Modification of the cardiovascular effects of l-dopa by decarboxylase inhibitors

Abstract

Intravenously infused L-dopa (0.3 mg/kg per min) produced hypertension and cardiac arrhythmias in halothane anesthetized dogs. Biochemical studies showed that the heart, kidney, and brain of these animals accumulated significant amounts of catecholamines formed from the administered precursor. Pretreatment of dogs with an extracerebral inhibitor of dopa decarboxylase [D,L-alpha-hydrazino-alpha-methyl-beta-(3.4-dihydroxyphenyl) propionic acid] prevented the development of hypertension and arrhythmias with infusion of L-dopa. Instead, these animals developed significant hypotension. The heart and kidney of these animals accumulated markedly reduced amounts of catecholamines formed from L-dopa compared with dogs receiving L-dopa alone: the amount of catecholamines accumulated in brain was unchanged. L-dopa, after extracerebral decarboxylase inhibition, appeared to produce hypotension by reducing peripheral vascular resistance without altering sympathetic nerve function. During hypotension, cardiac output was not altered and arterial pressure in perfused hindlimbs fell, even though flow was maintained. The pressor response to intravenous injections of norepinephrine and dopamine was unchanged. Hindlimb arterial pressure response to direct electrical stimulation of the lumbar sympathetic trunk was also unchanged. Pretreatment with a drug which inhibits brain as well as extracerebral dopa decarboxylase [D,L-seryl-2,3,4-trihydroxybenzylhydrazine hydrochloride] abolished all effects of L-dopa on blood pressure. In these animals, there was a marked reduction of catecholamine formation from L-dopa in the brain as well as the heart and kidney. It appears that L-dopa produces opposite effects on blood pressure depending on the site of accumulation of its metabolic products, dopamine and norepinephrine. If L-dopa is rapidly decarboxylated to catecholamines in peripheral organs, hypertension and cardiac arrhythmias occur. If peripheral dopa decarboxylase is selectively inhibited, a centrally mediated hypotensive effect, probably secondary to the accumulation of catecholamines in the brain, becomes apparent. If dopa decarboxylase is inhibited in the brain in addition to extracerebral organs, L-dopa has no effect on blood pressure.