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 first aim of the present study was to assess plasma and kidney angiotensin II (ANG II) levels and renal cortical ANG II receptor subtype 1A (AT1A) mRNA expression in hypertensive Ren-2 transgenic rats (TGR) and in normotensive Hannover Sprague-Dawley (HanSD) rats. The second aim was to investigate potential differences between TGR and HanSD in blood pressure (BP) and renal functional responses to either intravenous (i.v.), i.e. systemic, or intrarenal (i.r.) AT1 receptor blockade with candesartan. METHODS: Rats were anesthetized and prepared for clearance experiments. In series 1, ANG II concentrations were assayed by radioimmunoassay and renal cortical AT1A mRNA expression by semiquantitative reverse transcriptase-polyacrylamide gel electrophoresis. In series 2, BP and renal functional responses were evaluated after either i.v. or i.r. bolus administration of candesartan. RESULTS: Plasma and kidney ANG II levels were significantly lower in TGR than in HanSD (39 +/- 5 versus 107 +/- 19 fmol/ml and 251 +/- 41 versus 571 +/- 95 fmol/g, respectively, P < 0.05). Renal AT1A mRNA expression was not different between TGR and HanSD. Intravenous candesartan caused comparable decreases in BP in TGR and HanSD and did not change renal plasma flow (RPF) or absolute and fractional sodium excretion in HanSD. In contrast, i.v. candesartan significantly increased RPF (+27 +/- 6%, P < 0.05) and absolute and fractional sodium excretion (+49 +/- 10 and + 42 +/- 9%, respectively P < 0.05) in TGR without changing glomerular filtration rate (GFR). Acute i.r. candesartan increased RPF by +36 +/- 6% (P < 0.05) in TGR but not in HanSD with a greater rise in absolute and fractional sodium excretion in TGR (+124 +/-8 and 97 +/- 9%, respectively) than in HanSD (+81 +/- 9 and +69 +/- 8%, respectively) (P < 0.05). CONCLUSIONS: The enhanced responses of RPF and sodium excretion to AT1 receptor blockade in TGR suggest that renal hemodynamics and sodium excretion in TGR are under strong ANG II influence. The compromised ability of the kidney to respond to BP elevations by appropriate increases in sodium excretion may contribute to the maintenance of high BP in TGR. Thus, the present findings provide new insights into the pathophysiology of hypertension in this model.

• MeSH
• angiotensin II krev   metabolismus   MeSH
• antagonisté receptorů pro angiotenzin * MeSH
• antihypertenziva farmakologie   MeSH
• benzimidazoly farmakologie   MeSH
• bifenylové sloučeniny MeSH
• geneticky modifikovaná zvířata genetika   MeSH
• hodnoty glomerulární filtrace účinky léků   MeSH
• hypertenze genetika   metabolismus   MeSH
• krysa rodu Rattus MeSH
• messenger RNA genetika   metabolismus   MeSH
• potkani Sprague-Dawley MeSH
• receptor angiotensinu typ 1 metabolismus   MeSH
• renální průtok plazmy účinky léků   MeSH
• sodík moč   MeSH
• tetrazoly farmakologie   MeSH
• vyšetření funkce ledvin MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• srovnávací studie MeSH
• Názvy látek
• angiotensin II MeSH
• antagonisté receptorů pro angiotenzin * MeSH
• antihypertenziva MeSH
• benzimidazoly MeSH
• bifenylové sloučeniny MeSH
• candesartan MeSH Prohlížeč
• messenger RNA MeSH
• receptor angiotensinu typ 1 MeSH
• sodík MeSH
• tetrazoly MeSH

Previous studies have indicated that in normotensive rats, NO produced by neuronal NO synthase (nNOS) plays an important role in modulating tubuloglomerular feedback (TGF)-mediated afferent arteriolar constriction. It has also been shown that in angiotensin (Ang) II-infused hypertensive rats, there is a reduced ability of nNOS-derived NO to counteract this vasoconstriction. The present study was performed to (1) assess in vivo renal functional responses to intrarenal nNOS inhibition in control and Ang II-infused rats and (2) determine whether changes in renal function following nNOS inhibition are mediated by unopposed stimulation of Ang II receptor subtype 1 (AT(1)). Wistar rats were infused with either saline (SAL) or Ang II (80 ng/min) by osmotic minipumps implanted subcutaneously. Mean arterial blood pressure of SAL- and Ang II-infused rats on day 13 after implantation averaged 121+/-4 (n=28) and 151+/-5 (n=30), respectively (P<0.05). There were no differences in glomerular filtration rate (GFR) (0.68+/-0.09 versus 0.59+/-0.09 mL. min(-1). g(-1)), renal plasma flow (RPF) (2.66+/-0.31 versus 2.34+/-0.39 mL. min(-1). g(-1)), and absolute sodium excretion (0.37+/-0.07 versus 0.42+/-0.09 micromol. min(-1). g(-1)). Intrarenal infusion of SAL did not change GFR, RPF, and sodium excretion in either SAL-infused (n=7) or Ang II-infused rats (n=8). Acute intrarenal administration of the nNOS inhibitor S-methyl-L-thiocitrulline (L-SMTC; 0.3 mg/h) decreased GFR, RPF, and sodium excretion in SAL-infused rats (n=9) by 29+/-4%, 38+/-4%, and 70+/-4% compared with control values (P<0.05). The pretreatment by the AT(1) receptor antagonist candesartan (750 ng IR) in SAL-infused rats (n=7) effectively prevented the decrease in RPF (-3+/-3%) elicited by nNOS inhibition and resulted in an increase in GFR (+25+/-12, P<0.05) and a concomitant greater increase in sodium excretion (84+/-12%, P<0.05) compared with control values. In contrast, in Ang II-infused rats (n=10) intrarenal inhibition of nNOS by L-SMTC did not cause significant decreases in GFR, RPF and sodium excretion (-2+/-2%, -15+/-10%, and -14+/-10%, respectively). These results suggest that in normotensive rats nNOS-derived NO counteracts Ang II-mediated vasoconstriction in the pre- and postglomerular microcirculation. Furthermore, Ang II-infused rats exhibit an impaired ability to release NO by nNOS. Decreased nNOS activity is likely to account at least partially for the enhanced TGF responsiveness in Ang II-infused rats and thus may contribute to the maintenance of hypertension in this model.

• MeSH
• angiotensin II MeSH
• antagonisté receptorů pro angiotenzin MeSH
• benzimidazoly farmakologie   MeSH
• bifenylové sloučeniny MeSH
• citrulin analogy a deriváty   farmakologie   MeSH
• hodnoty glomerulární filtrace účinky léků   MeSH
• inhibitory enzymů farmakologie   MeSH
• krevní tlak účinky léků   MeSH
• krysa rodu Rattus MeSH
• ledviny krevní zásobení   enzymologie   patofyziologie   MeSH
• natriuréza účinky léků   MeSH
• potkani Wistar MeSH
• receptor angiotensinu typ 1 MeSH
• receptor angiotensinu typ 2 MeSH
• renální hypertenze chemicky indukované   enzymologie   patofyziologie   MeSH
• renální průtok plazmy účinky léků   MeSH
• synthasa oxidu dusnatého, typ I MeSH
• synthasa oxidu dusnatého antagonisté a inhibitory   fyziologie   MeSH
• tetrazoly farmakologie   MeSH
• thiomočovina analogy a deriváty   farmakologie   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• angiotensin II MeSH
• antagonisté receptorů pro angiotenzin MeSH
• benzimidazoly MeSH
• bifenylové sloučeniny MeSH
• candesartan MeSH Prohlížeč
• citrulin MeSH
• inhibitory enzymů MeSH
• Nos1 protein, rat MeSH Prohlížeč
• receptor angiotensinu typ 1 MeSH
• receptor angiotensinu typ 2 MeSH
• S-methylthiocitrulline MeSH Prohlížeč
• synthasa oxidu dusnatého, typ I MeSH
• synthasa oxidu dusnatého MeSH
• tetrazoly MeSH
• thiomočovina MeSH

The present study was performed to validate a simple means for assessing renal function in anesthetized mice and to characterize the renal hemodynamic responses to acute volume expansion and how these responses are altered by concurrent angiotensin II (AngII) infusions. Inulin and para-aminohippurate clearances were used to assess GFR and renal plasma flow (RPF) in three groups of male C57Bl/6 mice anesthetized with inactin (100 mg/kg, intraperitoneally) and ketamine (10 mg/kg). To avoid the hypotension associated with repeated blood sampling, a single blood sample was taken after three timed urine collections. Renal function and mean arterial pressure (MAP) were measured under euvolemic conditions (2.5 microl/min, intravenously, n = 7) during isotonic saline volume expansion (12.5 microl/min, intravenously, n = 5) and during volume expansion with concurrent AngII infusion (5 ng/min x g, n = 5). MAP in the control group was 77 +/- 2 mmHg; volume expansion alone did not change MAP significantly (83 +/- 2 mmHg), but led to significantly greater values in both GFR and RPF (1.35 +/- 0.14 versus 1.01 +/- 0.1 ml/min x g and 11.26 +/- 1.39 versus 6.29 +/- 0.5 ml/min x g, respectively). Infusion of AngII during volume expansion led to significant elevations of MAP (100 +/- 3 mmHg, P < 0.05) and prevented the increases in GFR and RPF elicited by volume expansion (0.77 +/- 0.08 and 5.35 +/- 0.48 ml/min x g, respectively). Volume expansion also elicited marked increases in absolute and fractional sodium excretion (6.1 +/- 1.0 versus 0.62 +/- 0.2 microEq/min x g and 3.1 +/- 0.7 versus 0.4 +/- 0.1%, respectively). AngII infusion attenuated the absolute and fractional sodium excretion responses to volume expansion (3.4 +/- 1.2 microEq/min x g and 2.5 +/- 0.5%, respectively). The present findings demonstrate that anesthetized mice exhibit marked renal hemodynamic and excretory responses to isotonic saline volume expansion. Concomitant AngII infusion attenuates these responses in spite of greater increases in arterial pressure.

• MeSH
• angiotensin II farmakologie   MeSH
• extracelulární prostor fyziologie   MeSH
• hodnoty glomerulární filtrace účinky léků   fyziologie   MeSH
• ledviny účinky léků   fyziologie   MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• natriuréza účinky léků   fyziologie   MeSH
• renální průtok plazmy účinky léků   fyziologie   MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, U.S. Gov't, P.H.S. MeSH
• Názvy látek
• angiotensin II MeSH