• Publikační typ
• abstrakt z konference MeSH

In 2011 Fujita and coworkers proposed that ß-adrenergic stimulation causes decreased serine/threonine-protein kinase WNK4 transcription leading to the activation of Na-Cl cotransporter (NCC) which participates in salt sensitivity and salt hypertension development in rodents. The aim of our study was to investigate whether the above hypothesis is also valid for salt hypertension of Dahl rats, which are characterized by high sympathetic tone and abnormal renal sodium handling. Male 8-week-old salt-sensitive (SS/Jr) and salt-resistant (SR/Jr) Dahl rats were fed either low-salt diet (LS, 0.4 % NaCl) or high-salt diet (HS, 4 % NaCl) for 6 weeks. Half of the animals on either diet were chronically treated with non-selective ß-blocker propranolol (100 mg/kg/day). At the end of the experiment diuresis and sodium excretion were measured prior and after hydrochlorothiazide injection (HCTZ, 10 mg/kg i.p.). Furthermore, blood pressure (BP), heart rate (HR), sympathetic (pentolinium 5 mg/kg i.v.) and NO-dependent (L-NAME 30 mg/kg i.v.) BP components were determined. Chronic HS diet feeding increased BP through sympathoexcitation in SS/Jr but not in SR/Jr rats. Concomitant propranolol treatment did not lower BP in either experimental group. Under the conditions of low salt intake HCTZ increased diuresis, natriuresis and fractional sodium excretion in SR/Jr but not in SS/Jr rats. HS diet feeding attenuated renal response to HCT in SR/Jr rats, whereas no HCTZ effect was observed in SS/Jr rats fed HS diet. Propranolol treatment did not modify diuresis or natriuresis in any experimental group. In conclusions, our present data do not support the idea on the essential importance of renal ß-adrenergic-WNK4-NCC pathway in pathogenesis and/or maintenance of salt hypertension in Dahl rats.

• MeSH
• beta blokátory terapeutické užití   MeSH
• hypertenze chemicky indukované   farmakoterapie   metabolismus   MeSH
• krevní tlak účinky léků   fyziologie   MeSH
• krysa rodu rattus MeSH
• kuchyňská sůl aplikace a dávkování   škodlivé účinky   MeSH
• potkani inbrední Dahl MeSH
• propranolol farmakologie   terapeutické užití   MeSH
• protein-serin-threoninkinasy metabolismus   MeSH
• rodina nosičů rozpuštěných látek 12, člen 1 metabolismus   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

• Publikační typ
• abstrakt z konference MeSH

The insertion of mouse renin gene (Ren-2) into the genome of normotensive rats causes a spontaneous rise of blood pressure (BP), leading to an angiotensin II (Ang II)-dependent form of hypertension in transgenic (mRen-2)27 rats (TGR). However, enhanced sympathetic BP component was demonstrated in heterozygous TGR aged 20 weeks. In the present study we used another model, i.e. Cyp1a1-Ren-2 transgenic rats (iTGR) in which hypertension can be induced by natural xenobiotic indole-3 carbinol (I3C) added to the diet. We investigated whether the development of high blood pressure (BP) in 5-month-old iTGR animals fed I3C diet for 10 days is solely due to enhanced Ang II-dependent vasoconstriction or whether enhanced sympathetic vasoconstriction also participates in BP maintenance in this form of hypertension. Using acute sequential blockade of renin-angiotensin system (RAS), sympathetic nervous system (SNS) and NO synthase (NOS) we have demonstrated that the observed gradual increase of BP in iTGR fed I3C diet was entirely due to the augmentation of Ang II-dependent BP component without significant changes of sympathetic BP component. Thus, the hypertension in iTGR resembles to that of homozygous TGR in which high BP was entirely dependent on Ang II-dependent vasoconstriction. Moreover, our measurements of acute BP response to Rho kinase inhibitor fasudil in animals subjected to a combined blockade of RAS, SNS and NOS indicated the attenuation of basal calcium sensitization in both iTGR and homozygous TGR.

• MeSH
• angiotensin II genetika   metabolismus   MeSH
• cytochrom P-450 CYP1A1 genetika   metabolismus   MeSH
• hypertenze genetika   patofyziologie   MeSH
• krevní tlak fyziologie   MeSH
• krysa rodu rattus MeSH
• potkani transgenní MeSH
• renin-angiotensin systém fyziologie   MeSH
• renin genetika   metabolismus   MeSH
• sympatický nervový systém fyziologie   MeSH
• vazokonstrikce fyziologie   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

