BACKGROUND/AIMS: A growing body of evidence suggests that the interplay between the endothelin (ET) and the renin-angiotensin systems (RAS) plays an important role in the development of the malignant phase of hypertension. The present study was performed to evaluate the role of an interaction between ET and RAS in the development of hypertension and hypertension-associated end-organ damage in homozygous male transgenic rats harboring the mouse Ren-2 renin gene (TGRs) under conditions of normal-salt (NS, 0.45% NaCl) and high-salt (HS, 2% NaCl) intake. METHODS: Twenty-eight-day-old homozygous male TGRs and age-matched transgene-negative male normotensive Hannover Sprague-Dawley (HanSD) rats were randomly assigned to groups with NS or HS intake. Nonselective ET(A/B) receptor blockade was achieved with bosentan (100 mg/kg/day). Systolic blood pressure (BP) was measured in conscious animals by tail plethysmography. Rats were placed into metabolic cages to determine proteinuria and clearance of endogenous creatinine. At the end of the experiment the final arterial BP was measured directly in anesthetized rats. Kidneys were taken for morphological examination. RESULTS: All male HanSD fed either the NS or HS diet exhibited a 100% survival rate until 180 days of age (end of experiment). The survival rate in untreated homozygous male TGRs fed the NS diet was 41%, which was markedly improved by treatment with bosentan to 88%. The HS diet reduced the survival rate in homozygous male TGRs to 10%. The survival rate in homozygous male TGRs on the HS diet was significantly improved by bosentan to 69%. Treatment with bosentan did not influence either the course of hypertension or the final levels of BP in any of the experimental groups of HanSD rats or TGRs. Although the ET-1 content in the renal cortex did not differ between HanSD rats and TGRs, ET-1 in the left heart ventricle of TGRs fed the HS diet was significantly higher compared with all other groups. Administration of bosentan to homozygous male TGRs fed either the NS or HS diet markedly reduced proteinuria, glomerulosclerosis and attenuated the development of cardiac hypertrophy compared with untreated TGR. CONCLUSIONS: Our data show that nonselective ET(A/B) receptor blockade markedly improves the survival rate and ameliorates end-organ damage in homozygous male TGRs without significantly lowering BP.

• MeSH
• antagonisté endotelinového receptoru * MeSH
• antihypertenziva farmakologie   MeSH
• bosentan MeSH
• elektrolyty moč   MeSH
• endotelin-1 metabolismus   MeSH
• geneticky modifikovaná zvířata MeSH
• homozygot MeSH
• kreatinin metabolismus   MeSH
• krevní tlak MeSH
• krysa rodu Rattus MeSH
• ledviny metabolismus   patologie   MeSH
• potkani Sprague-Dawley MeSH
• proteinurie farmakoterapie   mortalita   patologie   MeSH
• renální hypertenze farmakoterapie   mortalita   patologie   MeSH
• renin genetika   MeSH
• sodík dietní farmakologie   MeSH
• sulfonamidy farmakologie   MeSH
• velikost orgánu MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• antagonisté endotelinového receptoru * MeSH
• antihypertenziva MeSH
• bosentan MeSH
• elektrolyty MeSH
• endotelin-1 MeSH
• kreatinin MeSH
• Ren2 protein, mouse MeSH Prohlížeč
• renin MeSH
• sodík dietní MeSH
• sulfonamidy MeSH

