OBJECTIVE: Despite availability of an array of antihypertensive drugs, malignant hypertension remains a life-threatening condition, and new therapeutic strategies for the treatment of malignant hypertension and malignant hypertension-associated organ damage are needed. The aim of the present study was to assess the effects of nitric oxide (NO)-independent soluble guanylyl cyclase (sGC) stimulator on the course of malignant hypertension. The second aim was to investigate if the treatment with sodium-glucose cotransporter type 2 (SGLT2) inhibitor would augment the expected beneficial actions of the sGC stimulation on the course of malignant hypertension. METHODS: As a model of malignant hypertension, Ren-2 transgenic rats (TGR) treated with nonspecific NO synthase inhibitor (Nω-nitro- l -arginine methyl ester, l -NAME) was used. Blood pressure (BP) was monitored by radiotelemetry, and the treatment was started 3 days before administration of l -NAME. RESULTS: The treatment with sGC stimulator BAY 41-8543, alone or combined with SGLT2 inhibitor empagliflozin, abolished malignant hypertension-related mortality in TGR receiving l -NAME. These two treatment regimens also prevented BP increases after l -NAME administration in TGR, and even decreased BP below values observed in control TGR, and prevented cardiac dysfunction and malignant hypertension-related morbidity. The treatment with the SGLT2 inhibitor empagliflozin did not further augment the beneficial actions of sGC stimulator on the course of malignant hypertension-related mortality. CONCLUSION: The treatment with NO-independent sGC stimulator displayed marked protective actions on the course of malignant hypertension-related mortality and malignant hypertension-related cardiac damage. This suggests that application of sGC stimulator could be a promising therapeutic means for the treatment of malignant hypertension.

• Keywords
• malignant hypertension, renin–angiotensin system, sodium-glucose cotransporter type 2 inhibitor, soluble guanylyl cyclase stimulator,
• MeSH
• Benzhydryl Compounds pharmacology   MeSH
• Sodium-Glucose Transporter 2 Inhibitors MeSH
• Glucosides pharmacology   therapeutic use   MeSH
• Hypertension, Malignant * prevention & control   drug therapy   MeSH
• Blood Pressure drug effects   MeSH
• Rats MeSH
• NG-Nitroarginine Methyl Ester pharmacology   MeSH
• Rats, Transgenic MeSH
• Pyrazoles * pharmacology   therapeutic use   MeSH
• Pyrimidines * therapeutic use   pharmacology   MeSH
• Soluble Guanylyl Cyclase * metabolism   MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Male MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• BAY 41-8543 MeSH Browser
• Benzhydryl Compounds MeSH
• empagliflozin MeSH Browser
• Sodium-Glucose Transporter 2 Inhibitors MeSH
• Glucosides MeSH
• Morpholines MeSH
• NG-Nitroarginine Methyl Ester MeSH
• Pyrazoles * MeSH
• Pyrimidines * MeSH
• Soluble Guanylyl Cyclase * MeSH

The aim of the present study was to assess the autoregulatory capacity of renal blood flow (RBF) and of the pressure-natriuresis characteristics in the early phase of heart failure (HF) in rats, normotensive and with angiotensin II (ANG II)-dependent hypertension. Ren-2 transgenic rats (TGR) were employed as a model of ANG II-dependent hypertension. HF was induced by creating the aorto-caval fistula (ACF). One week after ACF creation or sham-operation, the animals were prepared for studies evaluating in vivo RBF autoregulatory capacity and the pressure-natriuresis characteristics after stepwise changes in renal arterial pressure (RAP) induced by aortic clamping. In ACF TGR the basal mean arterial pressure, RBF, urine flow (UF), and absolute sodium excretion (UNaV) were all significantly lower tha n in sham-operated TGR. In the latter, reductions in renal arterial pressure (RAP) significantly decreased RBF whereas in ACF TGR they did not change. Stepwise reductions in RAP resulted in marked decreases in UF and UNaV in sham-operated as well as in ACF TGR, however, these decreases were significantly greater in the former. Our data show that compared with sham-operated TGR, ACF TGR displayed well-maintained RBF autoregulatory capacity and improved slope of the pressure-natriuresis relationship. Thus, even though in the very early HF stage renal dysfunction was demonstrable, in the HF model of ANG II-dependent hypertensive rat such dysfunction and the subsequent HF decompensation cannot be simply ascribed to impaired renal autoregulation and pressure-natriuresis relationship.

