To slow ventricular rate during supraventricular tachycardia, a drug must have a strong rate-dependent depressant effect on atrioventricular (AV) conduction. We investigated the frequency-dependent effects of verapamil, amiodarone, digoxin, and diltiazem on AV conduction time (AVCT) in isolated guinea pig heart perfused by Langendorff method. Verapamil (0.01 microM), amiodarone (10 microM), digoxin (0.6 nM), and diltiazem (0.03 microM) caused comparable prolongation of AVCT and also a comparable reduction in sinus rate. To evaluate the time dependence of drug-induced alterations in AVCT, we abruptly increased the atrial pacing rate and shortened the pacing cycle length (CL) from 240 to 180 ms. The resulting time constant was longest in the presence of verapamil (tau = 194 +/- 45 beats, mean +/- SEM) and the shortest during perfusion with diltiazem (tau = 89 +/- 9 beats). The magnitude of AVCT prolongation after abrupt increase in pacing rate was significantly greater for digoxin as compared with all other drugs tested. The calculated beat-to-beat increase in AVCT evaluated by dividing the magnitude of AVCT prolongation by the time constant tau was greatest with diltiazem, which may explain the high efficacy of diltiazem in controlling ventricular rate during atrial fibrillation.