The aim was to evaluate the effects of renal denervation (RDN) on autoregulation of renal hemodynamics and the pressure-natriuresis relationship in Ren-2 transgenic rats (TGR) with aorto-caval fistula (ACF)-induced heart failure (HF). RDN was performed one week after creation of ACF or sham-operation. Animals were prepared for evaluation of autoregulatory capacity of renal blood flow (RBF) and glomerular filtration rate (GFR), and of the pressure-natriuresis characteristics after stepwise changes in renal arterial pressure (RAP) induced by aortic clamping. Their basal values of blood pressure and renal function were significantly lower than with innervated sham-operated TGR (p < 0.05 in all cases): mean arterial pressure (MAP) (115 ± 2 vs. 160 ± 3 mmHg), RBF (6.91 ± 0.33 vs. 10.87 ± 0.38 ml.min-1.g-1), urine flow (UF) (11.3 ± 1.79 vs. 43.17 ± 3.24 µl.min-1.g-1) and absolute sodium excretion (UNaV) (1.08 ± 0.27 vs, 6.38 ± 0.76 µmol.min-1.g-1). After denervation ACF TGR showed improved autoregulation of RBF: at lowest RAP level (80 mmHg) the value was higher than in innervated ACF TGR (6.92 ± 0.26 vs. 4.54 ± 0.22 ml.min-1.g-1, p < 0.05). Also, the pressure-natriuresis relationship was markedly improved after RDN: at the RAP of 80 mmHg UF equaled 4.31 ± 0.99 vs. 0.26 ± 0.09 µl.min-1.g-1 recorded in innervated ACF TGR, UNaV was 0.31 ± 0.05 vs. 0.04 ± 0.01 µmol min-1.g-1 (p < 0.05 in all cases). In conclusion, in our model of hypertensive rat with ACF-induced HF, RDN improved autoregulatory capacity of RBF and the pressure-natriuresis relationship when measured at the stage of HF decompensation.

• Klíčová slova
• Ren-2 transgenic hypertensive rat, Renal autoregulation, Renal blood flow, Volume-overload heart failure, sodium excretion,
• MeSH
• hodnoty glomerulární filtrace MeSH
• hypertenze * MeSH
• kardiorenální syndrom * MeSH
• krevní tlak MeSH
• krysa rodu Rattus MeSH
• ledviny MeSH
• natriuréza MeSH
• píštěle * MeSH
• potkani transgenní MeSH
• renální oběh MeSH
• srdeční selhání * MeSH
• sympatektomie MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Our previous studies in heterozygous Ren-2 transgenic rats (TGR) have shown that early treatment with selective endothelin (ET)(A) receptor blockade is superior to nonselective ET(A/B) receptor blockade. The aim of this study was to evaluate the role of the ET system in male heterozygous TGR with established hypertension (late-onset treatment). TGR and control Hannover Sprague-Dawley (HanSD) rats were fed a high-salt diet and were treated concomitantly with the nonselective ET(A/B) receptor blocker bosentan or the selective ET(A) receptor blocker atrasentan from day 52 of age on. Survival rate was partly increased by bosentan and fully normalized with atrasentan. Bosentan transiently decreased blood pressure (BP), whereas atrasentan significantly reduced BP as early as one week after the start of the treatment. This effect persisted for the whole experimental period. Atrasentan also substantially reduced cardiac hypertrophy, proteinuria, glomerulosclerosis and left ventricle ET-1 content. Bosentan improved and atrasentan almost restored podocyte architecture and reversed changes in podocyte phenotype represented by the expression of CD 10, desmin and vimentin. Our results demonstrate that selective ET(A) receptor blockade has more favorable effects than nonselective ET(A/B) receptor blockade and, unlike observed in homozygous TGR, ET(A) receptor blockade has similar effects in heterozygous rats with established hypertension as in young animals with developing hypertension.

• MeSH
• angiotensin II fyziologie   MeSH
• antagonisté endotelinového receptoru * MeSH
• elektronová mikroskopie MeSH
• endotelin-1 metabolismus   MeSH
• fokálně segmentální glomeruloskleróza patologie   MeSH
• geneticky modifikovaná zvířata MeSH
• heterozygot MeSH
• hypertenze maligní farmakoterapie   genetika   patologie   MeSH
• imunohistochemie MeSH
• krevní tlak účinky léků   genetika   MeSH
• krysa rodu Rattus MeSH
• ledviny patologie   MeSH
• míra přežití MeSH
• potkani Sprague-Dawley MeSH
• proteinurie genetika   MeSH
• renin genetika   fyziologie   MeSH
• sodík dietní farmakologie   MeSH
• tělesná hmotnost genetika   MeSH
• velikost orgánu genetika   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• angiotensin II MeSH
• antagonisté endotelinového receptoru * MeSH
• endotelin-1 MeSH
• renin MeSH
• sodík dietní MeSH

