The study of ontogenetic aspects of water and electrolyte metabolism performed in the Institute of Physiology (Czechoslovak Academy of Sciences) led to the research on the increased susceptibility of immature rats to salt-dependent forms of hypertension since 1966. Hemodynamic studies in developing rats paved the way to the evaluation of hemodynamic mechanisms during the development of genetic hypertension in SHR. A particular attention was focused on altered renal function and kidney damage in both salt and genetic hypertension with a special respect to renin-angiotensin system. Renal damage associated with hypertension progression was in the center of interest of several research groups in Prague. The alterations in ion transport, cell calcium handling and membrane structure as well as their relationship to abnormal lipid metabolism were studied in a close cooperation with laboratories in Munich, Glasgow, Montreal and Paris. The role of NO and oxidative stress in various forms of hypertension was a subject of a joint research with our Slovak colleagues focused mainly on NO-deficient hypertension elicited by chronic L-NAME administration. Finally, we adopted a method enabling us to evaluate the balance of vasoconstrictor and vasodilator mechanisms in BP maintenance. Using this method we demonstrated sympathetic hyperactivity and relative NO deficiency in rats with either salt-dependent or genetic hypertension. At the end of the first decennium of this century we were ready to modify our traditional approach towards modern trends in the research of experimental hypertension. Keywords: Salt-dependent hypertension o Genetic hypertension o Body fluids o Hemodynamics o Ion transport o Cell membrane structure and function o Renal function o Renin-angiotensin systems.

• MeSH
• dějiny 20. století MeSH
• dějiny 21. století MeSH
• hypertenze * metabolismus   patofyziologie   MeSH
• krevní tlak MeSH
• krysa rodu Rattus MeSH
• lidé MeSH
• modely nemocí na zvířatech MeSH
• renin-angiotensin systém MeSH
• zvířata MeSH
• Check Tag
• dějiny 20. století MeSH
• dějiny 21. století MeSH
• krysa rodu Rattus MeSH
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• historické články 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
• Názvy látek
• blokátory receptorů AT1 pro angiotensin II MeSH
• cytochrom P-450 CYP1A1 MeSH
• epoxid hydrolasy MeSH
• indole-3-carbinol MeSH Prohlížeč
• indoly MeSH
• inhibitory enzymů MeSH
• losartan MeSH
• Ren2 protein, rat MeSH Prohlížeč
• renin MeSH

In the present study, we examined the effects of soluble epoxide hydrolase (sEH) inhibition on the development of angiotensin II-dependent hypertension and on renal function in transgenic rats with inducible expression of the mouse renin gene (strain name Cyp1a1-Ren-2). Hypertension was induced in these rats by indole-3-carbinol (I3C; 0.3% in the diet) for 12 days. The sEH inhibitor cis-4-[4-(3-adamantan-1-yl-ureido)-cyclohexyloxy]-benzoic acid (c-AUCB) was given in two doses (13 or 26 mg l-1) in drinking water. Blood pressure (BP), body weight (BW) and renal excretory parameters were monitored in conscious animals during the experiment. Renal haemodynamics was assessed at the end of treatment in anaesthetized rats. I3C administration resulted in severe hypertension with a rise in systolic BP from 118 ± 2 to 202 ± 3 mmHg, a loss of BW from 266 ± 5 to 228 ± 4 g and a rise in proteinuria from 14 ± 2 to 34 ± 3 mg day-1. Both doses of c-AUCB significantly attenuated the development of hypertension (systolic BP of 181 ± 4 and 176 ± 4 mmHg, respectively), the loss in BW (256 ± 4 and 259 ± 3 g, respectively) and the degree of proteinuria (27 ± 2 and 25 ± 3 mg day-1, respectively) to a similar extent. Moreover, c-AUCB prevented the reduction in renal plasma flow (5.4 ± 0.4 vs. 4.6 ± 0.3 ml min-1 g-1) and significantly increased sodium excretion (0.84 ± 0.16 vs. 0.38 ± 0.08 μmol min-1 g-1) during I3C administration. These data suggest that the oral administration of c-AUCB displays antihypertensive effects in Ren-2 transgenic rats with inducible malignant hypertension via an improvement of renal function.

• MeSH
• angiotensin II MeSH
• antihypertenziva aplikace a dávkování   farmakologie   MeSH
• aplikace orální MeSH
• benzoáty aplikace a dávkování   farmakologie   MeSH
• časové faktory MeSH
• cytochrom P-450 CYP1A1 genetika   MeSH
• epoxid hydrolasy antagonisté a inhibitory   metabolismus   MeSH
• hodnoty glomerulární filtrace účinky léků   MeSH
• hypertenze chemicky indukované   enzymologie   genetika   patofyziologie   prevence a kontrola   MeSH
• inhibitory enzymů aplikace a dávkování   farmakologie   MeSH
• krevní tlak účinky léků   MeSH
• krysa rodu Rattus MeSH
• kyseliny arachidonové metabolismus   MeSH
• kyseliny hydroxyeikosatetraenové metabolismus   MeSH
• ledviny krevní zásobení   účinky léků   enzymologie   patofyziologie   MeSH
• močovina aplikace a dávkování   analogy a deriváty   farmakologie   MeSH
• modely nemocí na zvířatech MeSH
• myši MeSH
• promotorové oblasti (genetika) MeSH
• proteinurie metabolismus   patofyziologie   prevence a kontrola   MeSH
• renální průtok plazmy účinky léků   MeSH
• renin genetika   metabolismus   MeSH
• sodík moč   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• 4-(4-(3-adamantan-1-ylureido)cyclohexyloxy)benzoic acid MeSH Prohlížeč
• angiotensin II MeSH
• antihypertenziva MeSH
• benzoáty MeSH
• cytochrom P-450 CYP1A1 MeSH
• EPHX2 protein, rat MeSH Prohlížeč
• epoxid hydrolasy MeSH
• inhibitory enzymů MeSH
• kyseliny arachidonové MeSH
• kyseliny hydroxyeikosatetraenové MeSH
• močovina MeSH
• Ren2 protein, mouse MeSH Prohlížeč
• renin MeSH
• sodík 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
• Názvy látek
• 11,12-epoxy-5,8,14-eicosatrienoic acid MeSH Prohlížeč
• 20-hydroxy-5,8,11,14-eicosatetraenoic acid MeSH Prohlížeč
• amidy MeSH
• angiotensin II MeSH
• antihypertenziva MeSH
• DDMS MeSH Prohlížeč
• kyselina 8,11,14-eikosatrienová MeSH
• kyseliny hydroxyeikosatetraenové MeSH
• noradrenalin MeSH
• sulfony MeSH
• vazokonstriktory MeSH