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

OBJECTIVE: The present study was performed to examine in two-kidney, one-clip (2K1C) Goldblatt hypertensive mice: first, the relative contribution of angiotensin II receptor subtypes 1A (AT(1A)) and 1B (AT(1B)); second, the role of angiotensin II type 2 (AT(2)) receptors in the development of hypertension in wild-type (AT(1A)+/+) and AT(1A) receptor knockout (AT(1A)-/-) mice; and third, the role of increased nitric oxide synthase activity in counteracting the hypertensinogenic action of angiotensin II in this model. METHODS: AT(1A)+/+ and AT(1A)-/- mice underwent clipping of one renal artery and were infused with either saline vehicle or selective AT(2) receptor agonist CGP-42112A (CGP). Blood pressure was monitored by radiotelemetry. Blood pressure responses to the nitric oxide synthase inhibitor nitro-L-arginine-methyl-ester were evaluated. RESULTS: AT(1A)+/+ mice responded to clipping by a rise in blood pressure that was not modified by CGP infusion. Clip placement caused a slight increase in blood pressure in AT(1A)-/- mice that remained significantly lower than in AT(1A)+/+ mice. Acute nitric oxide synthase inhibition caused greater increase in blood pressure in 2K1C/AT(1A)+/+ than in AT(1A)+/+ mice. CONCLUSION: The present data support the critical role of AT(1A) receptors in the development of 2K1C hypertension, whereas AT(1B) receptors play only a minor role in blood pressure regulation in this model of angiotensin II-dependent hypertension. Activation of AT(2) receptors does not play an antagonistic role in the AT(1) receptor-mediated hypertensinogenic actions of angiotensin II in this model. Finally, enhanced nitric oxide synthase activity plays a protective role by counteracting the vasoconstrictor influences of angiotensin II in 2K1C hypertensive mice.

• MeSH
• arteria renalis MeSH
• hypertenze genetika   patofyziologie   MeSH
• ligace MeSH
• modely nemocí na zvířatech MeSH
• myši knockoutované MeSH
• myši MeSH
• receptor angiotensinu typ 1 genetika   fyziologie   MeSH
• receptor angiotensinu typ 2 genetika   fyziologie   MeSH
• renin-angiotensin systém fyziologie   MeSH
• synthasa oxidu dusnatého fyziologie   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
• receptor angiotensinu typ 1 MeSH
• receptor angiotensinu typ 2 MeSH
• synthasa oxidu dusnatého MeSH