Potential additive effect of the treatment wirh endothelin receptor blocker (atrasentan) to low salt diet and renin-angiotensin system blockade in a rat model transenic for mouse renin gene and/or 5/6 nephrectomy will be studied. The aim is to further decrease the development of renal failure and cardiac hypertrophy.

Bude studován potenciální aditivní účinek léčby blokátorem endotelinových receptorů (atrasentan) k podávání diety s nízkým obsahem sodíku spolu s blokádou renin-angiotenzinového systému u modelu potkanů transgenních pro myší reninový gen a/nebo s 5/6 nefrektomií. Cílem je další zpomalení rozvoje renální insuficience a hypertrofie srdeční.

• MeSH
• blokátory receptorů AT1 pro angiotensin II MeSH
• endoteliny MeSH
• hypertenze MeSH
• hypertrofie levé komory srdeční MeSH
• inhibitory ACE MeSH
• krysa rodu rattus MeSH
• nefrektomie MeSH
• receptory endotelinů MeSH
• renální insuficience MeSH
• renin-angiotensin systém MeSH
• Check Tag
• krysa rodu rattus MeSH

• Konspekt
• Biochemie. Molekulární biologie. Biofyzika
• NLK Obory
• kardiologie
• angiologie
• biochemie
• NLK Publikační typ
• závěrečné zprávy o řešení grantu IGA MZ ČR

Our previous studies in rats with ablation nephrectomy have shown similar cardiorenal protective effects of renin-angiotensin system (RAS)-dependent treatment (combination of angiotensin-converting enzyme inhibitor and angiotensin II receptor blocker) and RAS-independent treatment (combination of α- and β-adrenoreceptor antagonist and diuretics). Moreover, selective blockade of endothelin (ET) receptor type A (ET(A)) improved survival rate and attenuated hypertension and organ damage in Ren-2 transgenic rats. Therefore, we were interested in whether ET(A) receptor blockade could have additive effects to the classical blockade of the RAS. Transgenic rats underwent 5/6 renal ablation at the age of 2 months and were treated for 20 weeks with RAS blockers alone (angiotensin II receptor blocker - losartan, and angiotensin-converting enzyme inhibitor - trandolapril), ET(A) receptor blocker alone (atrasentan) or with the combination of RAS and ET(A) receptor blockade. RAS blockade normalized blood pressure and improved survival. It decreased cardiac hypertrophy and proteinuria as well as tissue angiotensin II and ET-1 levels. In contrast, ET(A) receptor blockade only partially improved survival rate, reduced blood pressure, attenuated the development of cardiac hypertrophy and transiently reduced proteinuria. However, no additive cardio- and renoprotective effects of ET(A) and RAS blockade were noted at the end of the study.

• MeSH
• analýza přežití MeSH
• antagonisté endotelinového receptoru A MeSH
• blokátory receptorů AT1 pro angiotensin II farmakologie   MeSH
• chronická renální insuficience farmakoterapie   mortalita   patologie   MeSH
• indoly farmakologie   MeSH
• inhibitory ACE farmakologie   MeSH
• kombinovaná farmakoterapie MeSH
• krysa rodu rattus MeSH
• ledviny patologie   MeSH
• losartan farmakologie   MeSH
• modely nemocí na zvířatech MeSH
• nefrektomie metody   MeSH
• potkani Sprague-Dawley MeSH
• potkani transgenní MeSH
• pyrrolidiny farmakologie   MeSH
• receptor angiotensinu typ 1 metabolismus   MeSH
• receptor endotelinu A metabolismus   MeSH
• renální hypertenze farmakoterapie   mortalita   patologie   MeSH
• renin-angiotensin systém účinky léků   fyziologie   MeSH
• výsledek terapie MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Gender differences in the regulation of blood pressure (BP) and the contributions of the renin-angiotensin system remain controversial. We assessed the effect of castration on BP and organ damage, as well as angiotensin II (ANG II), estradiol and testosterone levels in heterozygous Ren-2 transgenic (TGR) rats and transgene-negative Hannover Sprague-Dawley control rats. Male TGR had severe hypertension throughout the experiment, while the BP of female TGR declined after 5 months to normotensive levels. Ovariectomy had no effect on BP, cardiac hypertrophy or proteinuria in female Ren-2 TGR. On the contrary, BP and cardiac hypertrophy were significantly reduced in castrated male TGR as compared to sham-operated TGR. Moreover, proteinuria in these animals was normalized to the levels of control rats. ANG II levels did not differ between male and female TGR, and no effect of castration on plasma and tissue ANG II levels was found either in male or female TGR at the end of the experiment. In conclusion, the contribution of the renin-angiotensin system to the gender difference in BP homeostasis seems to be negligible in aging heterozygous Ren-2 transgenic rats.

