Norepinephrine (

Abstract-We reported that norepinephrine and angiotensin II (Ang II) activate the Ras/mitogen-activated protein (MAP) kinase pathway primarily through the generation of cytochrome P450 (CYP450) metabolites. The purpose of the present study was to determine the contribution of Ras and CYP450 to Ang II-dependent hypertension in rats. Infusion of Ang II (350 ng/min for 6 days) elevated mean arterial blood pressure (MABP) (171Ϯ3 mm Hg for Ang II versus 94Ϯ5 for vehicle group, PϽ0.05). Ras is activated on farnesylation by farnesyl protein transferase (FPT). When Ang II was infused in combination with FPT inhibitor FPT III (232 ng/min) or BMS-191563 (578 ng/min), the development of hypertension was attenuated (171Ϯ3 mm Hg for Ang II plus vehicle versus 134Ϯ5 mm Hg for Ang II plus FPT III and 116Ϯ6 mm Hg for Ang II plus BMS-191563, PϽ0.05). Treatment with the MAP kinase kinase inhibitor PD-98059 (5 mg SC) reduced MABP. The CYP450 inhibitor aminobenzotriazole (50 mg/kg) also diminished the development of Ang II-induced hypertension to 113Ϯ8 mm Hg. The activities of Ras, MAP kinase, and CYP450 measured in the kidney were elevated in hypertensive animals. The infusion of FPT III, BMS-191563, or aminobenzotriazole reduced the elevation in Ras and MAP kinase activity. Morphological studies of the kidney showed that FPT III treatment ameliorated the arterial injury, vascular lesions, fibrinoid necrosis, focal hemorrhage, and hypertrophy of muscle walls observed in hypertensive animals. These data suggest that the activation of Ras and CYP450 contributes to the development of Ang II-dependent hypertension and associated vascular pathology. (Hypertension. 2000;36:604-609.)Key Words: angiotensin II Ⅲ Ras Ⅲ kinases Ⅲ hypertension, experimental Ⅲ cytochrome P450 Ⅲ kidney A ngiotensin II (Ang II), the major biologically active component of the renin-angiotensin system, contributes to the regulation of vascular tone, salt and water balance, and blood pressure. 1,2 It promotes vascular smooth muscle cell (VSMC) migration, hypertrophy, and delayed hyperplasia. [3][4][5] Ang II also stimulates NADPH oxidase, p 21 Ras, and phospholipase (PL)A 2 , PLC, and PLD. 6 -9 The activation of PLA 2 and PLD by Ang II leads to the release of arachidonic acid, 9 -11 which is metabolized by cyclooxygenase to prostaglandins and thromboxane A 2 and by lipoxygenase to hydroperoxyeicosatetraenoic acid (HPETE) and hydroxyeicosatetraenoic acid (HETE). The cyclooxygenase products prostaglandin (PG)E 2 and PGI 2 attenuate the vascular and renal actions of Ang II and contribute to the antihypertensive mechanisms. 12 On the other hand, the cyclooxygenase product thromboxane A 2 and the lipoxygenase product 12-HPETE, which inhibits PGI 2 synthase and thereby promotes the vasoconstrictor effect of endoperoxide PGH 2 , contribute to the prohypertensive mechanisms. 13 The level of blood pressure appears to be determined by the balance between the antihypertensive and prohypertensive eicosanoids. 13 Recently, it was reported that Ang II also promotes the metabol...

Abstract-Norepmephrme (NE) stimulates release of arachldomc acid (AA) f rom tissue lipids m blood vessels, which 1s metabolized via cyclooxygenase, hpoxygenase (LO), and cytochrome P-450 (CYP-450) pathways to blologcally active products Moreover, NE and AA have been shown to stimulate prohferatlon of vascular smooth muscle cells (VSMCs) of rat aorta The purpose of this study was to determme the possible contrlbutlon of AA and Its metabohtes to NE-Induced mltogenesls m VSMCs of rat aorta and the underlying mechanism of their actions NE (0 1 to 10 pmol/L) increased DNA synthesis as measured by [3H] Actlvatlon of a-aderenerglc receptors with NE has also been reported to stimulate AA release m a Ca2+/calmodulm-dependent manner via actlvatlon of cPLA, U" Recently, we have shown that NE stimulates cPLA, and AA release by activating Cazf/calmoduhn-dependent kmase II " AA and the products of its metabolism have been shown to stimulate growth m many cell types including VSMCs '8-z2 Moreover AA and LO metabohtes stimulate MAP kmase activity 22 These observatlons and the recent finding that NE-induced hyperplasla IS dependent on MAP kmase actlvatlon""' have led us to hypothesize that NE-induced VSMC prohferatlon 1s mediated by AA and/or Its metabohtes via MEK actlvatlon To test this hypothesis, we have mvestlgated the effect of NE and AA on rat aortlc smooth muscle cell prohferatlon, measured by

Abstract-We have reported that norepinephrine (NE) and angiotensin II (Ang II) increase CaM kinase II activity, which, in turn, activates cytosolic phospholipase A 2 (PLA 2 ) and releases arachidonic acid. The products of arachidonic acid generated via cytochrome P-450 and lipoxygenase contribute to the development of hypertension and vascular smooth muscle cell (VSMC) hyperplasia. Arachidonic acid is metabolized by cyclooxygenase, lipoxygenase and cytochrome P-450 monooxygenase into various products with marked cardiovascular actions. 12 A cytochrome P-450 metabolite 20-hydroxyeicosatetraenoic acid (20-HETE) constricts blood vessels, promotes proliferation of VSMC and has been shown to contribute to the regulation of myogenic tone and development of high blood pressure in some models of hypertension. [13][14][15][16] These observations and the evidence that CaM kinase II regulates smooth muscle contraction 5,6 raises the possibility that CaM kinase II might play a key role in the regulation of cardiovascular function and alterations in its activity may lead to vascular disease. To test this hypothesis, we have studied the effect of CaM kinase II inhibition on rabbit VSMC proliferation caused by NE and

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