Recent studies in humans have revealed the limits of renin angiotensin system (RAS) blockade in the treatment and prevention of hypertensive organ damage. Endothelin type A (ETA) receptors and epoxyeicosanoid acids (EETs) play an important role in this process. We hypothesize that combined ETA blockade and increased availability of EETs, by soluble epoxyde hydrolase (sEH) inhibition, will decrease blood pressure and lead to prevention or regression of hypertensive organ damage. TGR (mRen2)27 hypertensive rats (TGR) after 5/6 nephrectomy (5/6NX) will be treated with the combination of ETA blocker atrasentan and sEH inhibitor c-AUCB. This will be compared to standard RAS blockade. Normotensive HanSD rats and sham-operated TGR will serve as controls. Short term and long term protocols with immediate or delayed treatment will be used. Expected results: Combined ETA blockade and sEH inhibition will potentially be a new effective pharmacological approach for the treatment of hypertension and/or prevention of the hypertensive organ damage, or regression of a damage already established.

Nedávné klinické studie u lidí narazily na omezení blokády renin-angiotensinového systému (RAS) v léčbě a prevenci hypertenzního orgánového poškození. Endotelinové receptory typu A (ETA) a epoxyeikosatrienové kyseliny (EETs) v tomto procesu hrají důležitou roli. Předpokládáme, že kombinovaná blokáda ETA a zvýšená dostupnost EETs, dosažená inhibicí solubilní epoxydové hydrolázy (sEH), sníží krevní tlak a povede k prevenci nebo regresi hypertenzního orgánového poškození. Hypertenzní kmen potkanů TGR (mRen2)27 (TGR) po 5/6 nefrektomii (5/6)NX bude léčen kombinací ETA blokátoru atrasentanu a sEH inhibitoru c-AUCB. Výsledky budou porovnány se strandardní blokádou RAS. Normotenzní HanSD potkani a TGR po zdánlivé nefrektomii budou sloužit jako kontroly. Léčba bude probíhat podle krátkodobých a dlouhodobých protokolů s okamžitou nebo odloženou léčbou. Očekávané výsledky: Kombinovaná blokáda ETA a sEH bude potenciálně efektivním farmakologickým postupem v léčbě hypertenze a/nebo prevence hypertenzního orgánového poškození, případně regrese poškození již vzniklého.

• MeSH
• antagonisté endotelinového receptoru A terapeutické užití   MeSH
• antagonisté receptorů pro angiotenzin terapeutické užití   MeSH
• epoxid hydrolasy antagonisté a inhibitory   MeSH
• hypertenze farmakoterapie   komplikace   MeSH
• kombinovaná farmakoterapie metody   MeSH
• lidé MeSH
• modely nemocí na zvířatech MeSH
• potkani transgenní MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• srovnávací studie MeSH

• Konspekt
• Patologie. Klinická medicína
• NLK Obory
• farmakoterapie
• angiologie
• NLK Publikační typ
• závěrečné zprávy o řešení grantu AZV MZ ČR

INTRODUCTION: Previous studies in Ren-2 transgenic hypertensive rats (TGR) after 5/6 renal ablation (5/6 NX) have shown that besides pharmacological blockade of the renin-angiotensin system (RAS) also increasing kidney tissue epoxyeicosatrienoic acids (EET) levels by blocking soluble epoxide hydrolase (sEH), an enzyme responsible for degradation of EETs, and endothelin type A (ETA) receptor blockade retards chronic kidney disease (CKD) progression. This prompted us to evaluate if this progression will be alleviated by the addition of sEH inhibitor and ETA receptor antagonist to the standard complex blockade of RAS (angiotensin-converting enzyme inhibitor plus angiotensin II type 1 receptor blocker) in rats with established CKD. METHODS: The treatment regimens were initiated 6 weeks after 5/6 NX in TGR, and the follow-up period was 60 weeks. RESULTS: The addition of sEH inhibition to RAS blockade improved survival rate, further reduced albuminuria and renal glomerular and kidney tubulointerstitial injury, and attenuated the decline in creatinine clearance - all this as compared with 5/6 NX TGR treated with RAS blockade alone. Addition of ETA receptor antagonist to the combined RAS and sEH blockade not only offered no additional renoprotection but, surprisingly, also abolished the beneficial effects of adding sEH inhibitor to the RAS blockade. CONCLUSION: These data indicate that pharmacological strategies that combine the blockade of RAS and sEH could be a novel tool to combat the progression of CKD. Any attempts to further extend this therapeutic regimen should be made with extreme caution.

• MeSH
• antagonisté endotelinového receptoru A farmakologie   MeSH
• chronická renální insuficience prevence a kontrola   MeSH
• epoxid hydrolasy antagonisté a inhibitory   MeSH
• hypertenze MeSH
• krysa rodu rattus MeSH
• nefrektomie MeSH
• potkani transgenní MeSH
• receptor endotelinu A MeSH
• renin-angiotensin systém účinky léků   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

BACKGROUND/AIMS: We found recently that increasing renal epoxyeicosatrienoic acids (EETs) levels by blocking soluble epoxide hydrolase (sEH), an enzyme responsible for EETs degradation, shows renoprotective actions and retards the progression of chronic kidney disease (CKD) in Ren-2 transgenic hypertensive rats (TGR) after 5/6 renal ablation (5/6 NX). This prompted us to examine if additional protection is provided when sEH inhibitor is added to the standard renin-angiotensin system (RAS) blockade, specifically in rats with established CKD. METHODS: For RAS blockade, an angiotensin-converting enzyme inhibitor along with an angiotensin II type receptor blocker was used. RAS blockade was compared to sEH inhibition added to the RAS blockade. Treatments were initiated 6 weeks after 5/6 NX in TGR and the follow-up period was 60 weeks. RESULTS: Combined RAS and sEH blockade exhibited additional positive impact on the rat survival rate, further reduced albuminuria, further reduced glomerular and tubulointerstitial injury, and attenuated the decline in creatinine clearance when compared to 5/6 NX TGR subjected to RAS blockade alone. These additional beneficial actions were associated with normalization of the intrarenal EETs deficient and a further reduction of urinary angiotensinogen excretion. CONCLUSION: This study provides evidence that addition of pharmacological inhibition of sEH to RAS blockade in 5/6 NX TGR enhances renoprotection and retards progression of CKD, notably, when applied at an advanced stage.

