Modification of the cardiovascular effects of L-dopa in anesthetized dogs by inhibitors of enzymes involved in catecholamine metabolism.

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 /3-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-a-hydrazino-a-methyldopa) prevented the tachycardia but not the hypotension. DL-tTweo-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. KEY WORDS heart rate angiotensin dopamine /3-oxidase inhibition blood pressure DL-<Jtreo-dihydroxyphenylserine norepinephrine MAO inhibition decarboxylase inhibition • Interest in the cardiovascular actions of L-dopa 1 has been renewed with the discovery that hypotension attributable to the drug has frequently attended its use in the treatment of Parkinsonism (1, 2). The hypotensive action may be due to L-dopa or a metabolite, since dopamine lowers blood pressure in guinea pigs (3) and in cats (4). Burn and Rand (4) suggested that the action might be due to competition of dopamine and norepinephrine at vascular receptor sites, resulting in a loss of tone because the weaker vasoconstrictor, dopamine, reduced their occupation by norepi-nephrine. More recently, other investigators (5, 6) have demonstrated that L-dopa causes impairment of peripheral sympathetic nerve function. An alternative hypothesis that hy-potension induced by L-dopa may rely on a central action has received support from experiments by Henning and Rubenson (7) in which L-dopa lowered blood pressure in rats, provided an opposing peripherally mediated vasoconstriction was suppressed. Osborne and Moe (8) concluded that L-dopa caused venous pooling in dogs by a central neural action because …