The aim of the present study was to assess systemic circulatory and tissue activities of both the classical arm and of the alternative arm of the renin-angiotensin system (RAS) in a new transgenic rat line (TG7371) that expresses angiotensin-(1-7) (ANG 1-7)-producing fusion protein; the results were compared with the activities measured in control transgene-negative Hannover Sprague-Dawley (HanSD) rats. Plasma and tissue concentrations of angiotensin II (ANG II) and ANG 1-7, and kidney mRNA expressions of receptors responsible for biological actions of ANG II and ANG 1-7 [i.e. ANG II type 1 and type 2 (AT1 and AT2) and Mas receptors] were assessed in TG7371 transgene-positive and in HanSD rats. We found that male TG7371 transgene-positive rats exhibited significantly elevated plasma, kidney, heart and lung ANG 1-7 concentrations as compared with control male HanSD rats; by contrast, there was no significant difference in ANG II concentrations and no significant differences in mRNA expression of AT1, AT2 and Mas receptors. In addition, we found that in male TG7371 transgene-positive rats blood pressure was lower than in male HanSD rats. These data indicate that the balance between the classical arm and the alternative arm of the RAS was in male TGR7371 transgene-positive rats markedly shifted in favor of the latter. In conclusion, TG7371 transgene-positive rats represent a new powerful tool to study the long-term role of the alternative arm of the RAS in the pathophysiology and potentially in the treatment of cardio-renal diseases.

• Keywords
• Angiotensin II, Angiotensin-(1-7), Renin-angiotensin system, TG7371 transgenic rat,
• MeSH
• Angiotensin I * metabolism   MeSH
• Angiotensin II * MeSH
• Cardiovascular Diseases metabolism   genetics   MeSH
• Blood Pressure physiology   MeSH
• Rats MeSH
• Kidney metabolism   MeSH
• Kidney Diseases metabolism   genetics   MeSH
• Peptide Fragments * metabolism   MeSH
• Rats, Sprague-Dawley * MeSH
• Rats, Transgenic * MeSH
• Proto-Oncogene Mas MeSH
• Receptor, Angiotensin, Type 1 genetics   metabolism   MeSH
• Receptors, G-Protein-Coupled genetics   metabolism   MeSH
• Recombinant Fusion Proteins metabolism   MeSH
• Renin-Angiotensin System * physiology   MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Male MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• angiotensin I (1-7) MeSH Browser
• Angiotensin I * MeSH
• Angiotensin II * MeSH
• Peptide Fragments * MeSH
• Proto-Oncogene Mas MeSH
• Receptor, Angiotensin, Type 1 MeSH
• Receptors, G-Protein-Coupled MeSH
• Recombinant Fusion Proteins MeSH

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

It is generally accepted that angiotensin II plays an important role in high blood pressure (BP) development in both 2-kidney-1-clip (2K1C) Goldblatt hypertension and in partial nephrectomy (NX) model of chronic kidney disease (CKD). The contribution of sympathetic nervous system and nitric oxide to BP control in these models is less clear. Partial nephrectomy or stenosis of the renal artery was performed in adult (10-week-old) male hypertensive heterozygous Ren-2 transgenic rats (TGR) and normotensive control Hannover Sprague Dawley (HanSD) rats and in Wistar rats. One and four weeks after the surgery, basal blood pressure (BP) and acute BP responses to the consecutive blockade of renin-angiotensin (RAS), sympathetic nervous (SNS), and nitric oxide (NO) systems were determined in conscious rats. Both surgical procedures increased plasma urea, a marker of renal damage; the effect being more pronounced following partial nephrectomy in hypertensive TGR than in normotensive HanSD rats with a substantially smaller effect in Wistar rats after renal artery stenosis. We demonstrated that the renin-angiotensin system does not play so fundamental role in blood pressure maintenance during hypertension development in either CKD model. By contrast, a more important role is exerted by the sympathetic nervous system, the activity of which is increased in hypertensive TGR-NX in the developmental phase of hypertension, while in HanSD-NX or Wistar-2K1C it is postponed to the established phase. The contribution of the vasoconstrictor systems (RAS and SNS) was increased following hypertension induction. The role of NO-dependent vasodilation was unchanged in 5/6 NX HanSD and in 2K1C Wistar rats, while it gradually decreased in 5/6 NX TGR rats.