• MeSH
• albuminurie farmakoterapie   MeSH
• chronická renální insuficience farmakoterapie   mortalita   patofyziologie   chirurgie   MeSH
• epoxid hydrolasy antagonisté a inhibitory   MeSH
• hypertenze MeSH
• inhibitory ACE terapeutické užití   MeSH
• kombinovaná farmakoterapie MeSH
• krysa rodu rattus MeSH
• míra přežití MeSH
• nefrektomie MeSH
• potkani transgenní MeSH
• renin-angiotensin systém účinky léků   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Drugs interfering with the renin-angiotensin-aldosterone system (RAAS) improved the prognosis in patients with hypertension, heart failure, diabetes and chronic kidney disease. However, combining different drugs brought no further benefit while increasing the risk of hyperkalemia, hypotension and acute renal failure. This was so with combining angiotensin converting enzyme inhibitors (ACEi) and angiotensin II receptors type 1 antagonists (ARB). Dissimilarly, in animal disease models this dual therapy proved clearly superior to single drug treatment and became the optimal standard regime for comparison with other treatments. This review analyzes the causes of the discrepancy of effects of the dual therapy between animal experiments versus clinical studies, and is focused on the outcomes in chronic kidney disease. Discussed is the role of species differences in RAAS, of the variability of the disease features in humans versus relative stability in animals, of the genetic uniformity in the animals but not in humans, and of the biased publication habits of experimental versus clinical studies. We attempt to understand the causes and reconcile the discordant findings and suggest to what extent dual RAAS inhibition should be continued in animal experiments and why its application in the clinics should be limited to strictly selected groups of patients.

• MeSH
• akutní poškození ledvin chemicky indukované   imunologie   prevence a kontrola   MeSH
• blokátory receptoru 1 pro angiotenzin II aplikace a dávkování   MeSH
• chronická renální insuficience farmakoterapie   imunologie   MeSH
• druhová specificita MeSH
• hyperkalemie chemicky indukované   imunologie   prevence a kontrola   MeSH
• hypertenze chemicky indukované   imunologie   prevence a kontrola   MeSH
• inhibitory ACE aplikace a dávkování   škodlivé účinky   MeSH
• lidé MeSH
• medicína založená na důkazech MeSH
• modely nemocí na zvířatech * MeSH
• renin-angiotensin systém účinky léků   imunologie   MeSH
• výsledek terapie MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

BACKGROUND: Early addition of endothelin (ET) type A (ETA) receptor blockade to complex renin-angiotensin system (RAS) blockade has previously been shown to provide better renoprotection against progression of chronic kidney disease (CKD) in Ren-2 transgenic hypertensive rats (TGR) after 5/6 renal ablation (5/6 NX). In this study, we examined if additional protection is provided when ETA blockade is applied in rats with already developed CKD. METHODS: For complex RAS inhibition, an angiotensin-converting enzyme inhibitor along with angiotensin II type 1 receptor blocker was used. Alternatively, ETA receptor blocker was added to the RAS blockade. The treatments were initiated 6 weeks after 5/6 NX and the follow-up period was 50 weeks. RESULTS: When applied in established CKD, addition of ETA receptor blockade to the complex RAS blockade brought no further improvement of the survival rate (30% in both groups); surprisingly, aggravated albuminuria (588 ± 47 vs. 245 ± 38 mg/24 h, p < 0.05) did not reduce renal glomerular injury index (1.25 ± 0.29 vs. 1.44 ± 0.26), did not prevent the decrease in creatinine clearance (203 ± 21 vs. 253 ± 17 μl/min/100 g body weight), and did not attenuate cardiac hypertrophy to a greater extent than observed in 5/6 NX TGR treated with complex RAS blockade alone. CONCLUSIONS: When applied in the advanced phase of CKD, addition of ETA receptor blockade to the complex RAS blockade brings no further beneficial renoprotective effects on the CKD progression in 5/6 NX TGR, in addition to those seen with RAS blockade alone.

• MeSH
• albuminurie MeSH
• angiotensiny účinky léků   metabolismus   MeSH
• antagonisté endotelinového receptoru A farmakologie   MeSH
• blokátory receptoru 1 pro angiotenzin II farmakologie   MeSH
• chronická renální insuficience metabolismus   MeSH
• hodnoty glomerulární filtrace účinky léků   MeSH
• hypertenze MeSH
• indoly farmakologie   MeSH
• inhibitory ACE farmakologie   MeSH
• kardiomegalie MeSH
• kombinovaná farmakoterapie MeSH
• kreatinin metabolismus   MeSH
• krevní tlak účinky léků   MeSH
• krysa rodu rattus MeSH
• ledviny účinky léků   metabolismus   MeSH
• losartan farmakologie   MeSH
• míra přežití MeSH
• nefrektomie MeSH
• potkani Sprague-Dawley MeSH
• potkani transgenní MeSH
• progrese nemoci MeSH
• pyrrolidiny farmakologie   MeSH
• receptor endotelinu A účinky léků   metabolismus   MeSH
• receptor endotelinu B účinky léků   metabolismus   MeSH
• renin-angiotensin systém účinky léků   MeSH
• renin účinky léků   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH