The cardiovascular effects of the antihypertensive drug debrisoquin: A contribution to the pharmacology of chronic treatment. II. Eight-week administration to dogs

Abstract

Debrisoquin was administered twice daily at the dose of 2.5 mg/kg p.o. to normotensive mongrel dogs for 8 weeks. Weekly measurements of systolic blood pressure in the conscious animals revealed a drug-induced fall by 10 to 12 mm Hg which was fully developed after 2 weeks and was maintained throughout the treatment period. Body weight, blood volume, hematocrit and plasma sodium and potassium did not change significantly under debrisoquin while there was a slight but just significant increase in plasma volume. No adverse effects were observed. Sixteen hours after the last dose, the animals were anesthetized with chloralose-urethane and subjected to several hemodynamic and biochemical measurements. The following results obtained after prolonged treatment with debrisoquin were not different from those after subacute administration (1-week treatment) reported in the preceding paper: decrease in blood pressure and cardiac output, reduction of the pressor response to bilateral carotid occlusion and of the vasoconstrictor effect of sympathetic nerve stimulation in the perfused hind legs and the isolated perfused mesenteric arteries, decrease in sympathetic tone to the vasculature of the hind leg and depletion of norepinephrine from adrenergic nerve endings. The sensitivity of arterial blood vessels to norepinephrine was not altered. However, the bradycardic effects of debrisoquin did fade in the course of the treatment. The results indicate the absence of the development of tolerance to nearly all cardiovascular effects of debrisoquin during a treatment of 8 weeks.