Evidence that alpha-methylepinephrine is an antihypertensive metabolite of alpha-methyldopa.
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 alpha-methylnorepinephrine, a metabolite of alpha-methyldopa, has been shown to be a substrate for adrenal PNMT, we postulated that alpha-methylnorepinephrine would also be a substrate for central PNMT, resulting in the synthesis of alpha-methylepinephrine. Therefore, alpha-methylepinephrine could be an active metabolite of alpha-methyldopa. We have investigated this hypothesis. 1) The centrally-active PNMT inhibitor SKF-64139 attenuated the hypotensive response to alpha-methyldopa in spontaneously hypertensive rats at doses that had little effect on the hypotensive response to clonidine. 2) In radioligand binding studies, alpha-methylepinephrine was as potent as norepinephrine in competing for alpha 2-receptors, more potent than epinephrine, norepinephrine, or alpha-methylnorepinephrine in competing for beta-receptors, and less potent than epinephrine, norepinephrine, or alpha-methylnorepinephrine in competing for alpha 1-receptors. 3) Intracerebroventricular administration of methylepinephrine (1-40 micrograms) to Sprague-Dawley rats elicited profound hypotension and bradycardia. alpha-Methylepinephrine was more potent than epinephrine in lowering blood pressure. We conclude that alpha-methylepinephrine is a centrally active depressor agent and could therefore be an active metabolite of alpha-methyldopa.
D000818:Animals; D001711:Biotransformation; D001794:Blood Pressure / Q000187:drug effects; D003000:Clonidine / Q000494:pharmacology; D004837:Epinephrine / Q000031:analogs & derivatives* / Q000494:pharmacology; D006339:Heart Rate / Q000187:drug effects; D006973:Hypertension / Q000188:drug therapy*; D007546:Isoquinolines / Q000494:pharmacology*; D008297:Male; D008750:Methyldopa / Q000378:metabolism* / Q000494:pharmacology; D010625:Phenylethanolamine N-Methyltransferase / Q000037:antagonists & inhibitors*; D051381:Rats; D044005:Tetrahydroisoquinolines
D007546:Isoquinolines; D044005:Tetrahydroisoquinolines; C029205:alpha-methylepinephrine; D008750:Methyldopa; C012153:7,8-dichloro-1,2,3,4-tetrahydroisoquinoline; D010625:Phenylethanolamine N-Methyltransferase; D003000:Clonidine; D004837:Epinephrine