Abstract
The aim of the present study was to evaluate the hypothesis that the antihypertensive effects of inhibition of soluble epoxide hydrolase (sEH) are mediated by increased intrarenal availability of epoxyeicosatrienoic acids (EETs), with consequent improvement in renal haemodynamic autoregulatory efficiency and the pressure-natriuresis relationship. Ren-2 transgenic rats (TGR), a model of angiotensin (Ang) II-dependent hypertension, and normotensive transgene-negative Hannover Sprague-Dawley (HanSD) rats were treated with the sEH 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 HanSD rats. In contrast, c-AUCB treatment significantly reduced BP, increased intrarenal bioavailability of EETs and significantly suppressed AngII 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 sEH inhibition in TGR are predominantly mediated via significant suppression of intrarenal renin-angiotensin system activity.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 273-281 |
| Number of pages | 9 |
| Journal | Clinical and Experimental Pharmacology and Physiology |
| Volume | 40 |
| Issue number | 4 |
| DOIs | |
| State | Published - Apr 2013 |
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Keywords
- Cytochrome P450 metabolites
- Epoxyeicosatrienoic acids
- Glomerular filtration rate
- Hypertension
- Pressure-natriuresis
- Renal blood flow
- Renin-angiotensin system
- Soluble epoxide hydrolase
ASJC Scopus subject areas
- Physiology
- Physiology (medical)
- Pharmacology
Cite this
Antihypertensive action of soluble epoxide hydrolase inhibition in Ren-2 transgenic rats is mediated by suppression of the intrarenal renin-angiotensin system. / Varcabova, Sarka; Huskova, Zuzana; Kramer, Herbert J.; Hwang, Sung Hee; Hammock, Bruce D.; Imig, John D.; Kitada, Kento; Cervenka, Ludek.
In: Clinical and Experimental Pharmacology and Physiology, Vol. 40, No. 4, 04.2013, p. 273-281.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Antihypertensive action of soluble epoxide hydrolase inhibition in Ren-2 transgenic rats is mediated by suppression of the intrarenal renin-angiotensin system
AU - Varcabova, Sarka
AU - Huskova, Zuzana
AU - Kramer, Herbert J.
AU - Hwang, Sung Hee
AU - Hammock, Bruce D.
AU - Imig, John D.
AU - Kitada, Kento
AU - Cervenka, Ludek
PY - 2013/4
Y1 - 2013/4
N2 - The aim of the present study was to evaluate the hypothesis that the antihypertensive effects of inhibition of soluble epoxide hydrolase (sEH) are mediated by increased intrarenal availability of epoxyeicosatrienoic acids (EETs), with consequent improvement in renal haemodynamic autoregulatory efficiency and the pressure-natriuresis relationship. Ren-2 transgenic rats (TGR), a model of angiotensin (Ang) II-dependent hypertension, and normotensive transgene-negative Hannover Sprague-Dawley (HanSD) rats were treated with the sEH 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 HanSD rats. In contrast, c-AUCB treatment significantly reduced BP, increased intrarenal bioavailability of EETs and significantly suppressed AngII 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 sEH inhibition in TGR are predominantly mediated via significant suppression of intrarenal renin-angiotensin system activity.
AB - The aim of the present study was to evaluate the hypothesis that the antihypertensive effects of inhibition of soluble epoxide hydrolase (sEH) are mediated by increased intrarenal availability of epoxyeicosatrienoic acids (EETs), with consequent improvement in renal haemodynamic autoregulatory efficiency and the pressure-natriuresis relationship. Ren-2 transgenic rats (TGR), a model of angiotensin (Ang) II-dependent hypertension, and normotensive transgene-negative Hannover Sprague-Dawley (HanSD) rats were treated with the sEH 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 HanSD rats. In contrast, c-AUCB treatment significantly reduced BP, increased intrarenal bioavailability of EETs and significantly suppressed AngII 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 sEH inhibition in TGR are predominantly mediated via significant suppression of intrarenal renin-angiotensin system activity.
KW - Cytochrome P450 metabolites
KW - Epoxyeicosatrienoic acids
KW - Glomerular filtration rate
KW - Hypertension
KW - Pressure-natriuresis
KW - Renal blood flow
KW - Renin-angiotensin system
KW - Soluble epoxide hydrolase
UR - http://www.scopus.com/inward/record.url?scp=84875652885&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84875652885&partnerID=8YFLogxK
U2 - 10.1111/1440-1681.12018
DO - 10.1111/1440-1681.12018
M3 - Article
C2 - 23039246
AN - SCOPUS:84875652885
VL - 40
SP - 273
EP - 281
JO - Clinical and Experimental Pharmacology and Physiology
JF - Clinical and Experimental Pharmacology and Physiology
SN - 0305-1870
IS - 4
ER -