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Quantification of rate-dependent effects of verapamil, diltiazem, and digoxin on atrioventricular conduction
I Schwarzl1, U Stark, K Kasper
1Department of Internal Medicine, Karl-Franzens-University, Graz, Austria.
Insights
Calcium channel blockers verapamil and diltiazem, and digoxin, alter atrioventricular conduction time (AVCT) differently. Their rate adaptation kinetics reveal distinct drug-specific binding properties to cardiac channels.
Area of Science:
- Pharmacology
- Cardiovascular Physiology
Background:
- Calcium channel blockers (verapamil, diltiazem) and digoxin affect cardiac conduction.
- Atrioventricular conduction time (AVCT) exhibits rate-dependent changes influenced by these drugs.
Purpose of the Study:
- To investigate the rate adaptation of AVCT in isolated guinea pig hearts.
- To understand drug-specific binding kinetics to ion channels.
Main Methods:
- Isolated guinea pig hearts perfused using the Langendorff method.
- Administration of verapamil, diltiazem, and digoxin at specific concentrations.
- Measurement of AVCT during stepwise heart rate changes (pacing).
Main Results:
- All tested drugs prolonged AVCT during sinus rhythm.
- Drug-specific time constants (tau-on, tau-off) characterized rate-dependent AVCT adaptation.
- Verapamil showed more pronounced AVCT adaptation than digoxin or diltiazem.
Conclusions:
- Differences in AVCT rate adaptation suggest distinct drug-channel binding kinetics.
- Verapamil exhibits slow association/dissociation kinetics; diltiazem shows fast kinetics.
- Digoxin's effect on AVCT adaptation may involve direct impacts on membrane properties.
Abstract:
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 (tau-on) or from 180 to 240 ms (tau-off). The adaptation of the AVCT in the presence of verapamil (tau-on = 178 +/- 45 beats, tau-off = 125 +/- 33 beats, mean +/- SEM) was more pronounced than in the presence of digoxin (tau-on = 144 +/- 24 beats, tau-off = 98 +/- 15 beats) or diltiazem (tau-on = 70 +/- 11 beats, tau-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 dilitiazem, whereas this phenomenon in the presence of digoxin may be explained by its direct effects on passive membrane properties.