Involvement of postsynaptic α₂-adrenoceptors and guanine nucleotide-binding protein in guanabenz-induced cardiovascular suppressant effects in the rat

In adult, male Sprague-Dawley rats anesthetized with pentobarbital sodium, pretreatment with the catecholamine-depleting agent, reserpine (150 μg, i.c.v.) significantly antagonized the hypotensive and negative inotropic and chronotropic effects of guanabenz, either given intravenously (100 μg/kg) or microinjected bilaterally (5 μg) into the nucleus reticularis gigantocellularis (NRGC), a medullary site of action for this centrally acting antihypertensive agent. Pretreating animals with microinjection of the selective norepinephrine neurotoxin, DSP4 (50 μg), into the bilateral NRGC, on the other hand, did not appreciably blunt the cardiovascular suppressive actions of the aminoguanidine compound. I.c.v. administration of pertussis toxin (2.5 μg), which potentially blocks the action of two guanine nucleotide-binding proteins (G_i and G_o), significantly antagonized the circulatory inhibitory effects of guanabenz (100 μg/kg, i.v.). More specifically, this blocking effect was still apparent upon miroinjecting pertussis toxin (250 ng) into the bilateral NRGC. These data suggest that both pre- and postsynaptic α₂-adrenoceptors, and a pertussis toxin sensitive G-protein(s) (G_i and/or G_o), in the NRGC are crucial to the expression of the cardiovascular suppressant actions of guanabenz.