title: Changes in brain alpha-adrenergic receptors after alpha-methyldopa administration to spontaneously hypertensive rats.
abstract: The hypotensive action of methyldopa has been linked to production of the metabolites methyldopamine and methylnorepinephrine in brain. We have studied the effect of long-term (72 hour) intravenous infusions of methyldopa to awake restrained spontaneously hypertensive rats and normotensive Wistar-Kyoto control animals to look for differences in hypotensive effect, differences in concentrations of natural and alpha-methylated catecholamines, and differences in alpha 1 and alpha 2-adrenergic receptor populations. Results described here indicate that hypertensive rats have a greater reduction in blood pressure and a larger increase in hypothalamic and brain stem methylnorepinephrine concentrations than do the normotensive animals. The methylnorepinephrine concentration reached a plateau value in hypothalamus in both strains while pons and medulla showed progressive, dose-related increases in concentration. These regional and strain differences in the metabolism of alpha-methyldopa suggest that the production of methylnorepinephrine in brain stem nuclei is most correlated with the hypotensive action of methyldopa. alpha 2 Agonist binding (p-amino-clonidine) declined in both hypothalamus and brain stem, and the fall was greater in hypertensive than in normotensive rats. alpha 1-Adrenergic receptor binding (prazosin) was increased, again more in hypertensive than in normotensive rats. The down regulation of alpha 2-adrenergic receptors and the up regulation of alpha 1-adrenergic receptors are compatible with increased alpha 2-adrenergic agonist presynaptic inhibition of catecholamine release with resultant postsynaptic alpha 1-adrenergic receptor supersensitivity. Spontaneously hypertensive rats showed greater methylnorepinephrine production, larger up regulation of alpha 1-adrenergic receptors, and greater down regulation of alpha 2-adrenergic receptors than did the normotensive animals; these changes may be physiological markers for the greater antisympathetic action of methyldopa in hypertensive animals.
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism*; D003846:Deoxyepinephrine / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D006973:Hypertension / Q000188:drug therapy* / Q000378:metabolism; D007031:Hypothalamus / Q000378:metabolism; D008297:Male; D008526:Medulla Oblongata / Q000378:metabolism; D008750:Methyldopa / Q000627:therapeutic use*; D008771:Nordefrin / Q000378:metabolism; D009638:Norepinephrine / Q000378:metabolism; D011149:Pons / Q000378:metabolism; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D011942:Receptors, Adrenergic, alpha / Q000378:metabolism*
chemical_list: D011942:Receptors, Adrenergic, alpha; D008750:Methyldopa; D003846:Deoxyepinephrine; D008771:Nordefrin; D004298:Dopamine; D009638:Norepinephrine