Reflex chronotropic and inotropic effects of calcium channel-blocking agents in conscious dogs: diltiazem, verapamil, and nifedipine compared

Abstract

In chronically instrumented, conscious dogs, rapid injection of equihypotensive doses of three calcium channel-blocking agents, verapamil (250 μg/kg), diltiazem (200 μg/kg) and nifedipine (50 μg/kg), produced disparate chronotropic and inotropic responses. Although they all decreased mean arterial pressure by about 10%, heart rate (93 ± 4 beats/min) was markedly increased to 175 ± 12 with nifedipine, to 163 ± 15 with verapamil, and only slightly increased to 118 ± 7 with diltiazem. Contractile responses measured before (left ventricular dP/dt(max), 2749 ± 131 mm Hg/sec) and during left ventricular ejection (endocardial dimension dD/dt(max), 57 ± 4 mm/sec) were increased by 24% and 14% with nifedipine, decreased by 26% and 22% with verapamil, and were unchanged with diltiazem. These chronotropic and ionotropic responses to rapid intravenous administration of the three drugs were increased in a dose-dependent manner. Similar results also were observed after slow infusion of these drugs. To determine the extent to which autonomic reflexes participated in these cardiac responses, propranolol (0.5 mg/kg) or propranolol plus atropine (0.1-0.2 mg/kg) was administered prior to injection of each calcium channel-blocking agent. Propranolol abolished the positive inotropic response to nifedipine and potentiated the negative inotropic response to verapamil. Positive chronotropic responses to verapamil, nifedipine, and diltiazem were attenuated by propranolol plus atropine. These results suggest that equihypotensive doses of three prominent channel-blocking agents exert different degrees of autonomic reflex activation in awake, unsedated dogs. These reflexes, which modulate the direct effects of calcium channel-blocking agents on chronotropic and inotropic variables of the heart, may have important clinical implications.