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The electrophysiologic effects of bepridil (10 mg/kg), verapamil (0.15 mg/kg) and diltiazem (0.6 mg/kg) were studied in the chronically instrumented conscious and pentobarbital-anesthetized dog. Sinus node automaticity assessed by the corrected sinus node recovery time and atrio-ventricular conduction assessed by the Wenckebach phenomenon were evaluated by atrial pacing via electrodes placed in the wall of the right atrium, and exteriorized in the neck region. Nineteen dogs were studied and groups of 6 dogs were used for each experimental session. The calcium channel blocking drugs were administered by slow i.v. infusion (15 min). Effects were measured over 45-60 min and compared with the pretreatment value. In conscious dogs, heart rate was initially markedly increased by bepridil and diltiazem and only slightly increased by verapamil. These chronotropic responses were reversed to bradycardia by diltiazem only. Corrected sinus node recovery time measured at the end of infusion was decreased by verapamil and diltiazem and was unchanged by bepridil. Lengthening of corrected sinus node recovery time was observed with verapamil at the end of the experiment. All 3 calcium channel blocking agents produced negative dromotropic responses. To determine to what extent electrophysiologic effects of pentobarbital were involved in the cardiac responses measured in the anesthetized dog, pentobarbital was administered prior to injection of each calcium channel blocking agent. Pentobarbital produced positive chronotropic and dromotropic effects which were attenuated by the 3 calcium channel blocking agents. The reduction of corrected sinus node recovery time induced by pentobarbital was diminished by bepridil and diltiazem and unchanged by verapamil. Pentobarbital anesthesia thus has important electrophysiologic implications on the effects of calcium channel blocking agents on chronotropic and dromotropic variables on the heart.

The electrophysiologic effects of diproteverine were studied in the conscious nonsedated chronically instrumented dog. Diproteverine at 0.25-0.75 mg/kg (i.e., at plasma levels within the assumed therapeutic range) dose-relatedly decreases heart rate, increases corrected sinus node recovery time, and decreases Wenckebach point. These effects are observed at plasma levels ranging between 16.2 +/- 4.1 and 144.7 +/- 12.5 ng/ml. After cholinergic blockade with N-methylscopolammonium, diproteverine lowers heart rate (greater than or equal to 0.25 mg/kg), increases corrected sinus node recovery time, and decreases Wenckebach point (greater than or equal to 0.5 mg/kg). After propranolol, diproteverine only significantly reduces corrected sinus node recovery time 5 min after the third administration (0.75 mg/kg). After pharmacologic autonomic blockade by N-methylscopolammonium propranolol combination, diproteverine lowers intrinsic heart rate (greater than or equal to 0.25 mg/kg) and Wenckebach point (greater than or equal to 0.5 mg/kg). Diproteverine does not modify mean blood pressure. These results show that diproteverine administered with and without pharmacologic autonomic blockade in the conscious dog causes dose-related depressant effects on sinus node function and atrioventricular conduction without producing significant vasodilatation.