Basal calcium sensitization is decreased in spontaneously hypertensive rats, although their blood pressure (BP) response to acute Rho-kinase inhibition is enhanced. Using fasudil (Rho-kinase inhibitor) or nifedipine (L-VDCC blocker), we evaluated the contribution of calcium sensitization and calcium entry to BP maintenance in hypertensive transgenic Ren-2 rats (TGR) focusing on the influence of major vasoactive systems and/or baroreflex efficiency on BP responses to these two drugs. Homozygous TGR and normotensive Hannover Sprague-Dawley (HanSD) control rats aged 5, 11, or 22 weeks were used. The acute BP-lowering effects of fasudil or nifedipine were studied in intact rats, nitric oxide-deficient L-NAME-pretreated rats and rats subjected to combined blockade of the renin-angiotensin system (RAS), sympathetic nervous system (SNS) and nitric oxide synthase (NOS). Fasudil- or nifedipine-induced BP reduction increased during hypertension development in TGR. By contrast, the nifedipine-induced BP response decreased, whereas the fasudil-induced BP response increased with age in HanSD controls. Our data indicated a major contribution of nifedipine-sensitive calcium entry and relative attenuation of calcium sensitization in hypertensive rats compared with normotensive controls. The BP responses to fasudil or nifedipine were enhanced by NOS inhibition and combined blockade in normotensive HanSD rats but not in hypertensive TGR. In conclusion, calcium sensitization is attenuated by endogenous nitric oxide in normotensive HanSD rats but not in hypertensive TGR. Moreover, BP reduction elicited by acute Rho-kinase inhibition is partially compensated by enhanced sympathetic vasoconstriction. The decreased compensation in hypertensive rats with impaired baroreflex efficiency explains their greater BP response to fasudil than in normotensive animals.

• MeSH
• 1-(5-isochinolinsulfonyl)-2-methylpiperazin analogy a deriváty   farmakologie   MeSH
• baroreflex účinky léků   fyziologie   MeSH
• blokátory kalciových kanálů farmakologie   MeSH
• hypertenze patofyziologie   MeSH
• krevní tlak účinky léků   fyziologie   MeSH
• krysa rodu rattus MeSH
• nifedipin farmakologie   MeSH
• potkani Sprague-Dawley MeSH
• potkani transgenní MeSH
• renin-angiotensin systém účinky léků   MeSH
• vazokonstrikce účinky léků   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Objective: Our previous study in heterozygous Ren-2 transgenic rats (TGR) demonstrated that long-term treatment with endothelin receptor A (ETA) blocker atrasentan added to the renin-angiotensin system (RAS) blockade had renoprotective effects in a model of chronic kidney disease (CKD) induced by partial nephrectomy. Since ETA blockade is known to cause edema, we were interested whether diuretic treatment added to this therapy would be beneficial. Design and Methods: Partial nephrectomy (NX) was performed at the age of 3 months in TGR rats which were subjected to: (i) RAS blockade alone (angiotensin receptor blocker losartan and angiotensin converting enzyme inhibitor trandolapril), (ii) combined RAS (losartan and trandolapril) and ETA receptor blockade (atrasentan), or (iii) diuretic (hydrochlorothiazide) added to the combined RAS + ETA blockade for 50 weeks following NX. Results: At the end of the study systolic blood pressure and cardiac hypertrophy were similarly decreased in all treated groups. Survival was significantly improved by ETA receptor blockade added to RAS blockade with no further effects of diuretic treatment. However, additional diuretic treatment combined with RAS + ETA blockade decreased body weight and had beneficial renoprotective effects - reductions of both kidney weight and kidney damage markers. Proteinuria gradually increased in rats treated with RAS blockade alone, while it was substantially lowered by additional ETA blockade. In rats treated with additional diuretic, proteinuria was progressively reduced throughout the experiment. Conclusion: A diuretic added to the combined RAS and ETA blockade has late renoprotective effects in CKD induced by partial nephrectomy in Ren-2 transgenic rats. The diuretic improved: renal function (evaluated as proteinuria and creatinine clearance), renal morphology (kidney mass, glomerular volume), and histological markers of kidney damage (glomerulosclerosis index, tubulointerstitial injury).

