Sex-related cardiovascular differences were observed in humans as well as in experimental animals. Our previous study demonstrated a marked sexual dimorphism in blood pressure (BP) of 9-month-old heterozygous transgenic Ren 2 rats (TGR), in which mouse Ren-2 renin gene was inserted into the genome of normotensive Hannover Sprague-Dawley rats (HanSD). We found significantly elevated BP only in male TGR, whereas BP of TGR females was similar to that of HanSD females. The aim of our present study was to compare BP of 3- and 6-month-old heterozygous TGR with age- and sex-matched HanSD under the same conditions as we measured in 9-month-old rats. We also monitored the amount of oxidative stress marker, thiobarbituric acid-reactive substances (TBARS), and a main intracellular antioxidant, reduced glutathione in the heart, kidneys and liver. We also measured plasma triglycerides and cholesterol levels. We found an increased mean arterial pressure in both female and male 3-month-old TGR (172±17 vs. 187±4 mm Hg, respectively) compared to HanSD (115±5 vs. 133±3 mm Hg, respectively) but there was a marked sexual dimorphism of 6 month-old TGR where only males were hypertensive (145±5 mm Hg) while females became normotensive (123±7 mm Hg). We did not find any relationship between BP values and concentrations of TBARS or glutathione or plasma lipid levels. Our results demonstrated that 6-month-old TGR exhibited a marked sexual BP dimorphism, which was not dependent on the abnormalities in oxidative stress or cholesterol metabolism.

• MeSH
• Cholesterol MeSH
• Glutathione MeSH
• Hypertension * MeSH
• Blood Pressure MeSH
• Rats MeSH
• Thiobarbituric Acid Reactive Substances MeSH
• Kidney MeSH
• Rats, Sprague-Dawley MeSH
• Rats, Transgenic MeSH
• Renin * genetics   MeSH
• Sex Factors MeSH
• Free Radicals MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Male MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Cholesterol MeSH
• Glutathione MeSH
• Thiobarbituric Acid Reactive Substances MeSH
• Renin * MeSH
• Free Radicals MeSH

Sex-related differences were observed not only in human but also in experimental hypertension. The aim of our study was to compare blood pressure (BP) of aged male and female heterozygous transgenic rats (TGR) harboring Ren-2 mouse gene, with their normotensive Hannover Sprague-Dawley (HanSD) controls. At the age of 9 months, systolic (SBP) and diastolic blood pressure (DBP) were measured by a direct puncture of carotid artery in rats awaking from isoflurane anesthesia. Thiobarbituric acid-reactive species (TBARS) formation was monitored as indicator of lipid peroxidation damage in heart, kidney and liver, whereas intracellular content of reduced glutathione was determined in the same organs as the main intracellular antioxidant. Furthermore, plasma triglycerides and total cholesterol as well as high-density lipoprotein (HDL) and low-density lipoprotein (LDL) fractions of cholesterol were measured. As compared to HanSD rats, we found significantly elevated BP only in male TGR (MAP: 123±1 vs. 171±5, SBP: 150±2 vs. 208±7, and DBP: 99±3 vs. 140±4 mm Hg), but not between TGR and HanSD females, which were both normotensive. We also did not find any significant differences in TBARS and reduced glutathione in the three above mentioned organs as well as in plasma cholesterol or its HDL and LDL fractions between transgene-negative HanSD and TGR animals of either sex. However, we found significant sex differences in TBARS, glutathione and plasma lipids in both rat strains. Our results confirmed that aged TGR exhibit a marked sexual BP dimorphism, which does not seem to be dependent on oxidative stress or abnormal cholesterol metabolism.

• MeSH
• Blood Pressure physiology   MeSH
• Rats MeSH
• Mice MeSH
• Oxidative Stress physiology   MeSH
• Sex Characteristics * MeSH
• Rats, Sprague-Dawley MeSH
• Rats, Transgenic MeSH
• Renin genetics   metabolism   MeSH
• Aging genetics   metabolism   MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Male MeSH
• Mice MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Ren2 protein, mouse MeSH Browser
• Renin 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.

• Keywords
• 5/6 nephrectomy, chronic kidney disease, cytochrome P450 enzymes, end-organ damage, epoxyeicosatrienoic acids, hypertension, renin-angiotensin system, soluble epoxide hydrolase,
• MeSH
• Angiotensin II pharmacology   MeSH
• Renal Insufficiency, Chronic drug therapy   metabolism   MeSH
• Epoxide Hydrolases antagonists & inhibitors   metabolism   MeSH
• Hypertension drug therapy   metabolism   MeSH
• Blood Pressure drug effects   MeSH
• Rats MeSH
• Survival Rate MeSH
• Nephrectomy methods   MeSH
• Rats, Sprague-Dawley MeSH
• Rats, Transgenic metabolism   MeSH
• Animals MeSH
• Check Tag
• Rats 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
• Angiotensin II MeSH
• Epoxide Hydrolases MeSH

The aim of the present study was to evaluate the hypothesis that the antihypertensive effects of inhibition of soluble epoxide hydrolase (sEH) are mediated by increased intrarenal availability of epoxyeicosatrienoic acids (EETs), with consequent improvement in renal haemodynamic autoregulatory efficiency and the pressure-natriuresis relationship. Ren-2 transgenic rats (TGR), a model of angiotensin (Ang) II-dependent hypertension, and normotensive transgene-negative Hannover Sprague-Dawley (HanSD) rats were treated with the sEH inhibitor cis-4-(4-(3-adamantan-1-yl-ureido)cyclohexyloxy)benzoic acid (c-AUCB; 26 mg/L) for 48 h. Then, the effects on blood pressure (BP), autoregulation of renal blood flow (RBF) and glomerular filtration rate (GFR), and on the pressure-natriuresis relationship in response to stepwise reductions in renal arterial pressure (RAP) were determined. Treatment with c-AUCB did not significantly change BP, renal autoregulation or pressure-natriuresis in normotensive HanSD rats. In contrast, c-AUCB treatment significantly reduced BP, increased intrarenal bioavailability of EETs and significantly suppressed AngII levels in TGR. However, treatment with c-AUCB did not significantly improve the autoregulatory efficiency of RBF and GFR in response to reductions of RAP and to restore the blunted pressure-natriuresis relationship in TGR. Together, the data indicate that the antihypertensive actions of sEH inhibition in TGR are predominantly mediated via significant suppression of intrarenal renin-angiotensin system activity.

• MeSH
• Antihypertensive Agents pharmacology   MeSH
• Benzoates pharmacology   MeSH
• Down-Regulation drug effects   MeSH
• Epoxide Hydrolases antagonists & inhibitors   MeSH
• Glomerular Filtration Rate drug effects   MeSH
• Hypertension physiopathology   MeSH
• Blood Pressure drug effects   MeSH
• Rats MeSH
• Kidney drug effects   metabolism   MeSH
• Urea analogs & derivatives   pharmacology   MeSH
• Rats, Sprague-Dawley MeSH
• Rats, Transgenic MeSH
• Renal Circulation drug effects   MeSH
• Renin-Angiotensin System drug effects   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
• Antihypertensive Agents MeSH
• Benzoates MeSH
• Epoxide Hydrolases MeSH
• Urea MeSH