• MeSH
• hypertenze krev   genetika   prevence a kontrola   MeSH
• kastrace MeSH
• krysa rodu rattus MeSH
• multiorgánové selhání krev   genetika   prevence a kontrola   MeSH
• orchiektomie MeSH
• ovarektomie MeSH
• pohlavní dimorfismus MeSH
• potkani Sprague-Dawley MeSH
• potkani transgenní MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• srovnávací studie MeSH

OBJECTIVE: In the present study, we compared the effects of treatment with the novel soluble epoxide hydrolase (sEH) inhibitor (c-AUCB) with those of the AT1 receptor antagonist losartan on blood pressure (BP), autoregulation of renal blood flow (RBF) and on glomerular filtration rate (GFR) and the pressure-natriuresis relationship in response to stepwise reduction in renal arterial pressure (RAP) in Cyp1a1-Ren-2 transgenic rats. METHODS: Hypertension was induced in Cyp1a1-Ren-2 rats through dietary administration for 11 days of the natural xenobiotic indole-3-carbinol (I3C) which activates the renin gene. Treatment with c-AUCB and losartan was started 48 h before initiating administration of the diet containing I3C. Rats were prepared for renal functional studies to evaluate in-vivo renal autoregulatory efficiency when RAP was gradually decreased by an aortic clamp. RESULTS: I3C administration resulted in the development of severe hypertension which was associated with markedly lower basal RBF and GFR and substantially impaired autoregulatory efficiency as well as a suppression of the pressure-natriuresis relationship when compared with noninduced rats. Treatment with c-AUCB significantly decreased BP, improved autoregulatory efficiency of RBF and GFR and the slope of pressure-natriuresis relationship. Treatment with losartan completely prevented the impaired autoregulation and pressure-natriuresis relationship as well as the development of hypertension in I3C-induced rats. CONCLUSION: Our present findings indicate that chronic treatment with the sEH inhibitor c-AUCB substantially attenuates the development of malignant hypertension in I3C-induced rats likely via improvement of the renal autoregulatory efficiency and the pressure-natriuresis relationship.

• MeSH
• blokátory receptorů AT1 pro angiotensin II farmakologie   MeSH
• cytochrom P-450 CYP1A1 genetika   MeSH
• epoxid hydrolasy antagonisté a inhibitory   MeSH
• hodnoty glomerulární filtrace účinky léků   fyziologie   MeSH
• hypertenze maligní chemicky indukované   patofyziologie   prevence a kontrola   MeSH
• indoly škodlivé účinky   MeSH
• inhibitory enzymů farmakologie   MeSH
• krevní tlak účinky léků   fyziologie   MeSH
• krysa rodu rattus MeSH
• ledviny krevní zásobení   patologie   patofyziologie   MeSH
• losartan farmakologie   MeSH
• modely nemocí na zvířatech MeSH
• natriuréza účinky léků   fyziologie   MeSH
• nemoci ledvin patofyziologie   prevence a kontrola   MeSH
• potkani transgenní MeSH
• regionální krevní průtok účinky léků   fyziologie   MeSH
• renin genetika   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• srovnávací studie MeSH

1. Hypertension plays a critical role in the progression of chronic kidney disease (CKD) to end-stage renal disease (ESRD), but it has also been postulated that antihypertensive drugs that block the renin-angiotensin system (RAS) show class-specific renoprotective actions beyond their blood pressure (BP)-lowering effects. 2. Because this notion has recently been questioned, in the present study we compared the effects of a RAS-dependent antihypertensive therapy (a combination of trandolapril, an angiotensin-converting enzyme inhibitor (ACEI) and losartan, an angiotensin-II (AngII) receptor subtype 1A receptor antagonist) with a 'RAS-independent' antihypertensive therapy (a combination of labetalol, an alfa- and beta-adrenoreceptor antagonist with the diuretics, hydrochlorothiazide and furosemide) on the progression of CKD after 5/6 renal ablation (5/6 NX) in Ren-2 renin transgenic rats (TGR), a model of AngII-dependent hypertension. Normotensive transgene-negative Hannover Sprague-Dawley (HanSD) rats after 5/6 NX served as controls. 3. RAS-dependent and -independent antihypertensive therapies normalized BP and survival rate, and prevented the development of cardiac hypertrophy and glomerulosclerosis to the same degree in 5/6 NX HanSD rats and in 5/6 NX TGR. The present findings show that renoprotection, at least in rats after 5/6 NX, is predominantly BP-dependent. When equal lowering of BP was achieved, leading to normotension, cardio- and renoprotective effects were equivalent irrespective of the type of antihypertensive therapy. 4. These findings should be taken into consideration in attempts to develop new therapeutic approaches and strategies aimed to prevent the progression of CKD and to lower the incidence of ESRD.

