Role of cytochromeP-450 metabolites in the regulation of renal function and blood pressure in 2-kidney 1-clip hypertensive rats

Abstract

Alterations in renal function contribute to Goldblatt two-kidney, one-clip (2K1C) hypertension. A previous study indicated that bioavailability of cytochrome P-450 metabolites epoxyeicosatrienoic acids (EETs) is decreased while that of 20-hydroxyeicosatetraenoic 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 HET-0016, 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. HET-0016 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(-1)·g(-1)). c-AUCB normalized RBF in 2K1C rats (6.5 ± 0.6 ml·min(-1)·g(-1)). HET-0016 also increased RBF in 2K1C rats (5.8 ± 0.2 ml·min(-1)·g(-1)). Although RBF and glomerular filtration rate (GFR) remained stable in normotensive rats during renal arterial pressure (RAP) reductions, both were significantly reduced at 100 mmHg RAP in 2K1C rats. c-AUCB did not improve autoregulation but increased RBF at all RAPs and shifted the pressure-natriuresis curve to the left. HET-0016-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 HET-0016 enhanced RBF, its anti-natriuretic effect likely prevented it from producing a blood pressure-lowering effect in the 2K1C model.

Renal Autoregulation in Health and Disease

“…However, restoring EETs did not restore autoregulation (1404), indicating that they were not the cause of defective renal autoregulation. Similarly, 20-HETE participated in basal vasoconstriction, but did not account for the attenuated autoregulation in the unclipped kidney of 2K,1C rats.…”

“…Dogs (1047) and some rats (705,707,1365,1566) with 2K,1C hypertension have maintained RBF and GFR autoregulation in the nonclipped kidney, although other studies in rats have reported weak autoregulation (1188,1404,1494) that was improved by NOS inhibition (1494). Blockade of AT 1 receptors in 2K,1C hypertensive rats did not affect RBF autoregulation in the nonclipped kidney but abolished GFR autoregulation (1566), presumably because of a reduced efferent arteriolar resistance.…”

Maternal fructose-intake-induced renal programming in adult male offspring

“…3C). Moreover, HF increased renal 14,15-DHET level, a marker representing sEH activity [20], in the 3-week-old kidney (Fig. 3D).…”

Reno-protective mechanisms of epoxyeicosatrienoic acids in cardiovascular disease

“…The reno-protective effect of sEH inhibition was quite obvious either during the progression of hypertension or after hypertension was established (49 -51, 131). In Goldblatt twokidney, one-clip (2K1C) hypertensive rats, inhibition of sEH decreased blood pressure and sodium excretion together with improved renal blood flow and glomerular filtration rate (GFR) (107,114). Inhibition of sEH also provides renal protection in stroke-prone SHR, as it decreased blood pressure, renal arteriolar hypertrophy, and proteinuria (59).…”