1. The aim of the present study was to test the hypothesis that increasing kidney tissue concentrations of epoxyeicosatrienoic acids (EETs) by preventing their degradation to the biologically inactive dihydroxyeicosatrienoic acids (DHETEs) using blockade of soluble epoxide hydrolase (sEH) would attenuate the progression of chronic kidney disease (CKD). 2. Ren-2 transgenic rats (TGR) after 5/6 renal mass reduction (5/6 NX) served as a model of CKD associated with angiotensin (Ang) II-dependent hypertension. Soluble epoxide hydrolase was inhibited using cis-4-[4-(3-adamantan-1-yl-ureido)cyclohexyloxy]benzoic acid (c-AUCB; 3 mg/L drinking water) for 20 weeks after 5/6 NX. Sham-operated normotensive transgene-negative Hannover Sprague-Dawley (HanSD) rats served as controls. 3. When applied in TGR subjected to 5/6 NX, c-AUCB treatment improved survival rate, prevented the increase in blood pressure, retarded the progression of cardiac hypertrophy, reduced proteinuria and the degree of glomerular and tubulointerstitial injury and reduced glomerular volume. All these organ-protective actions were associated with normalization of the intrarenal EETs:DHETEs ratio, an index of the availability of biologically active EETs, to levels observed in sham-operated HanSD rats. There were no significant concurrent changes of increased intrarenal AngII content. 4. Together, these results show that 5/6 NX TGR exhibit a profound deficiency of intrarenal availability of active epoxygenase metabolites (EETs), which probably contributes to the progression of CKD in this model of AngII-dependent hypertension, and that restoration of intrarenal availability of EETs using long-term c-AUCB treatment exhibits substantial renoprotective actions.

• Klíčová slova
• 5/6 nephrectomy, chronic kidney disease, cytochrome P450 enzymes, end-organ damage, epoxyeicosatrienoic acids, hypertension, renin-angiotensin system, soluble epoxide hydrolase,
• MeSH
• angiotensin II farmakologie   MeSH
• chronická renální insuficience farmakoterapie   metabolismus   MeSH
• epoxid hydrolasy antagonisté a inhibitory   metabolismus   MeSH
• hypertenze farmakoterapie   metabolismus   MeSH
• krevní tlak účinky léků   MeSH
• krysa rodu Rattus MeSH
• míra přežití MeSH
• nefrektomie metody   MeSH
• potkani Sprague-Dawley MeSH
• potkani transgenní metabolismus   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• angiotensin II MeSH
• epoxid hydrolasy MeSH

Hypothalamic paraventricular nucleus (PVN) and rostral ventrolateral medulla (RVLM) play an important role in brain control of blood pressure (BP). One of the important mechanisms involved in the pathogenesis of hypertension is the elevation of reactive oxygen species (ROS) production by nicotine adenine dinucleotide phosphate (NADPH) oxidase. The aim of our present study was to investigate NADPH oxidase-mediated superoxide (O(2)(-)) production and to search for the signs of lipid peroxidation in hypothalamus and medulla oblongata as well as in renal medulla and cortex of hypertensive male rats transgenic for the murine Ren-2 renin gene (Ren-2 TGR) and their age-matched normotensive controls - Hannover Sprague Dawley rats (HanSD). We found no difference in the activity of NADPH oxidase measured as a lucigenin-mediated O(2)(-) production in the hypothalamus and medulla oblongata. However, we observed significantly elevated NADPH oxidase in both renal cortex and medulla of Ren-2 TGR compared with HanSD. Losartan (LOS) treatment (10 mg/kg body weight/day) for 2 months (Ren-2 TGR+LOS) did not change NADPH oxidase-dependent O(2)(-) production in the kidney. We detected significantly elevated indirect markers of lipid peroxidation measured as thiobarbituric acid-reactive substances (TBARS) in Ren-2 TGR, while they were significantly decreased in Ren-2 TGR+LOS. In conclusion, the present study shows increased NADPH oxidase activities in renal cortex and medulla with significantly increased TBARS in renal cortex. No significant changes of NADPH oxidase and markers of lipid peroxidation were detected in the studied brain regions.

