This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Essential hypertension is a major risk factor for cardiovascular disease which is the leading cause of death in the United States. Over 50 million Americans are effected by essential hypertension but its mechanisms have yet to be defined. Vasoactive arachidonic acid metabolites of the cytochrome P450 (CYP) epoxygenase pathway, the epoxides, have been implicated in animal and human studies of hypertension. Hypertension is a common problem in patients with varying degrees of chronic renal failure. The epoxide 11, 12-epieicosatrienoic acid (11, 12-EET), the putative endothelium derived hyperpolarizing factor (EDHF) is formed by CYP2C9, CYP2C8, and converted to the corresponding DHET by the soluble epoxide hydrolase (sEH). CYP2C9, CYP2C8 and sEH exhibit a high prevalence of genetic polymorphisms which may lead to altered levels of epoxides and reduced formation of EDHF in hypertensive patients. The perturbed vasoactive epoxide profile produced by genetic polymorphisms in this pathway may play a major mechanistic role in a subgroup of patients with hypertension. If we detect a greater frequency of these mutant alleles in a hypertensive population then a genetic test could be developed to identify subgroups of patients at risk for the development of hypertension allowing early intervention. These results accompanied with altered levels of epoxides and brachial artery reactivity would also suggest that the epoxygenase pathway may be a novel therapeutic target for the development of drugs to treat hypertension. Investigations of altered brachial artery reactivity and eiconsanoid levels in normotensive subjects may demonstrate preclinical endothelial dysfunction produced by mutant epoxygenase genotypes. Further studies could be performed in patients with varying degrees of chronic renal failure to investigate whether this pathway is involved with hypertension associated with CRF.
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