Reduced functional expression and molecular synthesis of inducible nitric oxide synthase in rostral ventrolateral medulla of spontaneously hypertensive rats

Background-We demonstrated recently that the prevalence of neuronal (nNOS) over inducible (iNOS) nitric oxide synthase activity at the rostral ventrol ateral medulla (RVLM), the medullary origin of sympathetic neurogenic vasom otor tone, and the associated dominance of sympathoexcitation over sympatho inhibition underlie the maintenance of sympathetic vasomotor outflow by the endogenous NO. Here, we evaluated the hypothesis that a significant dawnre gulation of iNOS at the RVLM may play a crucial role in the genesis of augm ented sympathetic vasomotor tone during hypertension. Methods and Results-Spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto (WKY) rats anesthetized with propofol were used. Compared with SHR, the hypotension, bradycardia, or depression in sympathetic vasomotor tone induced by bilateral microinjection of lipopolysaccharide (5 or 10 ng) into the RVLM of WKY rats exhibited significantly shorter-onset latency, a ppreciably steeper slope, and a greater incidence of mortality. All these e ffects of lipopolysaccharide (10 ng) were significantly blunted by coadmini stration of the selective iNOS inhibitor S-methylisothiourea (250 pmol). Re verse transcription-polymerase chain reaction and Western blot analyses fur ther revealed significantly lower iNOS mRNA and protein levels at the ventr olateral medulla in SHR under basal conditions or on activation by lipopoly saccharide (10 ng). Conversely, nNOS mRNA and protein levels remained const ant in the RVLM and were comparable in both strains of rats. Conclusions-We conclude that a significant downregulation in both functiona l expression and molecular synthesis of iNOS at the RVLM may underlie the a ugmented sympathetic vasomotor tone during hypertension.