: Hypertension that develops following the long-term administration of initially subpressor doses of angiotensin II in rats has many of the same renal and vascular changes that are associated with human essential hypertension. In the past five years, we have provided compelling evidence that CYP45O-derived epoxyeicosatrienoic acids (EETs) have anti-hypertensive properties and play a part in the maintenance of renal microvascular function. A novel approach to increase EET levels is to inhibit epoxide hydrolase enzymes that are responsible for the conversion of the biologically active EETs to dihydroxyeicosatrienoic acids (DHETs) that are void of effects on the preglomerular vasculature. Recently, a role for soluble epoxide hydrolase (sEH) in the long-term control of arterial blood pressure and the pathogenesis of experimental hypertension has been proposed. Preliminary studies in our laboratory demonstrate increased kidney sEH protein expression during angiotensin II hypertension. In addition, we have observed a decrease in arterial blood pressure in angiotensin II hypertension following administration of a highly selective sEH inhibitor. Based on these observations, we hypothesis that during the development of hypertension increased kidney sEH will decrease kidney EET levels which contributes to increased renal microvascular reactivity, blood pressure and renal vascular injury. We will directly determine the involvement of epoxide hydrolases to the excessive preglomerular vasoconstriction during the development of angiotensin II hypertension using the juxtamedullary nephron preparation. We will also determine renal microvascular EET and DHET levels and the regulation of kidney epoxide hydrolase enzymes during hypertension. The proposed studies will employ newly developed highly selective epoxide hydrolase inhibitors to determine their ability to lower arterial blood pressure and improve renal microvascular function in angiotensin II hypertension. Collectively, these studies will provide a comprehensive understanding of epoxide hydrolases in the long-term regulation of blood pressure and renal hemodynamic function during angiotensin II hypertension.
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