Title: Role of Cytochrome P450 Metabolites in the Regulation of Renal Function and Blood Pressure in 2-Kidney 1-Clip Hypertensive Rats

Alterations in renal function contribute to Goldblatt 2-kidney 1-clip (2K1C) hypertension. A previous study indicated that bioavailability of cytochrome P450 metabolites epoxyeicosatrienoic acids (EETs) is decreased while 20hydroxyeicosatetraenoic acids (20-HETE) is increased in this model. We utilized the inhibitor of soluble epoxide hydrolase cis-4-[4-(3-Adamantan-1-yl-ureido)-cyclohexyloxy]benzoic acid (c-AUCB) and HET0016, the inhibitor of 20-HETE production, to study the role of EETs and 20-HETE in the regulation of renal function. Chronic c-AUCB treatment significantly decreased systolic blood pressure (SBP) (133 ± 1 vs. 163 ± 3 mmHg) and increased sodium excretion (1.23 ± 0.10 vs. 0.59 ± 0.03 mmol/day) in 2K1C rats. HET0016 did not affect SBP and sodium excretion. In acute experiments, renal blood flow (RBF) was decreased in 2K1C rats (5.0 ± 0.2 vs. 6.9 ± 0.2 ml.min.g). c-AUCB normalized RBF in 2K1C rats (6.5 ± 0.6 ml.min.g). HET0016 also increased RBF in 2K1C rats (5.8 ± 0.2 ml.min.g). Although RBF and GFR remained stable in normotensive rats during renal arterial pressure (RAP) reductions, both were significantly reduced at RAP 100 mmHg in 2K1C rats. c-AUCB did not improve autoregulation but increased RBF at all RAPs and shifted the pressurenatriuresis curve to the left. HET0016 treated 2K1C rats exhibited impaired autoregulation of RBF and GFR. Our data indicate that c-AUCB displays antihypertensive properties in 2K1C hypertension that are mediated by an improvement of RBF and pressure natriuresis. While HET0016 enhanced RBF, its anti-natriuretic effect likely prevented it from producing a BP-lowering effect in 2K1C model. 3