Evidence that α-Methylepinephrine is an Antihypertensive Metabolite of α-Methyldopa

Abstract

Several medullary cardiovascular relay nuclei contain high concentrations of epinephrine and phenylethanolamine-N-methyl transferase (PNMT), the enzyme which catalyzes the conversion of norepinephrine to epinephrine. Since α-methylnorepinephrine, a metabolite of α-methyldopa, has been shown to be a substrate for adrenal PNMT, we postulated that α-methylnorepinephrine would also be a substrate for central PNMT, resulting in the synthesis of α-methylepinephrine. Therefore, α-methylepineph-rine could be an active metabolite of α-methyldopa. We have investigated this hypothesis. 1) The centrally-active PNMT inhibitor SKF-64139 attenuated the hypotensive response to α-methyldopa in spontaneously hypertensive rats at doses that had little effect on the hypotensive response to clonidine. 2) In radioligand binding studies, α-methylepinephrine was as potent as norepinephrine in competing for α₂-receptors, more potent than epinephrine, norepinephrine, or α-methylnorepinephrine in competing for β-receptors, and less potent than epinephrine, norepinephrine, or α-methylnorepinephrine in competing for α₁-receptors. 3) Intracerebro-ventricular administration of methylepinephrine (1–40μg) to Sprague-Dawley rats elicited profound hypotension and bradycardia. α-Methyl-epinephrine was more potent than epinephrine in lowering blood pressure.