EFFECT OF METHYLDOPA ON CHRONOTROPIC RESPONSES TO CARDIOACCELERATOR NERVE STIMULATION IN DOGS

¹ Division of Clinical Pharmacology, Departments of Pharmacology and Internal Medicine, University of Cincinnati, College of Medicine, Cincinnati, Ohio

Indirect evidence in man suggests that methyldopa impairs reflex sympathetic cardiovascular responses; however, diverse effects of this drug have been reported on the responses to direct sympathetic stimulation in animals. The effects of a single injection and chronic treatment with methyldopa on the frequency-response characteristics of the dog heart cardioaccelerator nerve preparation and on the chronotropic effects of exogenous norepinephrine and methyl-norepinephrine were systematically studied. Acute methyldopa, 100 mg/kg of base, clearly reduced chronotropic responses to cardioaccelerator nerve stimulation after 90 min at a time when the chronotropic effects of norepinephrine and methyl-norepinephrine were identical and similar in magnitude to those in control dogs. Chronic methyldopa, 100 mg/kg/day for 4 to 5 days, did not affect the chronotropic responses to direct sympathetic stimulation; however, the dose-chronotropic response curves of both methyl-norepinephrine and norepinephrine were shifted equally and significantly to the left. These observations viewed collectively suggest the possibility that a reduced amount of transmitter, natural or false, may be released after acute or chronic treatment with methyldopa. Subnormal release of transmitter may also be partially responsible for the hypotensive effect of methyldopa in man, and the supersensitivity to methyl-norepinephrine and norepinephrine after chronic treatment with methyldopa may explain the tolerance to the antihypertensive effect of methyldopa seen in man.