• MeSH
• Renal Insufficiency, Chronic complications   metabolism   physiopathology   MeSH
• Hypertension complications   metabolism   physiopathology   MeSH
• Blood Pressure physiology   MeSH
• Rats MeSH
• Disease Models, Animal MeSH
• Rats, Sprague-Dawley MeSH
• Rats, Transgenic MeSH
• Rats, Wistar MeSH
• Renin-Angiotensin System * MeSH
• Sympathetic Nervous System physiopathology   MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Male MeSH
• Animals MeSH
• Publication type
• Journal Article 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
• Albuminuria drug therapy   MeSH
• Angiotensin I metabolism   MeSH
• Angiotensin II metabolism   MeSH
• Time Factors MeSH
• Cytochrome P-450 CYP1A1 genetics   MeSH
• Hypertension, Malignant chemically induced   physiopathology   prevention & control   MeSH
• Indoles MeSH
• Blood Pressure drug effects   MeSH
• Rats MeSH
• 8,11,14-Eicosatrienoic Acid analogs & derivatives   therapeutic use   MeSH
• Kidney metabolism   MeSH
• Peptide Fragments metabolism   MeSH
• Rats, Transgenic MeSH
• Renin-Angiotensin System drug effects   MeSH
• Renin genetics   MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Male MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• angiotensin I (1-7) MeSH Browser
• Angiotensin I MeSH
• Angiotensin II MeSH
• Cytochrome P-450 CYP1A1 MeSH
• indole-3-carbinol MeSH Browser
• Indoles MeSH
• 8,11,14-Eicosatrienoic Acid MeSH
• Peptide Fragments MeSH
• Ren2 protein, rat MeSH Browser
• Renin MeSH

The detailed mechanisms determining the course of congestive heart failure (CHF) and associated renal dysfunction remain unclear. In a volume overload model of CHF induced by creation of aorto-caval fistula (ACF) in Hannover Sprague-Dawley (HanSD) rats we explored the putative pathogenetic contribution of epoxyeicosatrienoic acids (EETs), active products of CYP-450 dependent epoxygenase pathway of arachidonic acid metabolism, and compared it with the role of the renin-angiotensin system (RAS). Chronic treatment with cis-4-[4-(3-adamantan-1-yl-ureido) cyclohexyloxy]benzoic acid (c-AUCB, 3 mg/l in drinking water), an inhibitor of soluble epoxide hydrolase (sEH) which normally degrades EETs, increased intrarenal and myocardial EETs to levels observed in sham-operated HanSD rats, but did not improve the survival or renal function impairment. In contrast, chronic angiotensin-converting enzyme inhibition (ACEi, trandolapril, 6 mg/l in drinking water) increased renal blood flow, fractional sodium excretion and markedly improved survival, without affecting left ventricular structure and performance. Hence, renal dysfunction rather than cardiac remodeling determines long-term mortality in advanced stage of CHF due to volume overload. Strong protective actions of ACEi were associated with suppression of the vasoconstrictor/sodium retaining axis and activation of vasodilatory/natriuretic axis of the renin-angiotensin system in the circulating blood and kidney tissue.

• MeSH
• Angiotensin I blood   MeSH
• Angiotensin II blood   MeSH
• Benzoates pharmacology   therapeutic use   MeSH
• Epoxide Hydrolases antagonists & inhibitors   MeSH
• Epoxy Compounds metabolism   MeSH
• Angiotensin-Converting Enzyme Inhibitors MeSH
• Rats MeSH
• 8,11,14-Eicosatrienoic Acid analogs & derivatives   blood   metabolism   MeSH
• Kidney metabolism   MeSH
• Urea analogs & derivatives   pharmacology   therapeutic use   MeSH
• Disease Models, Animal MeSH
• Myocardium metabolism   MeSH
• Random Allocation MeSH
• Peptide Fragments blood   MeSH
• Drug Evaluation, Preclinical MeSH
• Renal Insufficiency blood   etiology   prevention & control   MeSH
• Renin-Angiotensin System drug effects   MeSH
• Heart Failure blood   complications   diagnostic imaging   drug therapy   MeSH
• Ultrasonography 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
• 4-(4-(3-adamantan-1-ylureido)cyclohexyloxy)benzoic acid MeSH Browser
• angiotensin I (1-7) MeSH Browser
• Angiotensin I MeSH
• Angiotensin II MeSH
• Benzoates MeSH
• Epoxide Hydrolases MeSH
• Epoxy Compounds MeSH
• Angiotensin-Converting Enzyme Inhibitors MeSH
• 8,11,14-Eicosatrienoic Acid MeSH
• Urea MeSH
• Peptide Fragments MeSH