Membrane Potential and Dihydropyridine Block of Calcium Channels in the Heart: Influence of Drug Ionization on Blocking Activity

Abstract

The purpose of this contribution is to review the experiments that have contributed to our understanding of the mechanisms of action of nisoldipine and other dihydropyridine (DHP) calcium-channel antagonists in the heart. Electrophysiological experiments have shown that membrane potential modulates drug activity in a manner that is consistent with differential binding of this drug to voltage-determined states of the calcium channel (Bean 1984; Sanguinetti and Kass 1984). The predicted binding affinities from these electrical experiments agree well with data obtained from radioligand studies of partially depolarized cells (Kokubun et al. 1986; Janis and Triggle 1983). One theoretical framework in which these data have been interpreted is the modulated receptor hypothesis (Hille 1977 a, b; Hondeghem and Katzung 1977). Although this model was formulated to explain the interactions of local anesthetic molecules with receptors associated with sodium channels, this theory has been remarkably useful in understanding the mechanism of action of DHP compounds with regard to calcium-channel modulation. This is not, however, the only theory that has been proposed to explain these interactions (see Hess et al. 1984).