Frequency‐ and Potential‐Dependency of the Negative Inotropic Action of Various Dihydropyridine and Non‐Dihydropyridine Calcium Antagonists

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Abstract
Transmembrane voltage and beat frequency are important determinants of the action of several organic calcium antagonists. This is well‐known for the cationic amphiphilic calcium antagonists. We intended to assess the functional impact of these phenomena in cardiac muscle with special regard to dihydropyridines. Therefore, concentration‐response curves were constructed in isolated guinea‐pig left atria for the negative inotropic effect of various compounds. The dihydropyridines nifedipine, racemic nitrendipine, nisoldipine, and felodipine, and the enantiomers of isradipine were investigated at different stimulation frequencies (1 Hz, 2.5 Hz, 4.5 Hz), and at different extracellular K+concentrations (2.7 mM, 5.4 mM, 10.8 mM). These drugs were compared with the cationic amphiphilic compounds gallopamil, verapamil and diltiazem. The potency of some dihydropyridines, particularly nitrendipine, could be modulated to a remarkable extent, covering several orders of magnitude. The potential‐dependency of the drugs depended on stimulus frequency and ranged from less than a half to two orders of magnitude. At 2.5 Hz, the rank order of extent of potential‐dependency was gallopamil > nitrendipine > diltiazem > verapamil = (+)‐isradipine > (‐)‐isradipine ≥ nisoldipine ≥ felodipine = nifedipine. Based on data obtained from binding studies in intact atria and from patch‐clamp measurements of calcium current blockade, a mathematical model was used which describes the observed potency changes. The model was based on the assumptions that 1) binding takes place at a site with a time‐varying affinity, and that 2) alteration of experimental condition (frequency, membrane potential) changes the proportion of time the calcium channels display the high‐affinity or the low‐affinity state.