• MeSH
• blokátory receptorů AT1 pro angiotensin II farmakologie   terapeutické užití   MeSH
• hypertenze farmakoterapie   enzymologie   MeSH
• ledviny účinky léků   enzymologie   MeSH
• losartan farmakologie   terapeutické užití   MeSH
• mozek účinky léků   enzymologie   MeSH
• NADPH-oxidasy metabolismus   MeSH
• náhodné rozdělení MeSH
• peroxidace lipidů účinky léků   MeSH
• potkani transgenní MeSH
• superoxidy metabolismus   MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• blokátory receptorů AT1 pro angiotensin II MeSH
• losartan MeSH
• NADPH-oxidasy MeSH
• superoxidy MeSH

The present study was performed to evaluate the role of neuronal nitric oxide synthase (nNOS)-derived nitric oxide (NO) during the developmental phase of hypertension in transgenic rats harboring the mouse Ren-2 renin gene (TGR). The first aim of the present study was to examine nNOS mRNA expression in the renal cortex and to assess the renal functional responses to intrarenal nNOS inhibition by S-methyl-L-thiocitrulline (L-SMTC) in heterozygous TGR and in age-matched transgene-negative Hannover Sprague-Dawley rats (HanSD). The second aim was to evaluate the role of the renal sympathetic nerves in mediating the renal functional responses to intrarenal nNOS inhibition. Thus, we also evaluated the effects of intrarenal L-SMTC administration in acutely denervated TGR and HanSD. Expression of nNOS mRNA in the renal cortex was significantly increased in TGR compared with HanSD. Intrarenal administration of L-SMTC decreased the glomerular filtration rate (GFR), renal plasma flow (RPF) and sodium excretion and increased renal vascular resistance (RVR) in HanSD. In contrast, intrarenal inhibition of nNOS by L-SMTC did not alter GFR, RPF or RVR and elicited a marked increase in sodium excretion in TGR. This effect of intrarenal L-SMTC was not observed in acutely denervated TGR. These results suggest that during the developmental phase of hypertension TGR exhibit an impaired renal vascular responsiveness to nNOS derived NO or an impaired ability to release NO by nNOS despite enhanced expression of nNOS mRNA in the renal cortex. In addition, the data indicate that nNOS-derived NO increases tubular sodium reabsorption in TGR and that the renal nerves play an important modulatory role in this process.

• MeSH
• analýza párové shody MeSH
• analýza rozptylu MeSH
• citrulin analogy a deriváty   farmakologie   MeSH
• denervace MeSH
• geneticky modifikovaná zvířata MeSH
• hypertenze genetika   patofyziologie   MeSH
• inbrední kmeny potkanů MeSH
• inhibitory enzymů farmakologie   MeSH
• krysa rodu Rattus MeSH
• ledviny účinky léků   inervace   metabolismus   MeSH
• messenger RNA analýza   MeSH
• polymerázová řetězová reakce s reverzní transkripcí MeSH
• regulace genové exprese MeSH
• renální oběh účinky léků   MeSH
• renin genetika   MeSH
• sympatický nervový systém MeSH
• synthasa oxidu dusnatého, typ I MeSH
• synthasa oxidu dusnatého antagonisté a inhibitory   účinky léků   genetika   metabolismus   MeSH
• thiomočovina analogy a deriváty   farmakologie   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• citrulin MeSH
• inhibitory enzymů MeSH
• messenger RNA MeSH
• Nos1 protein, rat MeSH Prohlížeč
• Ren2 protein, mouse MeSH Prohlížeč
• renin MeSH
• S-methylthiocitrulline MeSH Prohlížeč
• synthasa oxidu dusnatého, typ I MeSH
• synthasa oxidu dusnatého MeSH
• thiomočovina MeSH

