EICOSANOID MEDIATED PRESSOR MECHANIMS IN HYPERTENSION

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This is a proposal to study the mechanisms and impact on blood pressure regulation of relationships between eicosanoid-mediated pressor and vasodepressor functions in normotensive and hypertensive rats. Research is proposed in two related areas. AREA l: The Influence of Arachidonic Acid Metabolism by Vascular Lipoxygenase(s) on Prostanoid-Mediated Mechanisms of Blood Pressure Regulation - The hypothesis to be tested is that excessive formation of lipoxygenase products, presumably arachidonic acid hydroperoxides, by the arterial vessels of rats with angiotensin-dependent hypertension contributes to the elevation of blood pressure by fostering the expression of a vasoconstrictor mechanism mediated by PGH2 and by limiting the activity of a vasodilatory mechanism mediated by PGI2. Experiments will be conducted in rats with angiotensin-dependent hypertension (aortic coarctation-induced hypertension; angiotensin II-infusion-induced hypertension), in rats with angiotensin-independent hypertension (DOCA- salt-induced hypertension) and in the corresponding normotensive controls. In these experimental models we propose experimentation (a) to identify and quantify lipoxygenase activity in vascular tissues of normotensive and hypertensive rats; (b)to examine the relationship between lipoxygenase(s) product formation and PGI2 production by vascular tissues of normotensive and hypertensive rats; (c) to investigate the contribution of lipoxygenase(s) products to mechanisms of hypertension by determining the consequences of lipoxygenase(s) inhibition on blood pressure and relevant renal functions of hypertensive and normotensive rats; (d) to explore relationships between the hemodynamic response to lipoxygenase inhibition and the activity of vasodepressor systems mediated by PGI2; (e) to examine the relationship between lipoxygenase product formation and the expression of PGH2-mediated mechanism of vasoconstriction in small arterial vessels of normotensive and hypertensive rats. AREA 2: The Influence of Arachidonic Acid Metabolism by Cytochrome P450 Oxygenases on the Blood Pressure of Normotensive and Hypertensive Rats - The hypothesis to be tested is that 2O-HETE contributes to increase blood pressure and vascular reactivity in young SHR and in other models of hypertension in which 20-HETE synthesis is hyperexpressed. Experiments will be conducted in SHR, in rats made hypertensive by treatment with DOCA-salt or with dexamethasone, and in the corresponding normotensive controls. In these models we propose experimentation (a) to investigate the effect of treatment with an inhibitor of 20-HETE synthesis on systemic hemodynamics and relevant renal functions in normotensive rats, SHR and other forms of experimental hypertension; (b)to explore the role of 20- HETE in regulation of vascular responsiveness to constrictor hormones in normotensive and hypertensive rats.