endothelin system Dotaz Zobrazit nápovědu
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.
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- 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
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
- MeSH
- angiotensiny fyziologie MeSH
- bradykinin MeSH
- katecholaminy MeSH
- skot MeSH
- techniky in vitro MeSH
- vápník MeSH
- zvířata MeSH
- Check Tag
- skot MeSH
- zvířata MeSH
- MeSH
- aldosteron MeSH
- dospělí MeSH
- endoteliny analýza krev MeSH
- hypertenze MeSH
- lidé MeSH
- renin-angiotensin systém MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
The first trimester of pregnancy is characterized by continuous proliferation, invasion and differentiation of cytotrophoblasts. These processes are precisely controlled both, in space and time by molecules such as endothelin-1 (ET-1). ET-1 is expressed in human first trimester trophoblast and is known to stimulate cytotrophoblast proliferation through endothelin A and B receptor subtypes (ET(A) and ET(B)), and cytotrophoblast invasion through ET(B). However, temporal changes of the ET system during the first trimester of pregnancy have not been previously studied. This study tested the hypothesis that ET-1 release, ET(A) and ET(B) expression are increased towards the end of the first trimester of pregnancy (weeks 10-12 vs. weeks 6-9), resulting in increased cytotrophoblast proliferation and invasion. Tissue samples were obtained from 17 surgical pregnancy interruptions (week 6-9: n=9; week 10-12: n=8). After cytotrophoblast isolation, the invasive and proliferative phenotypes were immune-separated by an alpha(6)-integrin antibody. Both proliferative and invasive cytotrophoblasts were cultured separately on plastic or Matrigel for 24 h. ET-1 release into the culture medium of both cytotrophoblast subtypes was measured by radioimmunoassay. ET(A) and ET(B) mRNA expression was measured by RT-PCR, and the ET-1 effect on cytotrophoblast proliferation and invasion was determined using proliferation and invasion assays, respectively. ET-1 release increased from early to late first trimester of pregnancy in both proliferative (1.8-4.5 fold) and invasive cytotrophoblasts (9.3-28 fold), especially when cultured on Matrigel. This was paralleled by less ET(B) mRNA on invasive cytotrophoblasts independent of the time period in first trimester, whereas ET(A) expression was similar on proliferative an invasive cytotrophoblasts. Proliferation and invasion of cytotrophoblasts under control conditions decreased from early to late first trimester. ET-1 stimulated both processes at both periods with the most pronounced effect (7-fold) on invasion in late first trimester. The ET-1/ET-receptor system changes between weeks 6-9 and 10-12 in pregnancy. Our data suggest an autocrine and endocrine ET-1 effect, which is stronger in late than in early first trimester of pregnancy paralleled by different stimulatory effects on trophoblast invasion and proliferation. In general, this suggests time as an additional effector of the critical processes governing placental development in the first trimester of human pregnancy.
- MeSH
- časové faktory MeSH
- endotelin-1 metabolismus MeSH
- kultivované buňky MeSH
- lidé MeSH
- placenta cytologie metabolismus MeSH
- proliferace buněk fyziologie MeSH
- první trimestr těhotenství metabolismus MeSH
- receptor endotelinu A metabolismus MeSH
- těhotenství MeSH
- trofoblasty metabolismus MeSH
- Check Tag
- lidé MeSH
- těhotenství MeSH
- ženské pohlaví 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
