appears here that both drugs interact by binding to the same channel molecule. We conclude that the interaction may be due to 1.: an amphiphilic drug (like bepridil) binding to the channel very transiently and thus briefly favouring the inactivated channel state, which means that 2.: the other drug (like nitrendipine) has a higher chance to be bound because of its high affinity towards inactivated channels. Alternative explanations are also discussed.