Role of cytochromeP-450 metabolites in the regulation of renal function and blood pressure in 2-kidney 1-clip hypertensive rats
- 1 June 2011
- journal article
- research article
- Published by American Physiological Society in American Journal of Physiology-Regulatory, Integrative and Comparative Physiology
- Vol. 300 (6), R1468-R1475
- https://doi.org/10.1152/ajpregu.00215.2010
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.Keywords
This publication has 67 references indexed in Scilit:
- 20-Hydroxyeicosatetraeonic Acid: A New Target for the Treatment of HypertensionJournal of Cardiovascular Pharmacology, 2010
- Targeting Epoxides for Organ Damage in HypertensionJournal of Cardiovascular Pharmacology, 2010
- Intrarenal cytochrome P-450 metabolites of arachidonic acid in the regulation of the nonclipped kidney function in two-kidney, one-clip Goldblatt hypertensive ratsJournal Of Hypertension, 2010
- Pharmacokinetic optimization of four soluble epoxide hydrolase inhibitors for use in a murine model of inflammationBritish Journal of Pharmacology, 2009
- Pivotal role of angiotensin II receptor subtype 1A in the development of two-kidney, one-clip hypertension: study in angiotensin II receptor subtype 1A knockout miceJournal Of Hypertension, 2008
- Afferent Arteriolar Dilation to 11, 12‐EET Analogs Involves PP2A Activity and Ca2+‐Activated K+ ChannelsMicrocirculation, 2008
- The Intrarenal Renin-Angiotensin System: From Physiology to the Pathobiology of Hypertension and Kidney DiseasePharmacological Reviews, 2007
- Orally Bioavailable Potent Soluble Epoxide Hydrolase InhibitorsJournal of Medicinal Chemistry, 2007
- CytochromeP-450 epoxygenases protect endothelial cells from apoptosis induced by tumor necrosis factor-α via MAPK and PI3K/Akt signaling pathwaysAmerican Journal of Physiology-Heart and Circulatory Physiology, 2007
- Endogenous nitric oxide and epoxyeicosatrienoic acids modulate angiotensin II-induced constriction in the rabbit afferent arterioleActa Physiologica Scandinavica, 2000