title: Depletion of brainstem epinephrine stores by alpha-methyldopa: possible relation to attenuated sympathetic outflow.
abstract: The antihypertensive effect of alpha-methyldopa (MD) is believed to be critically dependent on its ability to deplete endogenous catecholamines or cause the synthesis of false neurotransmitters. We used liquid chromatography with electrochemical detection (LCEC) and negative chemical ionization gas chromatography-mass spectrometry (GC-MS) for quantitation of catecholamines and MD metabolites in rat. MD intraperitoneally (100 mg/kg q12 hr X 12 days), significantly increased alpha-methylnorepinephrine (MNE) in brain (1.02 +/- 0.33 micrograms/g), heart (1.67 +/- 0.57 micrograms/g) and adrenal glands (114.93 +/- 50.47 micrograms/g) Endogenous norepinephrine (NE), epinephrine (E) and dopamine (DA) were reduced. ME levels were 2.19 +/- 0.44 micrograms/g (n = 6) in the adrenal gland but only 99 +/- 26 pg/g (n = 3) in the brainstem. MD-induced endogenous brainstem NE depletion was more than compensated by MNE production, but brainstem E depletion was not compensated for by a stoichiometric production of brainstem ME. We conclude (1) although ME is a metabolite of MD, it is present in extremely low concentrations in brainstem and (2) central epinephrine-containing neurons are depleted of neurotransmitter by MD therapy. If this selective epinephrine depletion occurs in the bulbospinal tract neurons responsible for maintaining sympathetic tone, then this effect could contribute to the antihypertensive effect of MD.
authors.affiliation: Department of Pharmacology, National Defense Medical Center, Taipei, Taiwan, Republic of China.
authors.forename: C S
authors.initials: CS
authors.lastname: Tung
authors.forename: M R
authors.initials: MR
authors.lastname: Goldberg
authors.forename: A S
authors.initials: AS
authors.lastname: Hollister
authors.forename: B J
authors.initials: BJ
authors.lastname: Sweetman
authors.forename: D
authors.initials: D
authors.lastname: Robertson
mesh_terms: D000311:Adrenal Glands / Q000378:metabolism; D000818:Animals; D001933:Brain Stem / Q000187:drug effects / Q000378:metabolism*; D002853:Chromatography, Liquid; D004298:Dopamine / Q000378:metabolism; D004837:Epinephrine / Q000031:analogs & derivatives / Q000378:metabolism*; D008401:Gas Chromatography-Mass Spectrometry; D008297:Male; D008750:Methyldopa / Q000494:pharmacology*; D009206:Myocardium / Q000378:metabolism; D008771:Nordefrin / Q000378:metabolism; D009638:Norepinephrine / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains
chemical_list: C029205:alpha-methylepinephrine; D008750:Methyldopa; D008771:Nordefrin; D004298:Dopamine; D009638:Norepinephrine; D004837:Epinephrine