• Publikační typ
• časopisecké články MeSH

Our studies in hypertensive Ren-2 transgenic rats (TGR) demonstrated that chronic administration of atrasentan (ETA receptor antagonist) decreased blood pressure by reduced Ca2+ influx through L-type voltage-dependent calcium channels (L-VDCC) and attenuated angiotensin II-dependent vasoconstriction. We were interested whether bosentan (nonselective ET(A)/ET(B) receptor antagonist) would have similar effects. Young 4-week-old (preventive study) and adult 8-week-old (therapeutic study) heterozygous TGR and their normotensive Hannover Sprague-Dawley (HanSD) controls were fed normal-salt (NS, 0.6 % NaCl) or high-salt (HS, 2 % NaCl) diet for 8 weeks. An additional group of TGR fed HS was treated with bosentan (100 mg/kg/day). Bosentan had no effect on BP of TGR fed high-salt diet in both the preventive and therapeutic studies. There was no difference in the contribution of angiotensin II-dependent and sympathetic vasoconstriction in bosentan-treated TGR compared to untreated TGR under the condition of high-salt intake. However, bosentan significantly reduced NO-dependent vasodilation and nifedipine-sensitive BP component in TGR on HS diet. A highly important correlation of nifedipine-induced BP change and the BP after L-NAME administration was demonstrated. Although bosentan did not result in any blood pressure lowering effects, it substantially influenced NO-dependent vasodilation and calcium influx through L-VDCC in the heterozygous TGR fed HS diet. A significant correlation of nifedipine-induced BP change and the BP after L-NAME administration suggests an important role of nitric oxide in the closure of L-type voltage dependent calcium channels.

• MeSH
• antagonisté endotelinového receptoru farmakologie   MeSH
• bosentan farmakologie   MeSH
• heterozygot MeSH
• hypertenze farmakoterapie   genetika   metabolismus   patofyziologie   MeSH
• krevní tlak účinky léků   MeSH
• kuchyňská sůl * MeSH
• modely nemocí na zvířatech MeSH
• oxid dusnatý metabolismus   MeSH
• potkani Sprague-Dawley MeSH
• potkani transgenní MeSH
• renin genetika   MeSH
• vápníková signalizace účinky léků   MeSH
• vápníkové kanály - typ L metabolismus   MeSH
• vazodilatace účinky léků   MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Chronic kidney disease (CKD) is a life-threatening disease arising as a frequent complication of diabetes, obesity and hypertension. Since it is typically undetected for long periods, it often progresses to end-stage renal disease. CKD is characterized by the development of progressive glomerulosclerosis, interstitial fibrosis and tubular atrophy along with a decreased glomerular filtration rate. This is associated with podocyte injury and a progressive rise in proteinuria. As endothelin-1 (ET-1) through the activation of endothelin receptor type A (ET(A)) promotes renal cell injury, inflammation, and fibrosis which finally lead to proteinuria, it is not surprising that ET(A) receptors antagonists have been proven to have beneficial renoprotective effects in both experimental and clinical studies in diabetic and non-diabetic CKD. Unfortunately, fluid retention encountered in large clinical trials in diabetic CKD led to the termination of these studies. Therefore, several advances, including the synthesis of new antagonists with enhanced pharmacological activity, the use of lower doses of ET antagonists, the addition of diuretics, plus simply searching for distinct pathological states to be treated, are promising targets for future experimental studies. In support of these approaches, our group demonstrated in adult subtotally nephrectomized Ren-2 transgenic rats that the addition of a diuretic on top of renin-angiotensin and ET(A) blockade led to a further decrease of proteinuria. This effect was independent of blood pressure which was normalized in all treated groups. Recent data in non-diabetic CKD, therefore, indicate a new potential for ET(A) antagonists, at least under certain pathological conditions.

