We found previously that selective blockade of endothelin ETA receptors is superior to nonselective ET(A)/ET(B) in attenuating hypertension and survival rate in Ren-2 transgenic rats (TGR). In the present pilot study, we were interested in whether similar effects will be found in TGR with inducible malignant hypertension (iTGR; official strain name Cyp1A1-Ren-2rats), which were derived from the original Ren-2 transgenic rat strain. Studies were performed in three-month old male iTGR. Treatment with either bosentan, a non-selective ET(A)/ET(B), or with atrasentan, a selective ET(A) receptor blocker, was started on day 2 of the experiment. Feeding with indole-3-carbinole (13C; 03% in rat chow), a natural xenobiotic which activates the Cyplal promoter of the mouse Ren-2 gene, began on day 3 and lasted for 4 days until day 6. Systolic BP, body weight, plasma ANG II and tissue ANG II and ET-1 concentrations were determined daily. Severe hypertension developed as early as 1 day after beginning of 13C feeding which was accompanied by a significant reduction in body weight and by increases in plasma and tissue ANG II and left ventricle ET-1 concentrations. Atrasentan or bosentan had no effects on the rise in BP or plasma and tissue ANG II concentrations but prevented the rise in heart ventricle ET-1 concentration. Our data show that blockade of the ET system does not prevent or attenuate the rapid development of severe hypertension in iTGR; a long-term protective effect of ET blockade on cardiac (and renal) damage, however, cannot be excluded and awaits further investigations.

• MeSH
• angiotensin II krev   metabolismus   MeSH
• antagonisté endotelinového receptoru MeSH
• antihypertenziva farmakologie   MeSH
• cytochrom P-450 CYP1A1 genetika   účinky léků   MeSH
• endotelin-1 MeSH
• hypertenze farmakoterapie   chemicky indukované   MeSH
• indoly škodlivé účinky   MeSH
• krevní tlak účinky léků   MeSH
• krysa rodu rattus MeSH
• ledviny metabolismus   MeSH
• modely nemocí na zvířatech MeSH
• potkani transgenní MeSH
• pyrrolidiny farmakologie   MeSH
• receptory endotelinů MeSH
• renin genetika   MeSH
• srdeční komory metabolismus   MeSH
• sulfonamidy farmakologie   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• práce podpořená grantem MeSH

Renin-angiotensin system (RAS) plays a key role in the regulation of renal function, volume of extracellular fluid and blood pressure. The activation of RAS also induces oxidative stress, particularly superoxide anion (O(2)(-)) formation. Although the involvement of O(2)(-) production in the pathology of many diseases is known for long, recent studies also strongly suggest its physiological regulatory function of many organs including the kidney. However, a marked accumulation of O(2)(-) in the kidney alters normal regulation of renal function and thus may contribute to the development of salt-sensitivity and hypertension. In the kidney, O(2)(-) acts as vasoconstrictor and enhances tubular sodium reabsorption. Nitric oxide (NO), another important radical that exhibits opposite effects than O(2)(-), is also involved in the regulation of kidney function. O(2)(-) rapidly interacts with NO and thus, when O(2)(-) production increases, it diminishes the bioavailability of NO leading to the impairment of organ function. As the activation of RAS, particularly the enhanced production of angiotensin II, can induce both O(2)(-) and NO generation, it has been suggested that physiological interactions of RAS, NO and O(2)(-) provide a coordinated regulation of kidney function. The imbalance of these interactions is critically linked to the pathophysiology of salt-sensitivity and hypertension.

• MeSH
• angiotensin II metabolismus   MeSH
• financování organizované MeSH
• hypertenze etiologie   metabolismus   patofyziologie   MeSH
• krevní tlak MeSH
• kuchyňská sůl škodlivé účinky   MeSH
• ledviny metabolismus   patofyziologie   MeSH
• lidé MeSH
• modely nemocí na zvířatech MeSH
• oxid dusnatý metabolismus   MeSH
• oxidační stres MeSH
• renin-angiotensin systém MeSH
• sodík metabolismus   MeSH
• superoxidy metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• přehledy MeSH

We have recently found in male homozygous hypertensive Ren-2 transgenic rats (TGRs) fed a high-salt diet that early onset selective endothelin (ET) A (ET(A)) or nonselective ET(A)/ET B (ET(B)) receptor blockade improved survival rate and reduced proteinuria, glomerulosclerosis, and cardiac hypertrophy, whereas selective ET(A) receptor blockade also significantly attenuated the rise in blood pressure. Because antihypertensive therapy in general is known to be more efficient when started at early age, our study was performed to determine whether onset of ET receptor blockade at a later age in animals with established hypertension will have similar protective effects as does early-onset therapy. Male homozygous TGRs and age-matched normotensive Hannover Sprague-Dawley rats were fed a high-salt diet between days 51 and 90 of age. TGRs received vehicle (untreated), the selective ET(A) receptor blocker atrasentan (ABT-627), or the nonselective ET(A)/ET(B) receptor blocker bosentan. Survival rates in untreated and bosentan-treated TGRs were 50% and 64%, respectively, whereas with atrasentan, survival rate of TGR was 96%, thus, similar to 93% in Hannover Sprague-Dawley rats. From day 60 on, systolic blood pressure in atrasentan-treated TGRs was transiently lower (P<0.05) than in untreated or bosentan-treated TGRs. Glomerular podocyte injury was substantially reduced with atrasentan treatment independent of severe hypertension and strongly correlated with survival (P<0.001). Our data indicate that in homozygous TGR ET receptors play an important role also in established hypertension. Selective ET(A) receptor blockade not only reduces podocyte injury and end-organ damage but also improves growth and survival independently of hypertension.

