Frequency-dependent effects of calcium antagonists on atrioventricular conduction and refractoriness: demonstration and characterization in anesthetized dogs.

Abstract

Calcium-channel blockers are known to affect slow inward current in a frequency-dependent fashion. The purpose of these experiments was to study use-dependent effects of verapamil, diltiazem, and nifedipine on atrioventricular conduction in vivo. Loading and maintenance infusion techniques were developed to study each drug at a series of stable plasma concentrations in autonomically blocked dogs anesthetized with morphine and alpha-chloralose. All three agents produced changes in atrioventricular conduction and refractoriness that increased with increasing stimulation frequency. The time dependence of drug-induced changes in atrioventricular conduction was characterized both by varying the coupling of single test stimuli and by abruptly changing activation frequency. The time constants for onset of (tau on) and recovery from (tau off) block were typical for each drug, with nifedipine having a faster time constant (tau off = 0.36 +/- 0.12 sec) than verapamil (tau off = 3.2 +/- 1.0 sec, tau on = 28 +/- 8 sec) or diltiazem (tau off = 2.7 +/- 1.2 sec, tau on = 13 +/- 4 sec). The time constants for each drug were independent of concentration but the magnitude of time-dependent change increased with increasing drug concentration. We conclude that calcium-channel blockers have important frequency-dependent effects on atrioventricular conduction in vivo. This frequency dependence may result in selective depression of atrioventricular conduction in the presence of supraventricular tachyarrhythmias, with important potential implications for the clinical use of these agents.