Inhibition of soluble epoxide hydrolase improves the impaired pressure–natriuresis relationship and attenuates the development of hypertension and hypertension-associated end-organ damage in Cyp1a1-Ren-2 transgenic rats

Abstract

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.

An Omega-3 Epoxide of Docosahexaenoic Acid Lowers Blood Pressure in Angiotensin-II–Dependent Hypertension

“…Although the P values that are associated with these differences were close to the threshold, mainly due to the efficacy of TPPU in lowering BP, 28, 34, 37, 38, 44 further analyses of the BP data supported these observations. The AUC analysis of the SBP data supported that the combination treatment is effective on both days 2–12 and days 6–12 (Figure S6).…”

“…One group received TPPU alone (Ang II + TPPU animals) to control for the previously reported anti-hypertensive effects associated with sEHIs. 37, 38, 44 In order to provide evidence for sEH inhibition, we determined the TPPU concentration in blood samples that were collected at the end of each week after Ang II infusion. Even though we observed a mild accumulation of TPPU, the difference in TPPU levels on day 7 vs .…”

“…The effectiveness of sEHIs and losartan has been compared previously in studies where both losartan and sEHIs lower BP and prevent hypertension induced renal damage in rodent models of hypertension. 44,53 While losartan acts through the RAAS system and does not affect the bioavailability of EETs, sEHIs target the ARA cascade through an increase in EETs and EDPs and influence RAAS only indirectly. In addition, EETs not only regulate BP but also display other beneficial effects including prevention of inflammation, pain, Ang-II induced cardiac hypertrophy and renal injury.…”

Role of haem oxygenase in the renoprotective effects of soluble epoxide hydrolase inhibition in diabetic spontaneously hypertensive rats

“…Increased EETs bioavailability via preventing EETs hydrolysis by sEH using pharmacological inhibition or gene knockout lowers blood pressure and renal injury in an experimental model of hypertension [13][14][15][16]. We and others have recently demonstrated that decreased EETs availability in streptozotocininduced diabetic mice was associated with a marked degree of renal injury and apoptosis and this effect was significantly reduced by increased EETs availability via the inhibition of sEH [9,17].…”

Kidney Response to Heart Failure: Proteomic Analysis of Cardiorenal Syndrome

“…In separate set of animals, renal function were measured as previously [10,16,17]. In 18 weeks after ACF induction, the animals (controls: n=9, HF: n=17) were placed in individual metabolic cages and their 24-hour urine was collected for determination of daily albuminuria.…”