The role of epoxyeicotrienoic acids in the pathophysiology of ANG II-dependent form of hypertension will be studied.

Bude studován vliv zvýšených koncentrací epoxyeikosatrienových kyselin navozený farmakologickou blokádou jejich degradace, tj. inhibicí solubilní epoxid hydrolázy, na rozvoj ANG II-dependentní formy hypertenze.

• MeSH
• epoxid hydrolasy farmakologie   MeSH
• hypertenze farmakoterapie   MeSH
• klinické lékařství MeSH
• kyseliny hydroxyeikosatetraenové farmakologie   MeSH
• receptor typu 2 angiotensinu II - blokátory terapeutické užití   MeSH
• systém (enzymů) cytochromů P-450 metabolismus   MeSH

• Konspekt
• Farmacie. Farmakologie
• NLK Obory
• kardiologie
• angiologie
• farmacie a farmakologie
• farmakoterapie
• NLK Publikační typ
• závěrečné zprávy o řešení grantu IGA MZ ČR

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

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