Endothelin system
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Plicní arteriální hypertenze (PAH) je závažné onemocnění charakterizované progredující prekapilární plicní hypertenzí. V posledních dvou desetiletích došlo k významnému pokroku v poznání patofyziologie a léčby PAH. Endotelin-1 je nejsilnější endogenní vazokonstriktor s vlastnostmi mitogenními a prozánětlivými. Jeho klíčová role v patofyziologii PAH je nepochybná. Aktivovaný endoteliální systém lze u nemocných s PAH ovlivnit blokádou endotelinových receptorů ETA a ETB. Bosentan je duální antagonista receptorů pro endotelin. Jeho účinek je doložen u řady typů PAH. Bosentan je první registrovaný perorální přípravek pro léčbu PAH a je považován za lék volby u nemocných ve stadiu NYHA II a III. Sitaxsentan a ambrisentan jsou selektivní antagonisté endotelinového receptoru ETA. Otázka superiority účinku selektivní nebo duální blokády receptorů pro endotelin v léčbě PAH zůstává nevyřešena, neboť schází dostatečně rozsáhlá studie s placebem kontrolovaným podáním selektivních a duálních antagonistů.
Pulmonary arterial hypertension (PAH) is a serious disease characterized by progressive precapillary pulmonary hypertension. Over the last two decades, substantial advances have been made in knowledge of the pathophysiology of PAH and its management. Endothelin-1, the most potent endogenous vasoconstrictor with mitogenic and antiinflammatory properties, is known to play a key role in the pathophysiology of PAH. The activated endothelial system in PAH patients can be controlled by ET A and ET B endothelin receptor blockade. Bosentan is a dual endothelin receptor antagonist. Its efficacy has been reported in PAH of various types. Bosentan is the first oral drug authorized for use in PAH treatment and is considered as the drug of choice in NYHA stages II and III. Sitaxsentan and ambrisentan are selective ET A endothelin receptor antagonists. The question of superiority of selective or dual endothelin receptor blockade in PAH management remains open, as a sufficiently extensive placebo controlled trial of selective versus dual endothelin receptor antagonists has not been carried out yet.
XII, 371 s. : obr., tab., grafy ; 24 cm
- MeSH
- endoteliny antagonisté a inhibitory škodlivé účinky fyziologie MeSH
- nemoci cév MeSH
- nemoci nervového systému MeSH
- patologické procesy MeSH
- Publikační typ
- sborníky MeSH
- Konspekt
- Biologické vědy
- NLK Obory
- biologie
- farmacie a farmakologie
Handbook of experimental pharmacology, ISSN 0171-2004 Vol. 152
xxiv, 532 s. : il.
- MeSH
- antagonisté endotelinového receptoru MeSH
- endoteliny MeSH
- receptory endotelinů fyziologie MeSH
- Publikační typ
- příručky MeSH
- Konspekt
- Farmacie. Farmakologie
- NLK Obory
- farmacie a farmakologie
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
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
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
AIM: Endothelin-1 (ET-1) plays an important role in the pathogenesis of salt-dependent forms of hypertension in adult rats, but its participation in salt hypertension elicited in immature rats is still unknown. Therefore, we compared ET-1 role in the development or the maintenance of salt hypertension induced in young (4-week-old) or adult (12-week-old) Dahl rats. METHODS: The contribution of pressor ET-1 effects to the maintenance of high blood pressure (BP) was studied using acute injection of ET(A) receptor antagonist ambrisentan (BSF 208075, 1 mg kg(-1) iv) to young or adult rats with established salt hypertension. Furthermore, using chronic ambrisentan treatment (30 mg kg(-1) day(-1) in the drinking fluid during 5 weeks of high salt intake), we investigated the age-dependent involvement of ET(A) receptors in salt hypertension development in these two age groups. RESULTS: Acute ET(A) receptor blockade lowered BP in both age groups of salt hypertensive Dahl rats more than in rats fed a low-salt diet (but without any age-dependent difference). Chronic ET(A) receptor blockade strongly attenuated the development of salt hypertension and cardiac hypertrophy in adult rats, but it had no significant effects on salt hypertension in young animals. Pronounced BP reduction induced in adult salt hypertensive rats by chronic ambrisentan treatment was attributed to attenuated sympathetic BP component, without changes in nitric oxide (NO)-dependent BP regulation. In contrast, chronic ambrisentan treatment of young animals did not modify sympathetic BP component but substantially attenuated NO-dependent vasodilatation. CONCLUSIONS: ET(A) receptor-mediated ET-1 effects play an important role in salt hypertension of adult but not young Dahl rats.
- MeSH
- antagonisté endotelinového receptoru A MeSH
- dieta s nízkým obsahem soli MeSH
- fenylpropionáty farmakologie MeSH
- hypertenze chemicky indukované patofyziologie MeSH
- krevní tlak účinky léků fyziologie MeSH
- krysa rodu rattus MeSH
- kuchyňská sůl farmakologie MeSH
- potkani inbrední Dahl MeSH
- pyridaziny farmakologie MeSH
- receptor endotelinu A MeSH
- sympatický nervový systém účinky léků patofyziologie MeSH
- věkové faktory MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
