Abstract

Calcium antagonists have rate-dependent effects on atrioventricular node refractoriness in autonomically blocked dogs. Autonomic reflexes can attenuate diltiazem's actions and could alter their frequency-dependence. We evaluated the effects of four steady-state drug concentrations in each of seven dogs with intact autonomic tone, six with muscarinic blockade (atropine) and eight with combined muscarinic and beta adrenergic blockade. Diltiazem depressed atrioventricular nodal function less in autonomically intact dogs than in the other two groups. The concentration-response relationship for increases in Wenckebach cycle length (compared to intact dogs) was twice as steep among dogs with muscarinic blockade (P less than .001) and three times as steep with combined blockade (P less than .001). For an equal dose of diltiazem, the slope of drug-induced refractory period prolongation vs. pacing cycle length was similar (-0.20 +/- 0.11%/msec, mean +/- S.D.) in intact dogs compared to atropinized dogs (-0.21 +/- 0.10%/msec) and dogs with combined blockade (-0.24 +/- 0.14%/msec). Amplification of diltiazem's actions by the rapid atrial rate during atrial fibrillation was associated with increases in mean RR interval which were 8.3 times as large as changes in refractory period produced by the drug at slow heart rates. We conclude: 1) autonomic reflexes reduce diltiazem's effect for any given plasma concentration; 2) changes in vagal tone can play an important role in the autonomic response to diltiazem; and 3) despite altering the magnitude of diltiazem's effects, autonomic mechanisms do not prevent frequency-dependent drug action.(ABSTRACT TRUNCATED AT 250 WORDS)