Calcium channel blockers depress atrioventricular (AV) nodal properties in vivo in a frequency-dependent manner, suggesting that selective drug action during supraventricular arrhythmias may result from use-dependent properties. The present study was designed to examine whether or not the rate-dependent actions of diltiazem account for its therapeutic effects during atrial fibrillation. The determinants of the ventricular response to atrial fibrillation (concealed AV nodal conduction and AV node functional refractory period, AVFRP) were evaluated at multiple cycle lengths (with extrastimulus techniques) and during electrically induced atrial fibrillation (with indirect indexes from RR interval histograms) in anesthetized dogs. In the presence of diltiazem, AVFRP increased progressively relative to control as rate accelerated. At cycle lengths comparable to sinus rhythm in humans, AVFRP increased 10%, 17%, and 32% after doses 1, 2, and 3 of diltiazem, respectively. Drug-induced increases in AVFRP were greater at basic cycle lengths just above the Wenckebach point (17%, 48%, and 81%) and were maximal during atrial fibrillation (39%, 86%, and 154% increases for doses 1, 2, and 3, respectively). Diltiazem also increased the AV conduction system effective refractory period, thereby increasing the potential zone of concealment into the AV node. Frequency-dependent increases in the zone of concealment were produced by diltiazem and were associated with marked increases in the standard deviation of RR interval histograms during atrial fibrillation (257%, 526%, and 923% increases after doses 1, 2, and 3, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)