BACKGROUND: Association of congestive heart failure (CHF) and chronic kidney disease (CKD) worsens the patient's prognosis and results in poor survival rate. The aim of this study was to examine if addition of endothelin type A (ETA) receptor antagonist to the angiotensin-converting enzyme inhibitor (ACEi) will bring additional beneficial effects in experimental rats. METHODS: CKD was induced by 5/6 renal mass reduction (5/6 NX) and CHF was elicited by volume overload achieved by creation of aorto-caval fistula (ACF). The follow-up was 24 weeks after the first intervention (5/6 NX). The treatment regimens were initiated 6 weeks after 5/6 NX and 2 weeks after ACF creation. RESULTS: The final survival in untreated group was 15%. The treatment with ETA receptor antagonist alone or ACEi alone and the combined treatment improved the survival rate to 64%, 71% and 75%, respectively, however, the difference between the combination and either single treatment regimen was not significant. The combined treatment exerted best renoprotection, causing additional reduction in albuminuria and reducing renal glomerular and tubulointerstitial injury as compared with ACE inhibition alone. CONCLUSIONS: Our results show that treatment with ETA receptor antagonist attenuates the CKD- and CHF-related mortality, and addition of ETA receptor antagonist to the standard blockade of RAS by ACEi exhibits additional renoprotective actions.

• MeSH
• antagonisté endotelinového receptoru A * farmakologie   terapeutické užití   MeSH
• chronická renální insuficience * komplikace   farmakoterapie   metabolismus   MeSH
• endotelin-1 metabolismus   MeSH
• inhibitory ACE farmakologie   terapeutické užití   MeSH
• krysa rodu rattus MeSH
• ledviny MeSH
• píštěle * metabolismus   MeSH
• potkani transgenní MeSH
• receptor endotelinu A metabolismus   MeSH
• renin-angiotensin systém MeSH
• srdeční selhání * farmakoterapie   etiologie   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Endothelin 1 (ET-1) seems essential in salt-dependent hypertension, and activation of ETA receptors causes renal vasoconstriction. However, the response in the renal medulla and the role of tissue NO availability has never been adequately explored in vivo. We examined effects of ETA and ETB receptor blockade (atrasentan and BQ788) on blood pressure (MAP), medullary blood flow (MBF) and medullary tissue NO. Effects of systemic and intramedullary blocker application were compared in anesthetized normotensive ET-1-pretreated Sprague-Dawley rats (S-D), in salt-dependent hypertension (HS/UNX) and in spontaneously hypertensive rats (SHR). Total renal blood flow (RBF) was measured using a Transonic renal artery probe, MBF as laser-Doppler flux, and tissue NO signal using selective electrodes. In normotensive rats ET-1 significantly increased MAP, decreased RBF (-20%) and renal medullary NO. In HS/UNX rats atrasentan decreased MAP and increased medullary NO, earlier and more profoundly with intravenous infusion. In SHR atrasentan decreased MAP, more effectively with intravenous infusion; the increase in tissue NO (∼10%) was similar with both routes; however, only intramedullary atrasentan increased MBF. No consistent responses to BQ788 were seen. We confirmed dominant role of ETA receptors in regulation of blood pressure and renal hemodynamics in normotensive and hypertensive rats and provided novel evidence for the role of ETA in control of intrarenal NO bioavailability in salt-dependent and spontaneous hypertension. Under conditions of activation of the endothelin system ETB stimulation preserved medullary perfusion.

• MeSH
• antagonisté endotelinového receptoru A farmakologie   terapeutické užití   MeSH
• antagonisté endotelinového receptoru B farmakologie   terapeutické užití   MeSH
• antihypertenziva farmakologie   terapeutické užití   MeSH
• atrasentan farmakologie   terapeutické užití   MeSH
• eliminace ledvinami účinky léků   MeSH
• endotelin-1 farmakologie   terapeutické užití   MeSH
• hemodynamika účinky léků   MeSH
• hypertenze farmakoterapie   metabolismus   MeSH
• krevní tlak účinky léků   MeSH
• ledviny účinky léků   metabolismus   MeSH
• modely nemocí na zvířatech MeSH
• oligopeptidy farmakologie   terapeutické užití   MeSH
• oxid dusnatý metabolismus   MeSH
• piperidiny farmakologie   terapeutické užití   MeSH
• potkani inbrední SHR MeSH
• potkani Sprague-Dawley MeSH
• receptor endotelinu A účinky léků   MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

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.; 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.

