The study has been designed to investigate the effect of 8-Br-cAMP, an activator of protein kinase A, in hypertension-induced vascular endothelial dysfunction. Rats were uninephroctomized and desoxycortisone acetate (DOCA) (40 mg/kg, s.c.) was administered to rats to produce hypertension (mean arterial blood pressure > 140 mmHg). Vascular endothelial dysfunction was assessed using isolated aortic ring preparation, electron microscopy of thoracic aorta and serum concentration of nitrite/nitrate. The expression of mRNA for p22phox and eNOS was assessed by using reverse transcriptase-polymerase chain reaction. Serum thiobarbituric acid reactive substances concentration and aortic superoxide anion concentration were estimated to assess oxidative stress. 8-Br-cAMP (5 mg/kg, i.p.) or atorvastatin (30 mg/kg, p.o.) prevented hypertension-induced attenuation of acetylcholine-induced endothelium-dependent relaxation, impairment of vascular endothelial lining, decrease in expression of mRNA for endothelial nitric oxide synthase (eNOS), serum nitrite/nitrate concentration and increase in expression of mRNA for p22phox, superoxide anion and serum TBARS. The ameliorative effect of 8-Br-cAMP was prevented by N-nitro-L-arginine methyl ester (25 mg/kg, i.p.) and glibenclamide (30 mg/kg, i.p.). It may be concluded that 8-Br-cAMP may stimulate expression and activity of eNOS and suppress expression of p22phox subunit of NADPH oxidase to reduce oxidative stress and subsequently improve vascular endothelial dysfunction.