We have demonstrated that activity of central neuronal nitric oxide synthase (nNOS) containing neurons and its mediated sympathoinhibition are enhanced in hypertensive Dahl salt-sensitive (DSS) rats (Tandai-Hiruma et al, 2005). However, it is not clear what enhances nNOS activity in these neurons in this rat strain (high salt intake, increased blood pressure or something else) or how these neurons are enhanced in salt-induced hypertension. Are the increases in activity compensatory to buffer the hypertension even though hypertension is not relieved? The aims of the present study were to identify the mechanism underlying enhanced nNOS activity in the brain of hypertensive DSS rats and the consequences of enhanced nNOS activity. Male 8-week-old rats (Dahl/J Seac, n=5 for each group) were fed either a regular (0.4% NaCl) or high-salt (8% NaCl) diet with or without 0.25% nifedipine, for 4 weeks. The effects of nifedipine, which lowers blood pressure peripherally, on central nNOS were determined by measuring nNOS activity, as well as the number of nNOS-positive neurons in the brain stem and diencephalon. The effects of chronic (12 days) intracerebroventricular (i.c.v.) infusion of 7 μg (0.5 μL/h) S-methyl-L-thiocitrulline (SMTC, nNOS inhibitor) on mean arterial pressure (MAP) were assessed in conscious freely moving DSS rats using a radiotelemetry system. Rats were anaesthetized with pentobarbital (50 mg/kg, i.p.) and telemetry transmitters installed. Continuous recordings of arterial pressure were made for 20 days (6 days on a regular diet followed by 14 days on a high-salt diet) prior to, and 12 days during, osmotic minipump driven i.c.v. infusion of SMTC. In addition, the number of central nNOS-positive neurons was compared between DSS and salt-insensitive Sprague-Dawley rats (n=5 for each group). Values are means ± S.E.M., compared by ANOVA. Normalization of blood pressure by nifedipine attenuated the increase in nNOS activity in the brain stem of DSS rats. Chronic i.c.v. infusion of SMTC further enhanced hypertension in DSS rats. Differences in average MAP from Day12 to Day 26 were significantly greater (p<0.05) in SMTC-infused DSS rats compared with aCSF-infused DSS rats in both the day (31.9 ± 4.7 vs. 17.2 ± 2.1 mmHg) and night (26.1 ± 3.3 vs.12.2 ± 2.2 mmHg) phases (Figure 1). Feeding of a high-salt diet increased nNOS-positive neurons in the lateral parabrachial nucleus, rostral ventrolateral medulla, and nucleus tractus solitarius of DSS compared with Sprague-Dawley rats, whereas nNOS-positive neurons in the paraventricular nucleus remained downregulated in DSS rats. These results suggest that hypertension, rather than a high-salt diet, increases central nNOS activity in hypertensive DSS rats to buffer high blood pressure. However, this compensatory response may be insufficient to relieve salt-induced hypertension.