The new antidiabetic drugs, gliflozins, inhibit sodium-glucose transporter-2 in renal proximal tubules promoting glucose and sodium excretion. This leads not only to a significant improvement of glucose control but also to the reduction of blood pressure and body weight in both diabetic patients and experimental models. We examined whether these beneficial effects can also be achieved in a non-diabetic hypertensive model, namely in Ren-2 transgenic rats (TGR). Adult 6-month-old hypertensive TGR and their normotensive controls (Hannover Sprague-Dawley rats), were either untreated or treated with empagliflozin (10 mg/kg/day) for two months. Telemetric blood pressure monitoring, renal parameters as well as cardiac function via echocardiography were analyzed during the experiment. At the end of the study, the contribution of major vasoactive systems to blood pressure maintenance was studied. Metabolic parameters and markers of oxidative stress and inflammation were also analyzed. Empagliflozin had no effect on plasma glucose level but partially reduced blood pressure in TGR. Although food consumption was substantially higher in empagliflozin-treated TGR compared to the untreated animals, their body weight and the amount of epididymal and perirenal fat was decreased. Empagliflozin had no effect on proteinuria, but it decreased plasma urea, attenuated renal oxidative stress and temporarily increased urinary urea excretion. Several metabolic (hepatic triglycerides, non-esterified fatty acids, insulin) and inflammatory (TNF-α, leptin) parameters were also improved by empagliflozin treatment. By contrast, echocardiography did not reveal any effect of empagliflozin on cardiac function. In conclusion, empagliflozin exerted beneficial antihypertensive, anti-inflammatory and metabolic effects also in a non-diabetic hypertensive model.

• Klíčová slova
• Cardiac, Renal and metabolic parameters, SGLT-2 inhibitor,
• MeSH
• adipozita účinky léků   MeSH
• antiflogistika farmakologie   MeSH
• antihypertenziva farmakologie   MeSH
• antioxidancia farmakologie   MeSH
• benzhydrylové sloučeniny farmakologie   MeSH
• energetický metabolismus účinky léků   MeSH
• glukosidy farmakologie   MeSH
• hmotnostní úbytek účinky léků   MeSH
• hypertenze farmakoterapie   genetika   metabolismus   patofyziologie   MeSH
• krevní tlak účinky léků   MeSH
• krysa rodu Rattus MeSH
• modely nemocí na zvířatech MeSH
• potkani Sprague-Dawley MeSH
• potkani transgenní MeSH
• renin genetika   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• antiflogistika MeSH
• antihypertenziva MeSH
• antioxidancia MeSH
• benzhydrylové sloučeniny MeSH
• empagliflozin MeSH Prohlížeč
• glukosidy MeSH
• renin MeSH

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.

• Klíčová slova
• Calcium sensitization, L type voltage-dependent calcium channels, RhoA/Rho kinase pathway, calcium entry, fasudil, nifedipine, nitric oxide,
• 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
• Názvy látek
• 1-(5-isochinolinsulfonyl)-2-methylpiperazin MeSH
• blokátory kalciových kanálů MeSH
• fasudil MeSH Prohlížeč
• nifedipin MeSH

Recently, we demonstrated that chronic blockade of the renin-angiotensin system (RAS) lowered the blood pressure (BP) of adult Ren-2 transgenic rats (TGR) mainly through the attenuation of central sympathoexcitation. However, the participation of central and peripheral mechanisms in the development of high BP in immature TGR remains unclear. In the present study, 6-week-old heterozygous TGR males were chronically treated with intracerebroventricular (ICV) or intraperitoneal (IP) infusions of the AT1 receptor inhibitor losartan (1 or 2 mg/kg/day) for 4 weeks. The influence of these treatments on sympathetic- and angiotensin II-dependent BP components (BP response to pentolinium or captopril, respectively) as well as on BP response to exogenous angiotensin II were determined to evaluate the participation of central and peripheral RAS in hypertension development. Chronic IP losartan administration (1 or 2 mg/kg/day) lowered the BP of immature TGR by reducing both sympathetic and angiotensin II-dependent BP components. The central action of IP-administered losartan was indicated by a reduced BP response to acute ICV angiotensin II injection. Chronic ICV administration of a lower losartan dose (1 mg/kg/day) reduced only the sympathetic BP component, whereas a higher ICV administered dose (2 mg/kg/day) was required to influence the angiotensin II-dependent BP component. Accordingly, chronic ICV losartan administration of 2 mg/kg/day (but not 1 mg/kg/day) attenuated the BP response to acute intravenous angiotensin II application. In conclusion, central sympathoexcitation seems to play an important role in hypertension development in immature TGR. Central sympathoexcitation is highly susceptible to inhibition by low doses of RAS-blocking agents, whereas higher doses also affect peripheral angiotensin II-dependent vasoconstriction.

