Angiotensin II-induced hypertension - Contribution of Ras GTPase/mitogen-activated protein kinase and cytochrome P450 metabolites

We reported that norepinephrine and angiotensin II (Ang II) activate the Ra s/mitogen-activated protein (MAP) kinase pathway primarily through the gene ration of cytochrome P450 (CYP450) metabolites. The purpose of the present study was to determine the contribution of Ras and CYP450 to Ang II-depende nt hypertension in rats. Infusion of Ang II (350 ng/min for 6 days) elevate d mean arterial blood pressure (MABP) (171+/-3 mm Hg for Ang LI versus 94+/ -5 for vehicle group, P<0.05). Ras is activated on farnesylation by farnesy l protein transferase (FPT). When Ang II was infused in combination with FP T inhibitor FPT III (232 ng/min) or BMS-191563 (578 ng/min), the developmen t of hypertension was attenuated (171+/-3 mm Hg for Ang II plus vehicle ver sus 134+/-5 mm Hg for Ang II plus FPT iii and 116+/-6 mm Hg for Ang II plus BMS-191563, P<0.05). Treatment with the MAP kinase kinase inhibitor PD-980 59 (5 mg SC) reduced MABP. The CYP450 inhibitor aminobenzotriazole (50 mg/k g) also diminished the development of Ang II-induced hypertension to 113+/- 8 min Hg. The activities of Ras, MAP kinase, and CYP450 measured in the kid ney were elevated in hypertensive animals. The infusion of FPT UI, BMS-1915 63, or aminobenzotriazole reduced the elevation in Ras and MAP kinase activ ity. Morphological studies of the kidney showed that FPT III treatment amel iorated the arterial injury, vascular lesions, fibrinoid necrosis, focal he morrhage, and hypertrophy of muscle walls observed in hypertensive animals. These data suggest that the activation of Ras and CYP450 contributes to th e development of Anp II-dependent hypertension and associated vascular path ology.