• 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

Endothelin alters central sympathetic responses, but the resultant effects on arrhythmogenesis are unknown. We examined ventricular tachyarrhythmias after endothelin receptor-A blockade in the brain of Wistar rats with acute myocardial infarction. For this aim, BQ-123 (n=6) or phosphate-buffered saline (n=6) were injected intracerebroventricularly. After 10 min, the left coronary artery was ligated, followed by implantation of telemetry transmitters. Electrocardiography and voluntary activity (as a surrogate of acute left ventricular failure) were continuously monitored for 24 h. Infarct-size was similar in the two groups. There were fewer episodes of ventricular tachyarrhythmias of shorter average duration in treated rats, leading to markedly shorter total duration (12.3+/-8.9 s), when compared to controls (546.2+/-130.3 s). Voluntary activity increased in treated rats during the last hours of recording, but bradyarrhythmic episodes were comparable between the two groups. Endothelin receptor-A blockade in the brain of rats decreases the incidence of ventricular tachyarrhythmias post-ligation, without affecting bradyarrhythmic episodes. These findings call for further research on the pathophysiologic role of endothelin during acute myocardial infarction.

• MeSH
• antagonisté endotelinového receptoru A aplikace a dávkování   MeSH
• cyklické peptidy aplikace a dávkování   MeSH
• infarkt myokardu farmakoterapie   komplikace   metabolismus   patofyziologie   MeSH
• injekce intraventrikulární MeSH
• komorová tachykardie etiologie   metabolismus   patofyziologie   prevence a kontrola   MeSH
• komorové extrasystoly etiologie   metabolismus   patofyziologie   prevence a kontrola   MeSH
• modely nemocí na zvířatech MeSH
• mozkové komory metabolismus   patofyziologie   účinky léků   MeSH
• potkani Wistar MeSH
• receptor endotelinu A metabolismus   účinky léků   MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

BACKGROUND: We evaluated and compared the effects of sparsentan, a dual endothelin type A (ETA) and angiotensin II type 1 receptor antagonist, with those of the angiotensin II type 1 receptor antagonist irbesartan in patients with primary FSGS. METHODS: In this phase 2, randomized, double-blind, active-control Efficacy and Safety of Sparsentan (RE-021), a Dual Endothelin Receptor and Angiotensin Receptor Blocker, in Patients with Focal Segmental Glomerulosclerosis (FSGS): A Randomized, Double-blind, Active-Control, Dose-Escalation Study (DUET), patients aged 8-75 years with biopsy-proven FSGS, eGFR>30 ml/min per 1.73 m2, and urinary protein-to-creatinine ratio (UP/C) ≥1.0 g/g received sparsentan (200, 400, or 800 mg/d) or irbesartan (300 mg/d) for 8 weeks, followed by open-label sparsentan only. End points at week 8 were reduction from baseline in UP/C (primary) and proportion of patients achieving FSGS partial remission end point (FPRE) (UP/C: ≤1.5 g/g and >40% reduction [secondary]). RESULTS: Of 109 patients randomized, 96 received study drugs and had baseline and week 8 UP/C measurements. Sparsentan-treated patients had greater reductions in UP/C than irbesartan-treated patients did when all doses (45% versus 19%; P=0.006) or the 400 and 800 mg doses (47% versus 19%; P=0.01) were pooled for analysis. The FSGS partial remission end point was achieved in 28% of sparsentan-treated and 9% of irbesartan-treated patients (P=0.04). After 8 weeks of treatment, BP was reduced with sparsentan but not irbesartan, and eGFR was stable with both treatments. Overall, the incidence of adverse events was similar between groups. Hypotension and edema were more common among sparsentan-treated patients but did not result in study withdrawals. CONCLUSIONS: Patients with FSGS achieved significantly greater reductions in proteinuria after 8 weeks of sparsentan versus irbesartan. Sparsentan was safe and well tolerated.

• MeSH
• antagonisté endotelinového receptoru A aplikace a dávkování   škodlivé účinky   terapeutické užití   MeSH
• blokátory receptorů AT1 pro angiotensin II aplikace a dávkování   škodlivé účinky   terapeutické užití   MeSH
• dítě MeSH
• dospělí MeSH
• dvojitá slepá metoda MeSH
• fokálně segmentální glomeruloskleróza farmakoterapie   moč   MeSH
• irbesartan aplikace a dávkování   škodlivé účinky   terapeutické užití   MeSH
• kreatinin moč   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• proteinurie farmakoterapie   moč   MeSH
• senioři MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze II MeSH
• multicentrická studie MeSH
• práce podpořená grantem MeSH
• randomizované kontrolované studie MeSH

• MeSH
• antagonisté endotelinového receptoru A aplikace a dávkování   škodlivé účinky   terapeutické užití   MeSH
• blokátory receptorů AT1 pro angiotensin II aplikace a dávkování   škodlivé účinky   terapeutické užití   MeSH
• dítě MeSH
• dospělí MeSH
• dvojitá slepá metoda MeSH
• fokálně segmentální glomeruloskleróza * etiologie   etnologie   farmakoterapie   patofyziologie   MeSH
• glukokortikoidy terapeutické užití   MeSH
• imunosupresivní léčba MeSH
• irbesartan aplikace a dávkování   škodlivé účinky   MeSH
• lidé středního věku MeSH
• lidé MeSH
• proteinurie farmakoterapie   MeSH
• senioři MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• senioři MeSH
• Publikační typ
• randomizované kontrolované studie MeSH

The endothelin axis (endothelins and their receptors) is strongly involved in physiological and pathological processes. ET-1 plays a crucial role in particular in tumor diseases. Endothelin-1 receptors (ET(A) and ET(B)) are deregulated and overexpressed in several tumors such as melanoma and glioma. We studied the binding of 24 monoclonal antibodies directed against human ET(B) receptors (hET(B)) to different melanoma cell lines. Few of these mAbs bound to all the melanoma cell lines. One of them, rendomab B49, bound to ET(B) receptors expressed at the surface of human glioma stem cells. More recently, we produced new antibodies directed against human ET(A) receptor (hET(A)). Several antibodies have been isolated and have been screened on different tumoral cells lines. As for the mAbs directed against the hET(B) receptor only some of new antibodies directed against ET(A) receptor are capable to bind the human tumoral cell lines. Rendomab A63 directed against hET(A) is one of them. We report the specificity and binding properties of these mAbs and consider their potential use in diagnosis by an in vivo imaging approach.

• MeSH
• antagonisté endotelinového receptoru A aplikace a dávkování   metabolismus   MeSH
• CHO buňky MeSH
• Cricetulus MeSH
• endotelin-1 genetika   metabolismus   MeSH
• křečci praví MeSH
• lidé MeSH
• monoklonální protilátky aplikace a dávkování   metabolismus   MeSH
• myši nahé MeSH
• myši MeSH
• nádorové buněčné linie MeSH
• receptor endotelinu A genetika   metabolismus   MeSH
• receptor endotelinu B genetika   metabolismus   MeSH
• sekvence aminokyselin MeSH
• vazba proteinů fyziologie   MeSH
• xenogenní modely - testy protinádorové aktivity metody   MeSH
• zvířata MeSH
• Check Tag
• křečci praví MeSH
• lidé MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Hypertension in obesity is associated with increased insulin resistance, vascular mass and body mass index (BMI). The purpose of the study was to visualize endothelin-1 (ET-1) mediated constriction in arteries isolated from subcutaneous adipose tissue from obese hypertensive women previously operated by gastric bypass. Functional studies were conducted in a microvascular myograph. Expressed as percentage of contraction elicited by 124 mM KCl concentration-response curves for ET-1 were shifted leftward in arteries from obese hypertensive patients compared to healthy normotensive subjects. The vasodilator response to the ET-1 antagonist BQ123 (1 microM) was significantly higher in arteries from obese hypertensive patients (p<0.001). BQ123 induced relaxation was inhibited by NO synthase inhibitor L-NAME (0.1 nM). Preincubation with BQ123 enhanced the relaxation induced by acetylcholine (ACh; 0.1 nM - 0.1 mM) (p<0.001), but not that induced by NO donor sodium nitroprusside (SNP; 0.1 nM - 0.1 mM), in arteries from obese hypertensive patients. The present study show that hypertension yet prevail after gastric bypass surgery and the ET(A) receptor antagonist BQ123 may be a useful tool in reducing blood pressure in obese hypertensive patients.

• MeSH
• antagonisté endotelinového receptoru A farmakologie   terapeutické užití   MeSH
• cévní endotel účinky léků   metabolismus   MeSH
• cyklické peptidy farmakologie   terapeutické užití   MeSH
• hypertenze farmakoterapie   metabolismus   chirurgie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• obezita farmakoterapie   metabolismus   chirurgie   MeSH
• orgánové kultury - kultivační techniky MeSH
• receptor endotelinu A fyziologie   MeSH
• tuková tkáň krevní zásobení   účinky léků   metabolismus   MeSH
• vazodilatace účinky léků   fyziologie   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• žaludeční bypass trendy   MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

The global epidemic of diabetes is of significant concern. Diabetes associated vascular disease signifies the principal cause of morbidity and mortality in diabetic patients. It is also the most rapidly increasing risk factor for cognitive impairment, a silent disease that causes loss of creativity, productivity, and quality of life. Small vessel disease in the cerebral vasculature plays a major role in the pathogenesis of cognitive impairment in diabetes. Endothelin system, including endothelin-1 (ET-1) and the receptors (ET(A) and ET(B)), is a likely candidate that may be involved in many aspects of the diabetes cerebrovascular disease. In this review, we took a brain-centric approach and discussed the role of the ET system in cerebrovascular and cognitive dysfunction in diabetes.

• MeSH
• antagonisté endotelinového receptoru A aplikace a dávkování   metabolismus   MeSH
• antagonisté endotelinového receptoru B aplikace a dávkování   metabolismus   MeSH
• endoteliny agonisté   antagonisté a inhibitory   metabolismus   MeSH
• komplikace diabetu farmakoterapie   metabolismus   MeSH
• lidé MeSH
• mozek účinky léků   metabolismus   MeSH
• mozkový krevní oběh účinky léků   fyziologie   MeSH
• receptor endotelinu A metabolismus   MeSH
• receptor endotelinu B metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH