EFFECT OF METHYLDOPA AND RELATED AGENTS ON PRESSOR RESPONSES TO TYRAMINE IN RESERPINE-PRETREATED RATS AND DOGS

¹ Merck Institute for Therapeutic Research, West Point, Pennsylvania

The relative effectiveness of the acute administration of norepinephrine, dopamine and dopa and their -methyl counterparts in restoring pressor responses to tyramine was evaluated in reserpine-treated rats and dogs. The restoring ability of dihydroxyphenylserine, metaraminol and harmine was also examined. In the rat, -methylnorepinephrine, -methyldopamine and methyldopa were more effective in restoring tyramine's pressor activity than their respective natural catechol derivatives. This was found in terms of duration, in dose required to demonstrate restoration and in the degree of restoration achieved. The degree of restoration achieved with harmine, dihydroxyphenylserine and metaraminol also exceeded that obtained with the natural catechol derivatives. Some species differences were encountered, in that the natural catechol derivatives, except dopamine, were relatively more effective in the dog than in the rat. Whereas -methylnorepinephrine was effective in producing restoration in the dog, -methyldopamine and methyldopa were relatively ineffective in the dog as compared to the rat. In addition, the degree of restoration in the rat appeared to be related to the dose of reserpine employed. The use of increasing doses of reserpine from 0.3 to 5.0 mg/kg resulted in a decrease in the restoring activity of norepinephrine, while at the same time the effectiveness of the -methyl derivatives increased. All reserpine doses tested produced maximal depletion (>90%) of atrial norepinephrine. The ability of the compounds studied to restore pressor responses to tyramine in reserpinetreated aninmals appeared to be unrelated to inherent sympathomimetic or catecholamine-depleting activities of the respective agents. However, restoration may depend not only of uptake and binding of exogenously administered compounds, but also on the conversion of precursors to active metabolites. This latter phenomenon was illustrated by the relative inactivity of methyldopa in restoring responses to tyramine in the dog. That protection of newly synthesized norepinephrine may also be important was suggested from the observation that a monoamine oxidase inhibitor, harmine, was also able to restore responses to tyramine in the reserpine-treated rat.