• MeSH
• aldosteron moč   MeSH
• angiotensin II krev   metabolismus   MeSH
• antihypertenziva farmakologie   MeSH
• blokátory receptorů AT1 pro angiotensin II farmakologie   MeSH
• chronické selhání ledvin farmakoterapie   metabolismus   prevence a kontrola   MeSH
• chymosin metabolismus   MeSH
• diabetické nefropatie farmakoterapie   prevence a kontrola   MeSH
• diuretika farmakologie   MeSH
• furosemid farmakologie   MeSH
• hydrochlorthiazid farmakologie   MeSH
• hypertenze farmakoterapie   metabolismus   MeSH
• indoly farmakologie   MeSH
• inhibitory ACE farmakologie   MeSH
• kardiomegalie farmakoterapie   prevence a kontrola   MeSH
• kombinovaná farmakoterapie MeSH
• kreatinin krev   metabolismus   moč   MeSH
• krevní tlak účinky léků   MeSH
• krysa rodu rattus MeSH
• labetalol farmakologie   MeSH
• losartan farmakologie   MeSH
• potkani Sprague-Dawley MeSH
• potkani transgenní MeSH
• proteinurie krev   metabolismus   moč   MeSH
• renin-angiotensin systém účinky léků   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Recent studies have shown that the renal CYP450 (cytochrome P450) metabolites of AA (arachidonic acid), the vasoconstrictor 20-HETE (20-hydroxyeicosatetraenoic acid) and the vasodilator EETs (epoxyeicosatrienoic acids), play an important role in the pathophysiology of AngII (angiotensin II)-dependent forms of hypertension and the associated target organ damage. The present studies were performed in Ren-2 renin transgenic rats (TGR) to evaluate the effects of chronic selective inhibition of 20-HETE formation or elevation of the level of EETs, alone or in combination, on the course of hypertension and hypertension-associated end-organ damage. Both young (30 days of age) prehypertensive TGR and adult (190 days of age) TGR with established hypertension were examined. Normotensive HanSD (Hannover Sprague-Dawley) rats served as controls. The rats were treated with N-methylsulfonyl-12,12-dibromododec-11-enamide to inhibit 20-HETE formation and/or with N-cyclohexyl-N-dodecyl urea to inhibit soluble epoxide hydrolase and prevent degradation of EETs. Inhibition in TGR of 20-HETE formation combined with enhanced bioavailability of EETs attenuated the development of hypertension, cardiac hypertrophy, proteinuria, glomerular hypertrophy and sclerosis as well as renal tubulointerstitial injury. This was also associated with attenuation of the responsiveness of the systemic and renal vascular beds to AngII without modifying their responses to noradrenaline (norepinephrine). Our findings suggest that altered production and/or action of 20-HETE and EETs plays a permissive role in the development of hypertension and hypertension-associated end-organ damage in this model of AngII-dependent hypertension. This information provides a basis for a search for new therapeutic approaches for the treatment of hypertension.

• MeSH
• amidy farmakologie   terapeutické užití   MeSH
• angiotensin II farmakologie   MeSH
• antihypertenziva farmakologie   terapeutické užití   MeSH
• hypertenze komplikace   farmakoterapie   patofyziologie   MeSH
• krevní tlak účinky léků   MeSH
• krysa rodu rattus MeSH
• kyselina 8,11,14-eikosatrienová analogy a deriváty   metabolismus   MeSH
• kyseliny hydroxyeikosatetraenové biosyntéza   MeSH
• multiorgánové selhání etiologie   prevence a kontrola   MeSH
• noradrenalin farmakologie   MeSH
• potkani Sprague-Dawley MeSH
• potkani transgenní MeSH
• preklinické hodnocení léčiv metody   MeSH
• renální oběh účinky léků   MeSH
• sulfony farmakologie   terapeutické užití   MeSH
• vazokonstriktory farmakologie   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH