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

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: 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

AIMS: Chronic endothelin receptor A (ETA) blockade lowered blood pressure (BP) by decreasing angiotensin-dependent vasoconstriction and attenuating calcium influx. We tested whether the addition of ETA blockade to renin-angiotensin system (RAS) blockade would have further effects on the principal vasoactive systems contributing to BP maintenance in Ren-2 transgenic rats (TGR). METHODS: Four-week-old TGR rats were fed with normal-salt diet and given either different renin-angiotensin system (RAS) blockers [angiotensin receptor blocker losartan, angiotensin converting enzyme inhibitor captopril, direct renin inhibitor aliskiren], or ETA blocker (atrasentan) alone, or a combination of atrasentan with RAS blockers for 4weeks. At the end of the study, basal BP and acute BP responses to sequential blockade of renin-angiotensin (RAS), sympathetic nervous (SNS), and nitric oxide (NO) systems were determined in conscious rats. Thereafter, BP responses to acute inhibition of nifedipine-sensitive calcium influx through voltage-dependent calcium channels (L-VDCC) were measured. KEY FINDINGS: All RAS blockers similarly decreased BP to normotension, their effects being mediated through substantially attenuated RAS-dependent and moderately decreased SNS-dependent vasoconstriction. Atrasentan alone partially lowered BP, while BP was normalized by combination of atrasentan with either RAS blocker. In combination therapies, BP lowering effects resulted from the attenuation of both RAS- and SNS-dependent vasoconstriction. Moreover, atrasentan-treated groups had substantially reduced NO-dependent vasodilation and significantly decreased calcium influx through L-VDCC. CONCLUSIONS: Although the BP-lowering effect of combined ETA and RAS blockades in TGR is predominantly dependent on the effects exerted by RAS blockade, further effects are attributable to decreased calcium influx due to chronic ETA blockade.

• MeSH
• antagonisté endotelinového receptoru farmakologie   MeSH
• krevní tlak účinky léků   MeSH
• krysa rodu rattus MeSH
• potkani Sprague-Dawley MeSH
• potkani transgenní MeSH
• receptor endotelinu A účinky léků   MeSH
• renin-angiotensin systém účinky léků   MeSH
• renin genetika   fyziologie   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

• MeSH
• inhibitory fosfodiesterasy 5 farmakokinetika   terapeutické užití   MeSH
• lékové formy MeSH
• lidé MeSH
• nežádoucí účinky léčiv MeSH
• plicní hypertenze * diagnóza   farmakoterapie   patofyziologie   MeSH
• příčina smrti MeSH
• prognóza MeSH
• prostaglandiny farmakologie   terapeutické užití   MeSH
• receptor endotelinu A účinky léků   MeSH
• receptor endotelinu B účinky léků   MeSH
• receptory endotelinů účinky léků   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• novinové články MeSH

• MeSH
• chůze fyziologie   MeSH
• lidé MeSH
• plicní hypertenze * farmakoterapie   klasifikace   mortalita   MeSH
• prognóza MeSH
• pyrimidiny terapeutické užití   MeSH
• receptor endotelinu A * účinky léků   MeSH
• receptor endotelinu B účinky léků   MeSH
• sulfonamidy terapeutické užití   MeSH
• výsledek terapie MeSH
• zátěžový test metody   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• klinické zkoušky MeSH

• MeSH
• albuminurie diagnóza   etiologie   farmakoterapie   MeSH
• antagonisté receptorů pro angiotenzin farmakologie   terapeutické užití   MeSH
• diabetické nefropatie * farmakoterapie   MeSH
• dvojitá slepá metoda MeSH
• hodnoty glomerulární filtrace fyziologie   účinky léků   MeSH
• inhibitory ACE farmakologie   terapeutické užití   MeSH
• kombinovaná farmakoterapie MeSH
• lidé MeSH
• randomizované kontrolované studie jako téma * MeSH
• receptor endotelinu A fyziologie   účinky léků   MeSH
• renin-angiotensin systém fyziologie   účinky léků   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• novinové články MeSH