Cytochrome P450-4A (CYP450-4A) w-hydroxylase, which catalyzes the formation of 20-hydroxy- eicosatetraenoic acid (20-HETE) from arachidonic acid, may act as a vascular O2 sensor, with a crucial role n regulating vascular tone during both increases and decreases in O2 availability. Our studies indicate that enhanced activity of the CYP450-20-HETE system is a major candidate to elevate vascular resistance during the development of salt sensitive forms of hypertension by sensing O2 availability and mediating O2- dependent vasoconstriction in the peripheral circulation. This proposal represents a continuation of a successful line of studies investigating the role of 20-HETE and CYP450-4A w-hydroxylase in mediating altered responses to changes in O2 availability in the Dahl salt-sensitive (SS) rat. The overall hypothesis to be tested in this study is that the enhanced response of arterioles to elevated PO2 in Dahl SS hypertensive rats is due to one or a combination of three factors: increases in the production of 20-HETE, an increased sensitivity of the vessels to the vasoconstrictor effects of 20-HETE, and/or an altered expression of cytochrome P450-4A w-hydroxylase, the enzyme that catalyzes the synthesis of 20-HETE from arachidonic acid. To test this hypothesis, the proposed study has the following Specific Aims: 1) To utilize consomic and congenic rat models to evaluate the role of cytochrome P450 (CYP450) enzymes and 20-HETE in contributing to altered vascular O2 responses in SS rats on high salt (HS) diet;2) To determine whether HS diet changes the expression pattern of individual P450-4A w-hydroxylase isoforms and increases CYP- 4504A protein expression in arterioles and resistance arteries of SS rats;3): To determine whether 20-HETE production is elevated in arterioles and resistance arteries of SS rats on HS diet compared to normotensive SS rats on LS diet and rat strains lacking the SS CYP450-4A alleles;and 4) To determine whether HS diet increases 20-HETE sensitivity in arterioles of SS rats, and whether any salt-induced potentiation of arteriolar 20-HETE sensitivity is prevented by introgression of CYP450 genes from rat strains lacking the SS CYP450- 4A alleles. These studies should provide valuable insight into how vascular control mechanisms are altered during salt-sensitive hypertension in humans, particularly in members of the African-American population, who exhibit a form of salt sensitive hypertension that is strikingly similar to that occurring in the Dahl SS rat.
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