OBJECTIVE: The present study was performed to examine whether the blood pressure (BP)-lowering effects of soluble epoxide hydrolase (sEH) inhibition in two-kidney, one-clip (2K1C) Goldblatt hypertension are nitric oxide (NO) dependent. METHODS: Mice lacking the endothelial NO synthase (eNOS) gene (eNOS-/-) and their wild-type controls (eNOS+/+) underwent clipping of one renal artery. BP was monitored by radiotelemetry and the treatment with the sEH inhibitor cis-4-[4-(3-adamantan-1-yl-ureido)cyclohex-yloxy]-benzoic acid (c-AUCB) was initiated on day 25 after clipping and lasted for 14 days. Renal concentrations of epoxyeicosatrienoic acids (EETs) and their inactive metabolite dihydroxyeicosatrienoic acids (DHETs) were measured in the nonclipped kidney. Renal NO synthase (NOS) activity was determined by measuring the rate of formation of L-[(14)C]citruline from L-[(14)C]arginine. RESULTS: Treatment with the sEH inhibitor elicited similar BP decreases that were associated with increases in daily sodium excretion in 2K1C eNOS+/+ as well as 2K1C eNOS-/- mice. In addition, treatment with the sEH inhibitor increased the ratio of EETs/DHETs in the nonclipped kidney of 2K1C eNOS+/+ as well as 2K1C eNOS-/- mice. Treatment with the sEH inhibitor did not alter renal NOS activity in any of the experimental groups. CONCLUSIONS: Collectively, our present data suggest that the BP-lowering effects of chronic sEH inhibition in 2K1C mice are mainly associated with normalization of the reduced availability of biologically active EETs in the nonclipped kidney and their direct natriuretic actions.
- MeSH
- antihypertenziva farmakologie terapeutické užití MeSH
- epoxid hydrolasy antagonisté a inhibitory metabolismus MeSH
- inhibitory enzymů farmakologie terapeutické užití MeSH
- myši inbrední C57BL MeSH
- myši knockoutované MeSH
- myši MeSH
- oxid dusnatý * metabolismus MeSH
- renovaskulární hypertenze farmakoterapie enzymologie MeSH
- synthasa oxidu dusnatého, typ III nedostatek MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
- Názvy látek
- antihypertenziva MeSH
- Ephx2 protein, mouse MeSH Prohlížeč
- epoxid hydrolasy MeSH
- inhibitory enzymů MeSH
- Nos3 protein, mouse MeSH Prohlížeč
- oxid dusnatý * MeSH
- synthasa oxidu dusnatého, typ III MeSH
In the present study, we examined the effects of soluble epoxide hydrolase (sEH) inhibition on the development of angiotensin II-dependent hypertension and on renal function in transgenic rats with inducible expression of the mouse renin gene (strain name Cyp1a1-Ren-2). Hypertension was induced in these rats by indole-3-carbinol (I3C; 0.3% in the diet) for 12 days. The sEH inhibitor cis-4-[4-(3-adamantan-1-yl-ureido)-cyclohexyloxy]-benzoic acid (c-AUCB) was given in two doses (13 or 26 mg l-1) in drinking water. Blood pressure (BP), body weight (BW) and renal excretory parameters were monitored in conscious animals during the experiment. Renal haemodynamics was assessed at the end of treatment in anaesthetized rats. I3C administration resulted in severe hypertension with a rise in systolic BP from 118 ± 2 to 202 ± 3 mmHg, a loss of BW from 266 ± 5 to 228 ± 4 g and a rise in proteinuria from 14 ± 2 to 34 ± 3 mg day-1. Both doses of c-AUCB significantly attenuated the development of hypertension (systolic BP of 181 ± 4 and 176 ± 4 mmHg, respectively), the loss in BW (256 ± 4 and 259 ± 3 g, respectively) and the degree of proteinuria (27 ± 2 and 25 ± 3 mg day-1, respectively) to a similar extent. Moreover, c-AUCB prevented the reduction in renal plasma flow (5.4 ± 0.4 vs. 4.6 ± 0.3 ml min-1 g-1) and significantly increased sodium excretion (0.84 ± 0.16 vs. 0.38 ± 0.08 μmol min-1 g-1) during I3C administration. These data suggest that the oral administration of c-AUCB displays antihypertensive effects in Ren-2 transgenic rats with inducible malignant hypertension via an improvement of renal function.
- MeSH
- angiotensin II MeSH
- antihypertenziva aplikace a dávkování farmakologie MeSH
- aplikace orální MeSH
- benzoáty aplikace a dávkování farmakologie MeSH
- časové faktory MeSH
- cytochrom P-450 CYP1A1 genetika MeSH
- epoxid hydrolasy antagonisté a inhibitory metabolismus MeSH
- hodnoty glomerulární filtrace účinky léků MeSH
- hypertenze chemicky indukované enzymologie genetika patofyziologie prevence a kontrola MeSH
- inhibitory enzymů aplikace a dávkování farmakologie MeSH
- krevní tlak účinky léků MeSH
- krysa rodu Rattus MeSH
- kyseliny arachidonové metabolismus MeSH
- kyseliny hydroxyeikosatetraenové metabolismus MeSH
- ledviny krevní zásobení účinky léků enzymologie patofyziologie MeSH
- močovina aplikace a dávkování analogy a deriváty farmakologie MeSH
- modely nemocí na zvířatech MeSH
- myši MeSH
- promotorové oblasti (genetika) MeSH
- proteinurie metabolismus patofyziologie prevence a kontrola MeSH
- renální průtok plazmy účinky léků MeSH
- renin genetika metabolismus MeSH
- sodík moč MeSH
- zvířata MeSH
- Check Tag
- krysa rodu Rattus MeSH
- mužské pohlaví MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
- Názvy látek
- 4-(4-(3-adamantan-1-ylureido)cyclohexyloxy)benzoic acid MeSH Prohlížeč
- angiotensin II MeSH
- antihypertenziva MeSH
- benzoáty MeSH
- cytochrom P-450 CYP1A1 MeSH
- EPHX2 protein, rat MeSH Prohlížeč
- epoxid hydrolasy MeSH
- inhibitory enzymů MeSH
- kyseliny arachidonové MeSH
- kyseliny hydroxyeikosatetraenové MeSH
- močovina MeSH
- Ren2 protein, mouse MeSH Prohlížeč
- renin MeSH
- sodík MeSH