• MeSH
• antagonisté endotelinového receptoru A farmakologie   terapeutické užití   MeSH
• antihypertenziva farmakologie   terapeutické užití   MeSH
• chronická renální insuficience metabolismus   prevence a kontrola   MeSH
• diuretika farmakologie   terapeutické užití   MeSH
• endotelin-1 antagonisté a inhibitory   metabolismus   MeSH
• hypertenze farmakoterapie   metabolismus   MeSH
• lidé MeSH
• receptor endotelinu A metabolismus   MeSH
• renin-angiotensin systém účinky léků   fyziologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy 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

BACKGROUND: Our previous experiments demonstrated that selective endothelin A (ETA) receptor blockade had antihypertensive effects in Ren-2 transgenic rats (TGRs), but the mechanisms responsible for this change of blood pressure (BP) have not been explored yet. METHOD: Four-week-old male heterozygous TGRs and their normotensive controls--Hannover Sprague-Dawley (HanSD) rats--were fed high-salt diet (2% NaCl) and were treated with selective ETA receptor blocker atrasentan (5 mg/kg per day) for 8 weeks. At the end of the study, the contribution of principle vasoactive systems was evaluated by the sequential blockade of the renin-angiotensin system (captopril), sympathetic nervous system (pentolinium) and nitric oxide synthase [N-nitro-L-arginine methyl ester (L-NAME)]. The role of calcium influx through L-type voltage-dependent calcium channels in BP maintenance was evaluated using nifedipine. In a separate group of animals, the efficiency of distinct vasodilator systems--prostanoids (blocked by nonselective cyclooxygenase inhibitor indomethacin) and Ca-activated K channels (inhibited by tetraethylammonium)--was also analyzed. RESULTS: Atrasentan attenuated the development of hypertension in heterozygous TGRs, but had no effects in Hannover Sprague-Dawley rats. Moreover, atrasentan moderately attenuated renin-angiotensin system-dependent vasoconstriction, whereas it had no effect on sympathetic vasoconstriction. The nifedipine-sensitive BP component was markedly decreased by atrasentan treatment. In contrast, vasodilatation mediated by nitric oxide, endogenous prostanoids or Ca-activated K channels was reduced in atrasentan-treated TGRs, indicating the absence of compensatory augmentation of endothelin B receptor-mediated vasodilation in these animals. CONCLUSION: BP-lowering effect of chronic atrasentan treatment in TGRs was mainly caused by reduced Ca influx through L-type voltage-dependent calcium channels due to missing ETA receptor-dependent vasoconstriction and attenuated angiotensin II-dependent vasoconstriction.

• MeSH
• antagonisté endotelinového receptoru A chemie   MeSH
• antihypertenziva chemie   MeSH
• hypertenze patofyziologie   MeSH
• kaptopril chemie   MeSH
• krevní tlak fyziologie   MeSH
• krmivo pro zvířata MeSH
• krysa rodu rattus MeSH
• kuchyňská sůl farmakologie   MeSH
• NG-nitroargininmethylester chemie   MeSH
• nifedipin chemie   MeSH
• oxid dusnatý metabolismus   MeSH
• pentoliniumtartrát chemie   MeSH
• potkani Sprague-Dawley MeSH
• potkani transgenní MeSH
• pyrrolidiny terapeutické užití   MeSH
• renin-angiotensin systém účinky léků   MeSH
• renin genetika   MeSH
• sympatický nervový systém patofyziologie   MeSH
• synthasa oxidu dusnatého metabolismus   MeSH
• vápník chemie   metabolismus   MeSH
• vápníkové kanály - typ L metabolismus   MeSH
• vazodilatace účinky léků   MeSH
• vazokonstrikce účinky léků   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Hypertension is one of the major risk factors of cardiovascular diseases, but despite a century of clinical and basic research, the discrete etiology of this disease is still not fully understood. The same is true for obesity, which is recognized as a major global epidemic health problem nowadays. Obesity is associated with an increasing prevalence of the metabolic syndrome, a cluster of risk factors including hypertension, abdominal obesity, dyslipidemia, and hyperglycemia. Epidemiological studies have shown that excess weight gain predicts future development of hypertension, and the relationship between BMI and blood pressure (BP) appears to be almost linear in different populations. There is no doubt that obesity-related hypertension is a multifactorial and polygenic trait, and multiple potential pathogenetic mechanisms probably contribute to the development of higher BP in obese humans. These include hyperinsulinemia, activation of the renin-angiotensin-aldosterone system, sympathetic nervous system stimulation, abnormal levels of certain adipokines such as leptin, or cytokines acting at the vascular endothelial level. Moreover, some genetic and epigenetic mechanisms are also in play. Although the full manifestation of both hypertension and obesity occurs predominantly in adulthood, their roots can be traced back to early ontogeny. The detailed knowledge of alterations occurring in the organism of experimental animals during particular critical periods (developmental windows) could help to solve this phenomenon in humans and might facilitate the age-specific prevention of human obesity-related hypertension. In addition, better understanding of particular pathophysiological mechanisms might be useful in so-called personalized medicine.