This study evaluated the subacute morphologic alterations in renal artery wall and renal nerves in response to catheter-based renal denervation (RDN) in sheep and also compared the efficiency of single-point and multiple-point ablation catheters. Effect of each ablation catheter approved for the clinical use (Symplicity Flex(TM), Medtronic, Inc., or EnligHTN(TM), St. Jude Medical, INC.) was compared to intact contralateral renal artery in 12 sheep by histopathology and immunohistochemistry evaluation after a 10-day period post-RDN procedure. The safety was verified by extensive evaluation of kidney morphology. Vascular wall lesions and nerve injuries were more pronounced in those animals treated with multi-point EnligHTN catheter when compared with animals treated with single-point Symplicity Flex catheter. However, neither RDN procedure led to complete renal nerve ablation. Both systems, tested in the present study, provided only incomplete renal nerve ablation in sheep. Moreover, no appreciable progression of the nerve disintegration in subacute phase post-RDN procedure was observed. This study further supports the notion that the effectiveness remains fully dependent on anatomical inter-individual variability of the sympathetic nerve plexus accompanying the renal artery. Therefore, new systems providing deeper penetrance to targeted perivascular structure would be more efficient.

• MeSH
• arteria renalis * cytologie   inervace   MeSH
• katetrizační ablace * přístrojové vybavení   metody   MeSH
• katétry MeSH
• ledviny * krevní zásobení   cytologie   inervace   MeSH
• náhodné rozdělení MeSH
• ovce MeSH
• sympatektomie * přístrojové vybavení   metody   MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• hodnotící studie MeSH
• srovnávací studie MeSH

We showed recently that increasing kidney epoxyeicosatrienoic acids (EETs) by blocking soluble epoxide hydrolase (sEH), an enzyme responsible for EETs degradation, retarded the development of renal dysfunction and progression of aorto-caval fistula(ACF)-induced congestive heart failure (CHF) in Ren-2 transgenic hypertensive rats (TGR). In that study the final survival rate of untreated ACF TGR was only 14 % but increased to 41 % after sEH blockade. Here we examined if sEH inhibition added to renin-angiotensin system (RAS) blockade would further enhance protection against ACF-induced CHF in TGR. The treatment regimens were started one week after ACF creation and the follow-up period was 50 weeks. RAS was blocked using angiotensin-converting enzyme inhibitor (ACEi, trandolapril, 6 mg/l) and sEH with an sEH inhibitor (sEHi, c-AUCB, 3 mg/l). Renal hemodynamics and excretory function were determined two weeks post-ACF, just before the onset of decompensated phase of CHF. 29 weeks post-ACF no untreated animal survived. ACEi treatment greatly improved the survival rate, to 84 % at the end of study. Surprisingly, combined treatment with ACEi and sEHi worsened the rate (53 %). Untreated ACF TGR exhibited marked impairment of renal function and the treatment with ACEi alone or combined with sEH inhibition did not prevent it. In conclusion, addition of sEHi to ACEi treatment does not provide better protection against CHF progression and does not increase the survival rate in ACF TGR: indeed, the rate decreases significantly. Thus, combined treatment with sEHi and ACEi is not a promising approach to further attenuate renal dysfunction and retard progression of CHF.

• MeSH
• arteriovenózní píštěl MeSH
• benzoáty farmakologie   terapeutické užití   MeSH
• epoxid hydrolasy antagonisté a inhibitory   MeSH
• indoly terapeutické užití   MeSH
• inhibitory ACE terapeutické užití   MeSH
• kombinovaná farmakoterapie MeSH
• krysa rodu rattus MeSH
• močovina analogy a deriváty   farmakologie   terapeutické užití   MeSH
• potkani Sprague-Dawley MeSH
• potkani transgenní MeSH
• preklinické hodnocení léčiv MeSH
• renální insuficience etiologie   prevence a kontrola   MeSH
• srdeční selhání komplikace   farmakoterapie   mortalita   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• ženské 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

Solid organ transplantation is an established treatment modality in patients with end-stage organ damage in cases where other therapeutic options fail. The long-term outcomes of solid organ transplant recipients have improved considerably since the introduction of the first calcineurin inhibitor (CNI) - cyclosporine. In 1984, the potent immunosuppressive properties of another CNI, tacrolimus, were discovered. The immunosuppressive effects of CNIs result from the inhibition of interleukin-2 synthesis and reduced proliferation of T cells due to calcineurin blockade. The considerable side effects that are associated with CNIs therapy include arterial hypertension and nephrotoxicity. The focus of this article was to review the available literature on the pathophysiological mechanisms of CNIs that induce chronic nephrotoxicity and arterial hypertension. CNIs lead to activation of the major vasoconstriction systems, such as the renin-angiotensin and endothelin systems, and increase sympathetic nerve activity. On the other hand, CNIs are known to inhibit NO synthesis and NO-mediated vasodilation and to increase free radical formation. Altogether, these processes cause endothelial dysfunction and contribute to the impairment of organ function. A better insight into the mechanisms underlying CNI nephrotoxicity could assist in developing more targeted therapies of arterial hypertension or preventing CNI nephrotoxicity in organ transplant recipients, including heart transplantation.

