Changes in Brain α-Adrenergic Receptors After α-Methyldopa Administration to Spontaneously Hypertensive Rats

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 α-methylated catecholamines, and differences in α1, and α2-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, doserelated increases in concentration. These regional and strain differences in the metabolism of amethyldopa suggest that the production of methylnorepinephrine in brain stem nuclei is most correlated with the hypotensive action of methyldopa. α2 Agonist binding (p-amino-clonidine) declined in both hypothalamus and brain stem, and the fall was greater in hypertensive than in normotensive rats, α1,-Adrenergic receptor binding (prazosin) was increased, again more in hypertensive than in normotensive rats. The down regulation of α2-adrenergic receptors and the up regulation of α1,- adrenergic receptors are compatible with increased α2-adrenergic agonist presynaptic inhibition of catecholamine release with resultant postsynaptic α1,-adrenergic receptor supersensitivity. Spontaneously hypertensive rats showed greater methylnorepinephrine production, larger up regulation of α1,- adrenergic receptors, and greater down regulation of α2-adrenergic receptors than did the normotensive animals; these changes may be physiological markers for the greater antisympathetic action of methyldopa in hypertensive animals.