Contribution of Ras GTPase/MAP kinase and cytochrome P450 metabolites to deoxycorticosterone-salt-induced hypertension

We recently reported that norepinephrine and angiotensin II activate the Ra s/mitogen-activated protein (MAP) kinase pathway through generation of a cy tochrome P450 (CYP450) and lipoxygenase metabolites. The purpose of this st udy was to determine the contribution of Ras/MAP kinase to deoxycorticoster one acetate (DOCA)-salt-induced hypertension in rats. Administration of DOC A and 1% saline drinking water to uninephrectomized rats for 6 weeks signif icantly elevated mean arterial blood pressure (MABP) (166+/-5 mmHg, n=19) c ompared with that of normotensive controls (95+/-5 mm Hg, n=7) (P<0.05). Th e activity of Pas and MAP kinase measured in the heart was increased in DOC A-salt hypertensive rats. Infusion of the Pas farnesyl transferase inhibito rs FPT III (138 ng/min) and BMS-191563 (694 ng/min) significantly (P<0.05) attenuated MABP to 139+/-4 mm Hg (n=14) and 126+/-1 mm Hg (n=4), respective ly. Moreover, infusion of MAP kinase kinase inhibitor PD-98059 (694 ng/min) also reduced MABP in hypertensive rats. Morphological studies of the kidne y showed that treatment of rats with FPT III, which reduced Pas activity, m inimized the hyperplastic occlusive arteriosclerosis and fibrinoid vasculit is observed in untreated hypertensive rats. In addition, the rise in CYP450 activity and MABP in hypertensive rats was prevented by the CYP450 inhibit or aminobenzotriazole (50 mg/kg) and was associated with a decrease in Pas and MAP kinase activity in the heart. These data suggest that the Pas/MAP k inase pathway contributes to DOCA-salt-induced hypertension and associated vascular pathology consequent to activation of CYP450.