• MeSH
• antagonisté endotelinového receptoru A MeSH
• antagonisté endotelinového receptoru B MeSH
• financování organizované MeSH
• geneticky modifikovaná zvířata MeSH
• hypertenze genetika   mortalita   patofyziologie   prevence a kontrola   MeSH
• krysa rodu rattus MeSH
• míra přežití MeSH
• mutantní kmeny potkanů MeSH
• myši MeSH
• podocyty metabolismus   patologie   MeSH
• potkani Sprague-Dawley MeSH
• receptor endotelinu A fyziologie   MeSH
• receptor endotelinu B fyziologie   MeSH
• systola genetika   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• srovnávací studie MeSH

We have recently found that nonselective endothelin ETA/ETB receptor blockade markedly improves survival rate and ameliorates end-organ damage in male homozygous rats transgenic (TGR) for the mouse Ren-2 renin gene without lowering blood pressure. Because activation of the ETA receptor may be responsible for the detrimental effects of ET in the development of hypertension, this study was performed to determine whether ETA or ETA/ETB receptor blockade exerts these beneficial effects. TGR and age-matched normotensive Hannover Sprague-Dawley rats fed a high-salt diet received either vehicle or bosentan and atrasentan (ABT-627) as nonselective ETA/ETB and selective ETA receptor blockers, respectively, from 29 until 90 days of age. The survival rate of 48% in untreated TGR was significantly (P<0.01) improved to 79% by bosentan and to 92% by ABT-627 (ABT-627 versus bosentan P<0.05). Proteinuria, glomerulosclerosis, and cardiac hypertrophy, as well as ET-1 content in left ventricular tissue, were significantly reduced by bosentan and to a greater degree by ABT-627, which also significantly attenuated the rise in blood pressure (P<0.05). Our data indicate that the ET system, especially via ETA receptors, plays an important role in the development of hypertensive end-organ damage and confirm the concept that the predominant role of ETB receptors within the peripheral vasculature is to mediate the vasorelaxant actions of ET-1. They also demonstrate that selective blockade of ETA receptors is superior to nonselective ETA/ETB in attenuating hypertension, hypertensive organ damage, and survival rate.

• MeSH
• analýza přežití MeSH
• antagonisté endotelinového receptoru A MeSH
• endotelin-1 antagonisté a inhibitory   MeSH
• fokálně segmentální glomeruloskleróza patologie   MeSH
• geneticky modifikovaná zvířata MeSH
• hypertenze etiologie   metabolismus   patofyziologie   MeSH
• kardiomegalie patologie   MeSH
• krevní tlak MeSH
• krysa rodu rattus MeSH
• kuchyňská sůl MeSH
• ledviny patologie   MeSH
• myokard metabolismus   MeSH
• osmolární koncentrace MeSH
• potkani Sprague-Dawley MeSH
• proteinurie patofyziologie   MeSH
• pyrrolidiny farmakologie   MeSH
• receptor endotelinu A MeSH
• renin metabolismus   MeSH
• sulfonamidy farmakologie   MeSH
• tělesná hmotnost MeSH
• velikost orgánu MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH

• MeSH
• alfa blokátory aplikace a dávkování   farmakologie   MeSH
• homozygot MeSH
• hypertenze dietoterapie   farmakoterapie   prevence a kontrola   MeSH
• krysa rodu rattus MeSH
• přežití MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• zvířata MeSH

• MeSH
• antagonisté endotelinového receptoru MeSH
• antihypertenziva farmakologie   MeSH
• elektrolyty moč   MeSH
• finanční podpora výzkumu jako téma MeSH
• kreatinin metabolismus   MeSH
• krysa rodu rattus MeSH
• proteinurie mortalita   patologie   MeSH
• receptory endotelinů MeSH
• renální hypertenze farmakoterapie   mortalita   patologie   MeSH
• renin genetika   MeSH
• sulfonamidy farmakologie   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH

• MeSH
• finanční podpora výzkumu jako téma MeSH
• hypertenze patofyziologie   MeSH
• krysa rodu rattus MeSH
• renální oběh fyziologie   MeSH
• sympatický nervový systém fyziologie   patofyziologie   MeSH
• synthasa oxidu dusnatého antagonisté a inhibitory   fyziologie   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• zvířata MeSH