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

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

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

Chronic kidney disease (CKD) is a life-threatening disease arising as a frequent complication of diabetes, obesity and hypertension. Since it is typically undetected for long periods, it often progresses to end-stage renal disease. CKD is characterized by the development of progressive glomerulosclerosis, interstitial fibrosis and tubular atrophy along with a decreased glomerular filtration rate. This is associated with podocyte injury and a progressive rise in proteinuria. As endothelin-1 (ET-1) through the activation of endothelin receptor type A (ET(A)) promotes renal cell injury, inflammation, and fibrosis which finally lead to proteinuria, it is not surprising that ET(A) receptors antagonists have been proven to have beneficial renoprotective effects in both experimental and clinical studies in diabetic and non-diabetic CKD. Unfortunately, fluid retention encountered in large clinical trials in diabetic CKD led to the termination of these studies. Therefore, several advances, including the synthesis of new antagonists with enhanced pharmacological activity, the use of lower doses of ET antagonists, the addition of diuretics, plus simply searching for distinct pathological states to be treated, are promising targets for future experimental studies. In support of these approaches, our group demonstrated in adult subtotally nephrectomized Ren-2 transgenic rats that the addition of a diuretic on top of renin-angiotensin and ET(A) blockade led to a further decrease of proteinuria. This effect was independent of blood pressure which was normalized in all treated groups. Recent data in non-diabetic CKD, therefore, indicate a new potential for ET(A) antagonists, at least under certain pathological conditions.

• MeSH
• antagonisté endotelinového receptoru A farmakologie   terapeutické užití   MeSH
• antihypertenziva farmakologie   terapeutické užití   MeSH
• chronická renální insuficience metabolismus   prevence a kontrola   MeSH
• diuretika farmakologie   terapeutické užití   MeSH
• endotelin-1 antagonisté a inhibitory   metabolismus   MeSH
• hypertenze farmakoterapie   metabolismus   MeSH
• lidé MeSH
• receptor endotelinu A metabolismus   MeSH
• renin-angiotensin systém účinky léků   fyziologie   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

Plicní arteriální hypertenze (PAH) je velmi vzácné onemocnění, které však má zpravidla velmi nedobrou prognózu. Až do zavedení cílené specifické léčby jsme neměli k dispozici prakticky žádný způsob efektivní léčby. Poslední dvě dekády však naše terapeutické možnosti Zásadně změnily. Ačkoli kauzální léčbu stále nemáme, jsou dnes k dispozici nejméně čtyři lékové skupiny ovlivňující patofyziologickě mechanismy, které se na vzniku PAH podílejí. Díky tomu jsme schopni osud našich nemocných alespoň do určité míry zlepšit.

• Klíčová slova
• macitentan, Opsumit, studie SERAPHIN, epoprostenol i.v. podání, epoprostenol - termostabilní roztok, Veletri,
• MeSH
• antagonisté endotelinového receptoru A * aplikace a dávkování   farmakologie   terapeutické užití   MeSH
• časná diagnóza MeSH
• centralizované nemocniční služby MeSH
• familiární plicní arteriální hypertenze * diagnóza   farmakoterapie   MeSH
• hodnotící studie jako téma MeSH
• klinické zkoušky jako téma MeSH
• kombinovaná farmakoterapie MeSH
• lidé MeSH
• morbidita MeSH
• mortalita MeSH
• parenterální infuze * metody   škodlivé účinky   využití   MeSH
• plicní hypertenze * diagnóza   farmakoterapie   MeSH
• prognóza MeSH
• prostaglandiny * aplikace a dávkování   farmakologie   terapeutické užití   MeSH
• randomizované kontrolované studie jako téma MeSH
• Check Tag
• lidé MeSH