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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL034300-12
Application #
5213531
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
12
Fiscal Year
1996
Total Cost
Indirect Cost
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