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
• History, 20th Century MeSH
• History, 21st Century MeSH
• Hypertension * metabolism   physiopathology   MeSH
• Blood Pressure MeSH
• Rats MeSH
• Humans MeSH
• Disease Models, Animal MeSH
• Renin-Angiotensin System MeSH
• Animals MeSH
• Check Tag
• History, 20th Century MeSH
• History, 21st Century MeSH
• Rats MeSH
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Historical Article MeSH

OBJECTIVE: The present study was performed to examine whether the blood pressure (BP)-lowering effects of soluble epoxide hydrolase (sEH) inhibition in two-kidney, one-clip (2K1C) Goldblatt hypertension are nitric oxide (NO) dependent. METHODS: Mice lacking the endothelial NO synthase (eNOS) gene (eNOS-/-) and their wild-type controls (eNOS+/+) underwent clipping of one renal artery. BP was monitored by radiotelemetry and the treatment with the sEH inhibitor cis-4-[4-(3-adamantan-1-yl-ureido)cyclohex-yloxy]-benzoic acid (c-AUCB) was initiated on day 25 after clipping and lasted for 14 days. Renal concentrations of epoxyeicosatrienoic acids (EETs) and their inactive metabolite dihydroxyeicosatrienoic acids (DHETs) were measured in the nonclipped kidney. Renal NO synthase (NOS) activity was determined by measuring the rate of formation of L-[(14)C]citruline from L-[(14)C]arginine. RESULTS: Treatment with the sEH inhibitor elicited similar BP decreases that were associated with increases in daily sodium excretion in 2K1C eNOS+/+ as well as 2K1C eNOS-/- mice. In addition, treatment with the sEH inhibitor increased the ratio of EETs/DHETs in the nonclipped kidney of 2K1C eNOS+/+ as well as 2K1C eNOS-/- mice. Treatment with the sEH inhibitor did not alter renal NOS activity in any of the experimental groups. CONCLUSIONS: Collectively, our present data suggest that the BP-lowering effects of chronic sEH inhibition in 2K1C mice are mainly associated with normalization of the reduced availability of biologically active EETs in the nonclipped kidney and their direct natriuretic actions.

• MeSH
• Antihypertensive Agents pharmacology   therapeutic use   MeSH
• Epoxide Hydrolases antagonists & inhibitors   metabolism   MeSH
• Enzyme Inhibitors pharmacology   therapeutic use   MeSH
• Mice, Inbred C57BL MeSH
• Mice, Knockout MeSH
• Mice MeSH
• Nitric Oxide * metabolism   MeSH
• Hypertension, Renovascular drug therapy   enzymology   MeSH
• Nitric Oxide Synthase Type III deficiency   MeSH
• Animals MeSH
• Check Tag
• Male MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Research Support, N.I.H., Extramural MeSH
• Names of Substances
• Antihypertensive Agents MeSH
• Ephx2 protein, mouse MeSH Browser
• Epoxide Hydrolases MeSH
• Enzyme Inhibitors MeSH
• Nos3 protein, mouse MeSH Browser
• Nitric Oxide * MeSH
• Nitric Oxide Synthase Type III MeSH

The present study was undertaken to evaluate the effects of chronic treatment with c-AUCB {cis-4-[4-(3-adamantan-1-ylureido)cyclohexyl-oxy]benzoic acid}, a novel inhibitor of sEH (soluble epoxide hydrolase), which is responsible for the conversion of biologically active EETs (epoxyeicosatrienoic acids) into biologically inactive DHETEs (dihydroxyeicosatrienoic acids), on BP (blood pressure) and myocardial infarct size in male heterozygous TGR (Ren-2 renin transgenic rats) with established hypertension. Normotensive HanSD (Hannover Sprague-Dawley) rats served as controls. Myocardial ischaemia was induced by coronary artery occlusion. Systolic BP was measured in conscious animals by tail plethysmography. c-AUCB was administrated in drinking water. Renal and myocardial concentrations of EETs and DHETEs served as markers of internal production of epoxygenase metabolites. Chronic treatment with c-AUCB, which resulted in significant increases in the availability of biologically active epoxygenase metabolites in TGR (assessed as the ratio of EETs to DHETEs), was accompanied by a significant reduction in BP and a significantly reduced infarct size in TGR as compared with untreated TGR. The cardioprotective action of c-AUCB treatment was completely prevented by acute administration of a selective EETs antagonist [14,15-epoxyeicosa-5(Z)-enoic acid], supporting the notion that the improved cardiac ischaemic tolerance conferred by sEH inhibition is mediated by EETs actions at the cellular level. These findings indicate that chronic inhibition of sEH exhibits antihypertensive and cardioprotective actions in this transgenic model of angiotensin II-dependent hypertension.

