This Program Project Grant proposal aims at studying the regulation and functions of cytochrome P450-derived eicosanoids in relation to vascular and renal mechanisms of blood pressure control in normotensive and hypertensive animal models. The proposal focuses on 20- hydroxyeicosatetraenoic acid (20-HETE) which arises from arachidonic acid via metabolism by cytochrome P450 4A isoforms. The experimental strategies combine molecular, cellular, isolated organ and whole animal approaches. The proposed research activities are organized into four projects supported by three cores. Dr. Schwartzman's Project will characterize recombinant cytochrome P450 4A isoforms that manufacture 20-HETE and use multiple approaches (viz., isoform-specific inhibitors, antisense oligonucleotides plasmid DNA, and viral-mediated gene transfer) to define the functional consequences of altering 20-HETE synthesis on vascular reactivity and blood pressure. Dr. McGiff's Project will characterize the regulatory influence of angiotensin II, TNFalpha, nitric oxide (NO) and adrenal steroids on renal 20-HETE synthesis and cyclooxygenase-catalyzed 20-HETE metabolism, identify the cyclooxygenase products of 20-HETE metabolism, assess the relative contribution of 20-HETE synthesis and metabolism to the regulation of 20-HETE cellular levels and rates of release, and evaluate the role of 20- HETE and/or its metabolic products in the implementation of renal functional responses to cyclooxygenase inhibition. D. Nasgleti's Project 3 will examine the influence the influence of the vascular heme-heme- oxygenase carbon monoxide (CO) system on vascular production of 20- HETE and define the functional significance of CO-20-HETE interactions in relation to the regulation of vascular reactivity and blood pressure. Dr. Wang's Project will characterize interactions among 20-HETE, functions of the thick ascending limb of Henle. Core A serves the administrative needs of the program. Core B utilizes mass spectrometry to identify novel eicosanoids and determine levels of cytochrome P450 eicosanoids and CO. Core C provides gene transfer vectores to modify the expression of heme oxygenase(s), cytochrome P450 4A isoforms and cyclooxygenase.
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