• Keywords
• Ren-2 transgenic hypertensive rat, Renal autoregulation, Renal blood flow, Sodium excretion, Volume-overload heart failure,
• MeSH
• Angiotensin II pharmacology   MeSH
• Homeostasis MeSH
• Hypertension * MeSH
• Blood Pressure MeSH
• Rats MeSH
• Kidney MeSH
• Natriuresis MeSH
• Rats, Transgenic MeSH
• Renal Circulation MeSH
• Sodium MeSH
• Heart Failure * MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Angiotensin II MeSH
• Sodium MeSH

Epoxyeicosatrienoic acids (EETs) are also known as epoxyeicosanoids that have renal and cardiovascular actions. These renal and cardiovascular actions can be regulated by soluble epoxide hydrolase (sEH) that degrades and inactivates EETs. Extensive animal hypertension studies have determined that vascular, epithelial transport, and anti-inflammatory actions of EETs lower blood pressure and decrease renal and cardiovascular disease progression. Human studies have also supported the notion that increasing EET levels in hypertension could be beneficial. Pharmacological and genetic approaches to increase epoxyeicosanoids in several animal models and humans have found improved endothelial vascular function, increased sodium excretion, and decreased inflammation to oppose hypertension and associated renal and cardiovascular complications. These compelling outcomes support the concept that increasing epoxyeicosanoids via sEH inhibitors or EET analogs could be a valuable hypertension treatment.

• MeSH
• Antihypertensive Agents therapeutic use   MeSH
• Epoxide Hydrolases antagonists & inhibitors   metabolism   MeSH
• Hypertension drug therapy   metabolism   physiopathology   MeSH
• Eicosanoids metabolism   therapeutic use   MeSH
• Enzyme Inhibitors therapeutic use   MeSH
• Blood Pressure drug effects   MeSH
• Humans MeSH
• Signal Transduction MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Review MeSH
• Names of Substances
• Antihypertensive Agents MeSH
• Epoxide Hydrolases MeSH
• Eicosanoids MeSH
• Enzyme Inhibitors 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

Recent studies have shown that the long-term antihypertensive action of soluble epoxide hydrolase inhibition (sEH) in angiotensin-II (AngII)-dependent hypertension might be mediated by the suppression of intrarenal AngII levels. To test this hypothesis, we examined the effects of acute (2 days) and chronic (14 days) sEH inhibition on blood pressure (BP) in transgenic rats with inducible AngII-dependent hypertension. AngII-dependent malignant hypertension was induced by 10 days' dietary administration of indole-3-carbinol (I3C), a natural xenobiotic that activates the mouse renin gene in Cyp1a1-Ren-2 transgenic rats. BP was monitored by radiotelemetry. Acute and chronic sEH inhibition was achieved using cis-4-(4-(3-adamantan-1-yl-ureido)cyclohexyloxy) benzoic acid, given at doses of 0.3, 3, 13, 26, 60 and 130 mg/L in drinking water. At the end of experiments, renal concentrations of epoxyeicosatrienoic acids, their inactive metabolites dihydroxyeicosatrienoic acids and AngII were measured. Acute BP-lowering effects of sEH inhibition in I3C-induced rats was associated with a marked increase in renal epoxyeicosatrienoic acids to dihydroxyeicosatrienoic acids ratio and acute natriuresis. Chronic treatment with cis-4-(4-(3-adamantan-1-yl-ureido)cyclohexyloxy) benzoic acid in I3C-induced rats elicited dose-dependent persistent BP lowering associated with a significant reduction of plasma and kidney AngII levels. Our findings show that the acute BP-lowering effect of sEH inhibition in I3C-induced Cyp1a1-Ren-2 transgenic rats is mediated by a substantial increase in intrarenal epoxyeicosatrienoic acids and their natriuretic action without altering intrarenal renin-angiotensin system activity. Long-term antihypertensive action of cis-4-(4-(3-adamantan-1-yl-ureido)cyclohexyloxy) benzoic acid in I3C-induced Cyp1a1-Ren-2 transgenic rats is mediated mostly by suppression of intrarenal AngII concentration.

• Keywords
• angiotensin-II, cytochrome P-450 epoxygenase, eicosanoids, epoxyeicosatrienoic acids, hypertension, soluble epoxide hydrolase,
• MeSH
• Angiotensin II metabolism   MeSH
• Antihypertensive Agents pharmacology   MeSH
• Cytochrome P-450 CYP1A1 metabolism   MeSH
• Epoxide Hydrolases antagonists & inhibitors   metabolism   MeSH
• Hypertension drug therapy   metabolism   MeSH
• Indoles metabolism   MeSH
• Blood Pressure drug effects   MeSH
• Rats MeSH
• Kidney drug effects   metabolism   MeSH
• Mice MeSH
• Natriuresis drug effects   MeSH
• Rats, Inbred F344 MeSH
• Rats, Transgenic MeSH
• Renin-Angiotensin System drug effects   MeSH
• Renin metabolism   MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• 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
• Angiotensin II MeSH
• Antihypertensive Agents MeSH
• Cytochrome P-450 CYP1A1 MeSH
• Epoxide Hydrolases MeSH
• indole-3-carbinol MeSH Browser
• Indoles MeSH
• Ren2 protein, rat 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