Quantification of rate-dependent effects of verapamil, diltiazem, and digoxin on atrioventricular conduction

• Published in: Journal of pharmacological and toxicological methods 1996-12, Vol.36 (4), p.205-210
• Main Authors: Schwarzl, I., Stark, U., Kasper, K., Decrinis, M., Lindner, W., Stark, G.
• Format: Article
• Language: English
• Subjects: Adaptation, Physiological; Animals; Atrioventricular Node - drug effects; Atrioventricular Node - physiology; AV-node; Calcium Channel Blockers - pharmacokinetics; Calcium Channel Blockers - pharmacology; Digoxin - pharmacokinetics; Digoxin - pharmacology; Diltiazem - pharmacokinetics; Diltiazem - pharmacology; Drug-specific binding; Female; Guinea Pigs; Heart Rate - drug effects; In Vitro Techniques; Kinetic; Male; Rate-dependence; Sinoatrial Node - drug effects; Sinoatrial Node - physiology; Time constant; Time Factors; Verapamil - pharmacokinetics; Verapamil - pharmacology
• ISSN: 1056-8719; 1873-488X
• DOI: 10.1016/S1056-8719(96)00127-X

The calcium channel blocking agents, verapamil and diltiazem, and the digitalis compound, digoxin, caused drug specific rate-dependent changes of the atrioventricular conduction time (AVCT). The purpose of this study was to investigate this rate adaptation of the AVCT in isolated guinea pig hearts perfused by the method of Langendorff to get an insight in drug-specific binding kinetic to the respective channel. In the presence of 10 nM verapamil, 30 nM diltiazem, or 0.6 nM digoxin, the atrioventricular conduction time was prolonged to a comparable degree during sinus rhythm. The drug-specific time constant, characterizing the rate-dependent adaptation of the AVCT, in the presence of a substance was comparable if evaluated after abruptly changing the heart rate from the pacing cycle length of 240 ms to 180 ms (τ-on) or from 180 to 240 ms (τ-off). The adaptation of the AVCT in the presence of verapamil (τ-on = 178 ± 45 beats, τ-off = 125 ± 33 beats, mean ± SEM) was more pronounced than in the presence of digoxin (τ-on = 144 ± 24 beats, τ-off = 98 ± 15 beats) or diltiazem (τ-on = 70 ± 11 beats, τ-off = 98 ± 15 beats). In conclusion, the differences in the rate adaptation of the AVCT may be explained by the drug-specific association and dissociation kinetic to the calcium channel, slow in the case of verapamil, and fast in the case of diltiazem, whereas this phenomenon in the presence of digoxin may be explained by its direct effects on passive membrane properties.