• MeSH
• biologické modely MeSH
• hmotnostní přírůstek genetika   MeSH
• hypertenze genetika   patofyziologie   MeSH
• krevní tlak genetika   MeSH
• lidé MeSH
• metabolický syndrom genetika   patofyziologie   MeSH
• multifaktoriální dědičnost genetika   MeSH
• obezita genetika   patofyziologie   MeSH
• sympatický nervový systém patofyziologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH

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

Although Ren-2 transgenic rat (TGR) is defined as a model of angiotensin II-dependent hypertension, we studied whether the renin-angiotensin system (RAS) is really the main contributor to blood pressure (BP) elevation in hetero- and homozygous TGRs. Moreover, we examined whether repeated antisense (AS) therapy against AT(1) receptors would have a similar effect on the BP and the contribution of the principle vasoconstrictor/vasodilator systems to BP regulation in young and adult TGRs. From the age of 30 (young) and 100 (adult) days, rats were injected with AS for 40 days in 10-day intervals. After 10 and 40 days of AS therapy, the basal BP and acute BP responses to the sequential blockade of the RAS, sympathetic nervous (SNS) and nitric oxide systems were determined in conscious rats. The RAS system was the major system maintaining elevated BP in young homozygous animals, whereas there was an increasing contribution of the SNS in heterozygous TGR with age. The AS therapy in the young TGR had a transient BP-lowering effect that was associated with reduced cardiac hypertrophy; the AS therapy was most effective in young homozygous TGR, causing a substantial reduction of angiotensin-dependent vasoconstriction. In heterozygous rats, AS therapy at earlier stages was related to an inhibition of sympathetic vasoconstriction, whereas to RAS inhibition in established hypertension. In conclusion, repeated AS therapy had transient antihypertensive effects exclusively in young TGR. The contribution of the RAS to BP maintenance is highly important only in homozygous TGRs, whereas it is surpassed by SNS in heterozygous TGR.

• MeSH
• antihypertenziva terapeutické užití   MeSH
• antisense oligonukleotidy terapeutické užití   MeSH
• heterozygot MeSH
• homozygot MeSH
• hypertenze terapie   MeSH
• kardiomegalie farmakoterapie   patofyziologie   MeSH
• krysa rodu rattus MeSH
• modely nemocí na zvířatech MeSH
• oxid dusnatý fyziologie   MeSH
• potkani transgenní MeSH
• receptor angiotensinu typ 1 genetika   metabolismus   MeSH
• renin-angiotensin systém účinky léků   fyziologie   MeSH
• stárnutí genetika   fyziologie   MeSH
• sympatický nervový systém účinky léků   patofyziologie   MeSH
• vazokonstrikce účinky léků   fyziologie   MeSH
• věkové faktory 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