• Klíčová slova
• Ren-2 transgenic rats, angiotensin II, hypertension, intracerebroventricular, losartan,
• MeSH
• angiotensin II * MeSH
• hypertenze * MeSH
• krevní tlak fyziologie   MeSH
• krysa rodu Rattus MeSH
• losartan farmakologie   terapeutické užití   MeSH
• potkani transgenní MeSH
• renin-angiotensin systém MeSH
• renin metabolismus   MeSH
• vazokonstrikce MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• angiotensin II * MeSH
• losartan MeSH
• renin MeSH

The rat strain transgenic for the murine Ren-2 renin gene (TGR) is defined as a monogenic model of angiotensin II-dependent hypertension with endogenous activation of the renin-angiotensin system. Homozygous males TGR develop malignant hypertension with a strong salt-sensitive component. These animals show severe hypertension, proteinuria and high mortality. Morphological changes of renal parenchyma correspond to chronic ischemic glomerular changes. Heterozygous TGR develop only mild hypertension and thus provide a more suitable model of hypertension regarding to clinical studies. Within the renal parenchyma, secondary focal segmental glomerulosclerosis (FSGS) predominates. High-salt diet in heterozygous animals induces transition from benign to malignant phase of hypertension. In this case, ischemic glomerular changes are superimposed on preexisting secondary FSGS. In the regression model of hypertension (late-onset treatment) the effect of salt intake is attenuated. In homozygous TGR, early selective ET(A) receptor blockade decreased blood pressure and ameliorated end-organ damage. Late selective ET(A) receptor blockade reduced podocyte injury despite final severe hypertension. Survival rate was markedly improved in both regimens with ET(A) selective blockade, while there was only partial improvement with early non-selective blockade. Both bosentan and atrasentan decreased ET-1 levels in both regimens. In heterozygous TGR, early and late ET(A) treatment substantially while ET(A)/ET(B) treatment partially improved survival rate. Significant effect on BP was found with early and late ET(A) blockade, while ET(A)/ET(B) blockade had no effect. Bosentan and atrasentan similarly decreased ET-1 levels on both regimens. In conclusion, selective ET(A) receptor blockade is superior to nonselective ET(A)/ET(B) receptor blockade in attenuating hypertension and end-organ damage. Its effect is more pronounced when applied early in the life.

• MeSH
• antagonisté endotelinového receptoru A * MeSH
• antagonisté endotelinového receptoru B MeSH
• antihypertenziva farmakologie   MeSH
• atrasentan MeSH
• bosentan MeSH
• časové faktory MeSH
• endotelin-1 metabolismus   MeSH
• fokálně segmentální glomeruloskleróza genetika   metabolismus   patofyziologie   prevence a kontrola   MeSH
• heterozygot MeSH
• homozygot MeSH
• hypertenze komplikace   farmakoterapie   genetika   metabolismus   patofyziologie   MeSH
• krevní tlak účinky léků   MeSH
• krysa rodu Rattus MeSH
• kuchyňská sůl MeSH
• modely nemocí na zvířatech MeSH
• podocyty účinky léků   metabolismus   patologie   MeSH
• potkani transgenní MeSH
• progrese nemoci MeSH
• pyrrolidiny farmakologie   MeSH
• receptor endotelinu A metabolismus   MeSH
• receptor endotelinu B metabolismus   MeSH
• renin genetika   MeSH
• sulfonamidy farmakologie   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• antagonisté endotelinového receptoru A * MeSH
• antagonisté endotelinového receptoru B MeSH
• antihypertenziva MeSH
• atrasentan MeSH
• bosentan MeSH
• endotelin-1 MeSH
• kuchyňská sůl MeSH
• pyrrolidiny MeSH
• receptor endotelinu A MeSH
• receptor endotelinu B MeSH
• Ren2 protein, mouse MeSH Prohlížeč
• renin MeSH
• sulfonamidy MeSH