• MeSH
• Angiotensin II physiology   MeSH
• Antihypertensive Agents pharmacology   MeSH
• Benzoates pharmacology   MeSH
• Epoxide Hydrolases antagonists & inhibitors   MeSH
• Hypertension drug therapy   genetics   metabolism   MeSH
• Eicosanoids metabolism   urine   MeSH
• Myocardial Infarction drug therapy   pathology   MeSH
• Cardiotonic Agents pharmacology   MeSH
• Blood Pressure MeSH
• Rats MeSH
• Urea analogs & derivatives   pharmacology   MeSH
• Rats, Sprague-Dawley MeSH
• Rats, Transgenic MeSH
• Arrhythmias, Cardiac drug therapy   MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Male MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Research Support, N.I.H., Extramural MeSH
• Names of Substances
• 4-(4-(3-adamantan-1-ylureido)cyclohexyloxy)benzoic acid MeSH Browser
• Angiotensin II MeSH
• Antihypertensive Agents MeSH
• Benzoates MeSH
• Epoxide Hydrolases MeSH
• Eicosanoids MeSH
• Cardiotonic Agents MeSH
• Urea MeSH

Alterations in renal function contribute to Goldblatt two-kidney, one-clip (2K1C) hypertension. A previous study indicated that bioavailability of cytochrome P-450 metabolites epoxyeicosatrienoic acids (EETs) is decreased while that of 20-hydroxyeicosatetraenoic acids (20-HETE) is increased in this model. We utilized the inhibitor of soluble epoxide hydrolase cis-4-[4-(3-adamantan-1-yl-ureido)-cyclohexyloxy]-benzoic acid (c-AUCB) and HET-0016, the inhibitor of 20-HETE production, to study the role of EETs and 20-HETE in the regulation of renal function. Chronic c-AUCB treatment significantly decreased systolic blood pressure (SBP) (133 ± 1 vs. 163 ± 3 mmHg) and increased sodium excretion (1.23 ± 0.10 vs. 0.59 ± 0.03 mmol/day) in 2K1C rats. HET-0016 did not affect SBP and sodium excretion. In acute experiments, renal blood flow (RBF) was decreased in 2K1C rats (5.0 ± 0.2 vs. 6.9 ± 0.2 ml·min(-1)·g(-1)). c-AUCB normalized RBF in 2K1C rats (6.5 ± 0.6 ml·min(-1)·g(-1)). HET-0016 also increased RBF in 2K1C rats (5.8 ± 0.2 ml·min(-1)·g(-1)). Although RBF and glomerular filtration rate (GFR) remained stable in normotensive rats during renal arterial pressure (RAP) reductions, both were significantly reduced at 100 mmHg RAP in 2K1C rats. c-AUCB did not improve autoregulation but increased RBF at all RAPs and shifted the pressure-natriuresis curve to the left. HET-0016-treated 2K1C rats exhibited impaired autoregulation of RBF and GFR. Our data indicate that c-AUCB displays antihypertensive properties in 2K1C hypertension that are mediated by an improvement of RBF and pressure natriuresis. While HET-0016 enhanced RBF, its anti-natriuretic effect likely prevented it from producing a blood pressure-lowering effect in the 2K1C model.

• MeSH
• Amidines pharmacology   MeSH
• Epoxide Hydrolases antagonists & inhibitors   MeSH
• Enzyme Inhibitors pharmacology   MeSH
• Blood Pressure drug effects   physiology   MeSH
• Rats MeSH
• Arachidonic Acids metabolism   MeSH
• Hydroxyeicosatetraenoic Acids metabolism   MeSH
• Kidney blood supply   drug effects   physiology   MeSH
• Disease Models, Animal MeSH
• Regional Blood Flow drug effects   MeSH
• Hypertension, Renovascular metabolism   physiopathology   MeSH
• Sodium urine   MeSH
• Cytochrome P-450 Enzyme System metabolism   MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Male MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Research Support, N.I.H., Extramural MeSH
• Names of Substances
• 20-hydroxy-5,8,11,14-eicosatetraenoic acid MeSH Browser
• Amidines MeSH
• Epoxide Hydrolases MeSH
• HET0016 MeSH Browser
• Enzyme Inhibitors MeSH
• Arachidonic Acids MeSH
• Hydroxyeicosatetraenoic Acids MeSH
• Sodium MeSH
• Cytochrome P-450 Enzyme System 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
• Amides pharmacology   therapeutic use   MeSH
• Angiotensin II pharmacology   MeSH
• Antihypertensive Agents pharmacology   therapeutic use   MeSH
• Hypertension complications   drug therapy   physiopathology   MeSH
• Blood Pressure drug effects   MeSH
• Rats MeSH
• 8,11,14-Eicosatrienoic Acid analogs & derivatives   metabolism   MeSH
• Hydroxyeicosatetraenoic Acids biosynthesis   MeSH
• Multiple Organ Failure etiology   prevention & control   MeSH
• Norepinephrine pharmacology   MeSH
• Rats, Sprague-Dawley MeSH
• Rats, Transgenic MeSH
• Drug Evaluation, Preclinical methods   MeSH
• Renal Circulation drug effects   MeSH
• Sulfones pharmacology   therapeutic use   MeSH
• Vasoconstrictor Agents pharmacology   MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Male MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Research Support, N.I.H., Extramural MeSH
• Names of Substances
• 11,12-epoxy-5,8,14-eicosatrienoic acid MeSH Browser
• 20-hydroxy-5,8,11,14-eicosatetraenoic acid MeSH Browser
• Amides MeSH
• Angiotensin II MeSH
• Antihypertensive Agents MeSH
• DDMS MeSH Browser
• 8,11,14-Eicosatrienoic Acid MeSH
• Hydroxyeicosatetraenoic Acids MeSH
• Norepinephrine MeSH
• Sulfones MeSH
• Vasoconstrictor Agents MeSH