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We studied the effects of bepridil, a new antianginal agent, on the ambulatory electrocardiogram in seven human volunteers. The drug was administered in three sequential periods of 12 days separated by 24 days without treatment. Heart rate was not significantly altered at 200 mg/day, but fell from day 3 at 300 mg/day and from day 1 at 600 mg/day. Average fall in heart rate was approximately 8% at 300 mg/day and 11% at 600 mg/day (day 7). At 200 mg/day the peak plasma level was reached after 11 days of treatment (0.28 +/- 0.4 microgram/ml). At 300 mg/day, a plateau was reached on day 7 (0.44 +/- 0.04 micrograms/ml) and at 600 mg/day from day 8 (0.97 +/- 14 micrograms/ml). We found a highly significant relationship between blood concentration of bepridil and mean RR interval lengths over 24 h. The QTc interval was lengthened at all doses, but there was no significant correlation between plasma level and increase in QTc interval length.

We studied the effects of intravenous injections of three beta-adrenoceptor antagonists on cardiac automaticity in conscious dogs after sinoatrial node (SAN) excision. Injections were repeated for 60 days postoperatively. In controls, mean corrected sinoatrial node recovery time (CSNRT) was 535 +/- 24 ms. One milligram per kilogram of dl-propranolol did not modify heart rate but raised CSNRT (p less than 0.01). One-half milligram per kilogram of dl-pindolol raised heart rate (p less than 0.05) and reduced CSNRT (p less than 0.05). Ten milligrams per kilogram of dl-practolol were needed to significantly reduce heart rate and raise CSNRT (p less than 0.01). In dogs after SAN excision, 0.1 mg/kg and 0.5 mg/kg of dl-propranolol lowered heart rate on days 3, 30, 43, and 60. Corrected recovery time (CRT) at a cumulative dose of 0.5 mg/kg rose to 9015 +/- 1028 ms on day 3 and to 3064 +/- 810 ms on day 30 (p less than 0.001). dl-Pindolol stabilized the rhythm. With 0.1 mg/kg, heart rate and CRT were not modified significantly on days 9 and 46. dl-Practolol at cumulative doses of 1 and 5 mg/kg lowered heart rate significantly on days 7 and 46. On day 12, the same doses did not modify heart rate but raised CRT (p less than 0.05). This suggests that of the beta-adrenoceptor antagonists studied here pindolol may be preferable in treatment of certain supraventricular arrhythmias.

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.