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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