• MeSH
• hypertenze chemicky indukované   patologie   patofyziologie   MeSH
• imunosupresiva škodlivé účinky   MeSH
• inhibitory kalcineurinu aplikace a dávkování   škodlivé účinky   MeSH
• lidé MeSH
• nemoci ledvin chemicky indukované   patologie   patofyziologie   MeSH
• reaktivní formy kyslíku metabolismus   MeSH
• rejekce štěpu etiologie   prevence a kontrola   MeSH
• renin-angiotensin systém účinky léků   MeSH
• transplantace srdce škodlivé účinky   MeSH
• vazokonstrikce účinky léků   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

Renal sympathetic hyperactivity is critically involved in hypertension pathophysiology; renal denervation (RDN) presents a novel strategy for treatment of resistant hypertension cases. This study assessed effects of two RDN systems to detect acute intravascular, vascular and peri-vascular changes in the renal artery, and renal nerve alterations, in the sheep. The procedures using a single-point or multi-point ablation catheters, Symplicity Flex(TM), Medtronic versus EnligHTN(TM), St. Jude Medical were compared; the intact contralateral kidneys served as controls. Histopathological and immunohistochemical assessments were performed 48 h after RDN procedures; the kidney and suprarenal gland morphology was also evaluated. Special staining methods were applied for histologic analysis, to adequately score the injury of renal artery and adjacent renal nerves. These were more pronounced in the animals treated with the multi-point compared with the single-point catheter. However, neither RDN procedure led to complete renal nerve ablation. Forty-eight hours after the procedure no significant changes in plasma and renal tissue catecholamines were detected. The morphologic changes elicited by application of both RDN systems appeared to be dependent on individual anatomical variability of renal nerves in the sheep. Similar variability in humans may limit the therapeutic effectiveness of RDN procedures used in patients with resistant hypertension.

• MeSH
• arteria renalis patologie   chirurgie   MeSH
• katetrizační ablace přístrojové vybavení   metody   MeSH
• ledviny inervace   patologie   chirurgie   MeSH
• náhodné rozdělení MeSH
• ovce MeSH
• sympatektomie přístrojové vybavení   metody   MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

OBJECTIVE: We evaluated the therapeutic effectiveness of a new, orally active epoxyeicosatrienoic acid analog (EET-A) in rats with angiotensin II (ANG II)-dependent malignant hypertension. METHODS: Malignant hypertension was induced in Cyp1a1-Ren-2 transgenic rats by activation of the renin gene using indole-3-carbinol (I3C), a natural xenobiotic. EET-A treatment was started either simultaneously with I3C induction process (early treatment) or 10 days later during established hypertension (late treatment). Blood pressure (BP) (radiotelemetry), indices of renal and cardiac injury, and plasma and kidney levels of the components of the renin-angiotensin system (RAS) were determined. RESULTS: In I3C-induced hypertensive rats, early EET-A treatment attenuated BP increase (to 175 ± 3 versus 193 ± 4 mmHg, P < 0.05, on day 13), reduced albuminuria (15 ± 1 versus 28 ± 2 mg/24 h, P < 0.05), and cardiac hypertrophy as compared with untreated I3C-induced rats. This was associated with suppression of plasma and kidney ANG II levels (48 ± 6 versus 106 ± 9 and 122 ± 19 versus 346 ± 11 fmol ml or g, respectively, P < 0.05) and increases in plasma and kidney angiotensin (1-7) concentrations (84 ± 9 versus 37 ± 6 and 199 ± 12 versus 68 ± 9 fmol/ml or g, respectively, P < 0.05). Remarkably, late EET-A treatment did not lower BP or improve renal and cardiac injury; indices of RAS activity were not affected. CONCLUSION: The new, orally active EET-A attenuated the development of experimental ANG II-dependent malignant hypertension, likely via suppression of the hypertensiogenic axis and augmentation of the vasodilatory/natriuretic axis of RAS.

• MeSH
• albuminurie farmakoterapie   MeSH
• angiotensin I metabolismus   MeSH
• angiotensin II metabolismus   MeSH
• časové faktory MeSH
• cytochrom P-450 CYP1A1 genetika   MeSH
• hypertenze maligní chemicky indukované   patofyziologie   prevence a kontrola   MeSH
• indoly MeSH
• krevní tlak účinky léků   MeSH
• krysa rodu rattus MeSH
• kyselina 8,11,14-eikosatrienová analogy a deriváty   terapeutické užití   MeSH
• ledviny metabolismus   MeSH
• peptidové fragmenty metabolismus   MeSH
• potkani transgenní MeSH
• renin-angiotensin systém účinky léků   MeSH
• renin genetika   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH