OBJECTIVE: We evaluated the therapeutic effectiveness of a new, orally active epoxyeicosatrienoic acid analog (EET-A) in rats with angiotensin II (ANG II)-dependent malignant hypertension. METHODS: Malignant hypertension was induced in Cyp1a1-Ren-2 transgenic rats by activation of the renin gene using indole-3-carbinol (I3C), a natural xenobiotic. EET-A treatment was started either simultaneously with I3C induction process (early treatment) or 10 days later during established hypertension (late treatment). Blood pressure (BP) (radiotelemetry), indices of renal and cardiac injury, and plasma and kidney levels of the components of the renin-angiotensin system (RAS) were determined. RESULTS: In I3C-induced hypertensive rats, early EET-A treatment attenuated BP increase (to 175 ± 3 versus 193 ± 4 mmHg, P < 0.05, on day 13), reduced albuminuria (15 ± 1 versus 28 ± 2 mg/24 h, P < 0.05), and cardiac hypertrophy as compared with untreated I3C-induced rats. This was associated with suppression of plasma and kidney ANG II levels (48 ± 6 versus 106 ± 9 and 122 ± 19 versus 346 ± 11 fmol ml or g, respectively, P < 0.05) and increases in plasma and kidney angiotensin (1-7) concentrations (84 ± 9 versus 37 ± 6 and 199 ± 12 versus 68 ± 9 fmol/ml or g, respectively, P < 0.05). Remarkably, late EET-A treatment did not lower BP or improve renal and cardiac injury; indices of RAS activity were not affected. CONCLUSION: The new, orally active EET-A attenuated the development of experimental ANG II-dependent malignant hypertension, likely via suppression of the hypertensiogenic axis and augmentation of the vasodilatory/natriuretic axis of RAS.

• MeSH
• albuminurie farmakoterapie   MeSH
• angiotensin I metabolismus   MeSH
• angiotensin II metabolismus   MeSH
• časové faktory MeSH
• cytochrom P-450 CYP1A1 genetika   MeSH
• hypertenze maligní chemicky indukované   patofyziologie   prevence a kontrola   MeSH
• indoly MeSH
• krevní tlak účinky léků   MeSH
• krysa rodu Rattus MeSH
• kyselina 8,11,14-eikosatrienová analogy a deriváty   terapeutické užití   MeSH
• ledviny metabolismus   MeSH
• peptidové fragmenty metabolismus   MeSH
• potkani transgenní MeSH
• renin-angiotensin systém účinky léků   MeSH
• renin genetika   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• angiotensin I (1-7) MeSH Prohlížeč
• angiotensin I MeSH
• angiotensin II MeSH
• cytochrom P-450 CYP1A1 MeSH
• indole-3-carbinol MeSH Prohlížeč
• indoly MeSH
• kyselina 8,11,14-eikosatrienová MeSH
• peptidové fragmenty MeSH
• Ren2 protein, rat MeSH Prohlížeč
• renin MeSH

OBJECTIVE: The present study was performed to investigate in a model of malignant hypertension if the antihypertensive actions of soluble epoxide hydrolase (sEH) inhibition are nitric oxide (NO)-dependent. METHODS: ANG II-dependent malignant hypertension was induced through dietary administration for 3 days of the natural xenobiotic indole-3-carbinol (I3C) in Cyp1a1-Ren-2 transgenic rats. Blood pressure (BP) was monitored by radiotelemetry and treatment with the sEH inhibitor [cis-4-[4-(3-adamantan-1-yl-ureido)-cyclohexyl-oxy]-benzoic acid (c-AUCB)] was started 48 h before administration of the diet containing I3C. In separate groups of rats, combined administration of the sEH inhibitor and the nonspecific NO synthase inhibitor [Nω-nitro-L-arginine methyl ester (L-NAME)] on the course of BP in I3C-induced and noninduced rats were evaluated. In addition, combined blockade of renin-angiotensin system (RAS) was superimposed on L-NAME administration in separate groups of rats. After 3 days of experimental protocols, the rats were prepared for renal functional studies and renal concentrations of epoxyeicosatrienoic acids (EETs) and their inactive metabolites dihydroxyeicosatrienoic acids (DHETEs) were measured. RESULTS: Treatment with c-AUCB increased the renal EETs/DHETEs ratio, attenuated the increases in BP, and prevented the decreases in renal function and the development of renal damage in I3C-induced Cyp1a1-Ren-2 rats. The BP lowering and renoprotective actions of the treatment with the sEH inhibitor c-AUCB were completely abolished by concomitant administration of L-NAME and not fully rescued by double RAS blockade without altering the increased EETs/DHETEs ratio. CONCLUSION: Our current findings indicate that the antihypertensive actions of sEH inhibition in this ANG II-dependent malignant form of hypertension are dependent on the interactions of endogenous bioavailability of EETs and NO.

• MeSH
• angiotensin II fyziologie   MeSH
• antihypertenziva farmakologie   terapeutické užití   MeSH
• epoxid hydrolasy antagonisté a inhibitory   MeSH
• hypertenze farmakoterapie   patofyziologie   MeSH
• inhibitory enzymů farmakologie   MeSH
• krevní tlak účinky léků   MeSH
• krysa rodu Rattus MeSH
• látky reagující s kyselinou thiobarbiturovou metabolismus   MeSH
• ledviny účinky léků   patofyziologie   MeSH
• NG-nitroargininmethylester aplikace a dávkování   farmakologie   terapeutické užití   MeSH
• potkani transgenní MeSH
• synthasa oxidu dusnatého antagonisté a inhibitory   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• angiotensin II MeSH
• antihypertenziva MeSH
• epoxid hydrolasy MeSH
• inhibitory enzymů MeSH
• látky reagující s kyselinou thiobarbiturovou MeSH
• NG-nitroargininmethylester MeSH
• synthasa oxidu dusnatého MeSH

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

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