Nitric oxide discriminates the sites and mechanisms of action of centrally acting anti-hypertensive drugs in rabbits.

The aim of the present study was to further investigate the mechanisms of the central hypotensive action of catecholamines and imidazolines, in particular the role of nitric oxide (NO). Microinjections into the nucleus reticularis lateralis (NRL/RVLM) located in the rostroventrolateral part of the medulla (RVLM) and/or into the nucleus tractus solitarii (NTS) were performed in pentobarbital-anesthetized rabbits. Microinjections of brimonidine (1 ng/kg), which binds both alpha(2)-adrenergic receptors (alpha(2)-ARs) and I(1) imidazoline receptors (I(1)Rs), into the NRL/RVLM induced hypotension (69+/-2 vs. 88+/-2 mm Hg) (p<0.05). Microinjections of S23757 (1 microg/kg), an antagonist highly selective for I(1)Rs, into the same site, prevented the hypotensive effect of brimonidine. These data show that the hypotensive effects of low doses of brimonidine involve the I(1)Rs of the NRL/RVLM. Alpha-methylnoradrenaline (alpha-MNA) (0.5 microg/kg) microinjected into the NTS induced hypotension (76+/-4 vs. 91+/-4 mm Hg) (p<0.05). Microinjections of a low dose of brimonidine (1 ng/kg) into the NTS had no blood pressure (BP) effect at all. In contrast, a higher dose (10 ng/kg) acting on alpha(2)-ARs induced hypotension (72+/-3 vs. 96+/-2 mm Hg) (p<0.05). Nomega-Nitro-L-arginine (L-NNA) (1.5 microg/kg) injected into the NRL/RVLM prevented the hypotensive effect of both alpha-MNA and the higher dose of brimonidine injected into the NTS. Bicuculline (1.5 microg/kg) injected into the NRL/RVLM prevented the hypotensive effect of alpha-MNA injected into the NTS. It is demonstrated that (i) the activation of alpha(2)-ARs of NTS triggers a neuronal GABAergic pathway projecting to the NRL/RVLM region which is NO dependent (ii) both alpha(2)-adrenergic (NTS) and non-adrenergic I(1)R (NRL/RVLM) mechanisms account for the very powerful hypotensive effect of brimonidine, a compound with high affinities at both types of receptors.