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Antihypertensive action of soluble epoxide hydrolase inhibition in R en‐2 transgenic rats is mediated by suppression of the intrarenal renin–angiotensin system
Author(s) -
Varcabova Sarka,
Huskova Zuzana,
Kramer Herbert J,
Hwang Sung Hee,
Hammock Bruce D,
Imig John D,
Kitada Kento,
Cervenka Ludek
Publication year - 2013
Publication title -
clinical and experimental pharmacology and physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.752
H-Index - 103
eISSN - 1440-1681
pISSN - 0305-1870
DOI - 10.1111/1440-1681.12018
Subject(s) - natriuresis , epoxide hydrolase 2 , chemistry , endocrinology , medicine , blood pressure , autoregulation , renal blood flow , renin–angiotensin system , angiotensin ii , renal function , biochemistry , enzyme
Summary The aim of the present study was to evaluate the hypothesis that the antihypertensive effects of inhibition of soluble epoxide hydrolase (s EH ) are mediated by increased intrarenal availability of epoxyeicosatrienoic acids ( EET s), with consequent improvement in renal haemodynamic autoregulatory efficiency and the pressure–natriuresis relationship. Ren‐2 transgenic rats ( TGR ), a model of angiotensin ( A ng) II‐dependent hypertension, and normotensive transgene‐negative Hannover Sprague–Dawley (Han SD ) rats were treated with the s EH inhibitor cis ‐4‐(4‐(3‐adamantan‐1‐yl‐ureido)cyclohexyloxy)benzoic acid (c‐ AUCB ; 26 mg/L) for 48 h. Then, the effects on blood pressure ( BP ), autoregulation of renal blood flow ( RBF ) and glomerular filtration rate ( GFR ), and on the pressure–natriuresis relationship in response to stepwise reductions in renal arterial pressure ( RAP ) were determined. Treatment with c‐ AUCB did not significantly change BP , renal autoregulation or pressure‐natriuresis in normotensive Han SD rats. In contrast, c‐ AUCB treatment significantly reduced BP , increased intrarenal bioavailability of EET s and significantly suppressed A ngII levels in TGR . However, treatment with c‐ AUCB did not significantly improve the autoregulatory efficiency of RBF and GFR in response to reductions of RAP and to restore the blunted pressure–natriuresis relationship in TGR . Together, the data indicate that the antihypertensive actions of s EH inhibition in TGR are predominantly mediated via significant suppression of intrarenal renin–angiotensin system activity.