Modification of the Cardiovascular Effects of L -Dopa in Anesthetized Dogs by Inhibitors of Enzymes Involved in Catecholamine Metabolism

Abstract

The influence of various enzyme inhibitors on the cardiovascular effects of L-dopa (methylester) has been studied to determine the sites of action of the drug or a responsible metabolite. L-Dopa, 10 mg/kg, iv, had minor early effects on heart rate and blood pressure in normal dogs, but in animals with inhibition of monoamine oxidase (MAO), it caused tachycardia and severe hypotension of gradual onset. When MAO was inhibited, earlier doses of a dopamine β-oxidase inhibitor (FLA 63) did not significantly modify the effects of L-dopa; prior administration of a decarboxylase inhibitor, NSD 1055 or Ro 4-4602, prevented all but the initial effects; selective extracerebral decarboxylase inhibition with MK 486 (L-α-hydrazino-α-methyldopa) prevented the tachycardia but not the hypotension. DL-threo-Dihydroxyphenylserine caused an initial rise in blood pressure in dogs with MAO inhibition, had less pressor activity when peripheral decarboxylase was also inhibited, and in both cases did not cause the hypotension characteristic of L-dopa. L-Dopa enhanced pressor responses and especially associated bradycardic responses to norepinephrine in dogs with MAO inhibition. This action was prevented by all decarboxylase inhibitors but not FLA 63. Responses to angiotensin were similarly augmented. Thus, MAO inhibition enabled L-dopa to induce severe hypotension, which appeared to rely on a central conversion to dopamine; the other effects were probably mediated by peripherally formed dopamine.