Sympathoinhibitory mechanism of moxonidine: role of the inducible nitric oxide synthase in the rostral ventrolateral medulla

Aims The central antihypertensive drug moxonidine towers blood pressure (BP) through stimulating an imidazotine receptor within the rostral. ventrolateral medulla (RVLM). Nitric oxide (NO) generated by the inducible NO synthase (iNOS) in the RVLM has been suggested to be involved in tonic sympathetic inhibition. The aim of this study was to determine the role of NO generated by iNOS in mediating moxonidine-induced cardiovascular inhibition in rats. Methods and results In anaesthetized rats, the cardiovascular response to local or systemic injection of moxonidine was observed after treatment with the selective iNOS inhibitor S-methylisothiourea (SMT) in the brain. Using immunohistochemical staining and western blot techniques, the protein expression of MOS in the RVLM was measured in the moxonidine-infused rats. Intracerebroventricular (ICV) injection of SMT (1-100 nmol) dose-dependently attenuated the moxonidine (20 nmol, ICV)-induced decrease in BP and heart rate. Prior injection of SMT (20 and 200 pmol) into the RVLM also dose-dependently prevented the decrease in BP and renal sympathetic nerve activity evoked by RVLM microinjection of moxonidine (5 nmol) or intravenous injection of moxonidine (50 mu g/kg). We further found that expression of MOS protein following chronic ICV infusion of moxonidine (20 nmol, 2 weeks) is selectively upregulated in the RVLM but not in the nucleus tractus solitarius. Conclusion The present data suggest that an NO mechanism generated by MOS in the RVLM plays an important rote in mediating the sympathetic inhibition of the centrally acting drug moxonidine.