Our previous studies demonstrated that high dietary NaCl intake causes increases in blood pressure and plasma norepinephrine (NE) levels and a decrease in NE release associated with local upregulation of α2-adrenoceptor number in the anterior hypothalamic area (AHA) of NaCl-sensitive spontaneously hypertensive rats (SHR-S). Further, acute microinjection of clonidine into the AHA of SHR-S fed a high NaCl diet resulted in greater depressor and bradycardic responses than in SHR-S receiving a normal NaCl diet. The current study tested the hypothesis that the antihypertensive effect of chronic systemic administration of guanabenz (0.24 μg/kg/min, IV) is enhanced in SHR-S maintained on a high (8%) NaCl diet than in control rats on a normal (1% NaCl) diet. After two weeks on the diets, mean arterial pressure (MAP) and heart rate (HR) were measured and blood for NE and epinephrine (E) assay was collected from intra-arterial cannulas in conscious, unrestrained rats. The ratio of left ventricle and septum to body weight (LV + S/BW) was determined. Chronic infusion of guanabenz significantly decreased MAP (P < .05), HR (P < .01) and LV + S/BW (P < .01) in 8% NaCl fed SHR-S, but not in 1% NaCl fed SHR-S (P > .1). Guanabenz tended to reduce plasma NE levels in 8% NaCl fed SHR-S (.1 > P > .05), but not in 1% NaCl fed rats (P > .1). Our results demonstrate that the high NaCl diet induces enhanced antihypertensive and bradycardic responses to chronic systemic administration of guanabenz in SHR-S, confirming the functional significance of NaCl induced upregulation of α2-adrenoceptors in this model.