Recent studies have demonstrated that cerebral arteries from rats on high salt (HS) diet exhibit an impaired vasodilation and altered electrophysiological response to a reduction in PO₂. The present study examined whether an increase in salt intake alters the response of vascular smooth muscle cells (VSMC) to prostacyclin, a crucial mediator of hypoxic dilation in cerebral arteries. VSMC were isolated from cerebral arteries of male Sprague-Dawley rats maintained on a HS (4% NaCl) or low salt (LS) diet (0.4% NaCl) for 3 days. The stable prostacyclin analog iloprost (10 ng/ml) inhibited serotonin (0.1-10 µM) induced contractions and the increase in intracellular Ca²⁺ concentration ([Ca²⁺]_i) in VSMC isolated from arteries of animals fed a low salt diet. In contrast, iloprost had no effect on serotonin induced contractions and increases in [Ca²⁺]_i in VSMC isolated from arteries of rats fed a HS diet. Preventing the fall in angiotensin II (ANG II) in rats fed a HS diet by i.v. infusion of a low-dose of ANG II (5 ng x kg^-1 x min^-1 i.v) restored the inhibitory effect of iloprost on serotonin induced contractions and increases in [Ca²⁺]_i in VSMC from animals on the high salt diet. These effects were reversed by AT₁ receptor blockade with losartan. These results indicate that ANG II suppression secondary to elevated dietary salt intake impairs vascular relaxation and Ca²⁺ regulation by prostacyclin.