Renal mechanisms contributing to the antihypertensive action of soluble epoxide hydrolase inhibition in Ren‐2 transgenic rats with inducible hypertension

Abstract

In the present study, we examined the effects of soluble epoxide hydrolase (sEH) inhibition on the development of angiotensin II-dependent hypertension and on renal function in transgenic rats with inducible expression of the mouse renin gene (strain name Cyp1a1-Ren-2). Hypertension was induced in these rats by indole-3-carbinol (I3C; 0.3% in the diet) for 12 days. The sEH inhibitor cis-4-[4-(3-adamantan-1-yl-ureido)-cyclohexyloxy]-benzoic acid (c-AUCB) was given in two doses (13 or 26 mg l-1) in drinking water. Blood pressure (BP), body weight (BW) and renal excretory parameters were monitored in conscious animals during the experiment. Renal haemodynamics was assessed at the end of treatment in anaesthetized rats. I3C administration resulted in severe hypertension with a rise in systolic BP from 118 ± 2 to 202 ± 3 mmHg, a loss of BW from 266 ± 5 to 228 ± 4 g and a rise in proteinuria from 14 ± 2 to 34 ± 3 mg day-1. Both doses of c-AUCB significantly attenuated the development of hypertension (systolic BP of 181 ± 4 and 176 ± 4 mmHg, respectively), the loss in BW (256 ± 4 and 259 ± 3 g, respectively) and the degree of proteinuria (27 ± 2 and 25 ± 3 mg day-1, respectively) to a similar extent. Moreover, c-AUCB prevented the reduction in renal plasma flow (5.4 ± 0.4 vs. 4.6 ± 0.3 ml min-1 g-1) and significantly increased sodium excretion (0.84 ± 0.16 vs. 0.38 ± 0.08 μmol min-1 g-1) during I3C administration. These data suggest that the oral administration of c-AUCB displays antihypertensive effects in Ren-2 transgenic rats with inducible malignant hypertension via an improvement of renal function.

Epoxyeicosatrienoic acid analog attenuates the development of malignant hypertension, but does not reverse it once established

“…These detailed data support the growing evidence that the antihypertensive effect of pharmacologically enhanced tissue EETs is related to their ability to increase renal sodium excretion [17–24]. Therefore, it is plausible to assume the inhibitory action of EETs on sodium transport would act in concert with reduction of the known stimulatory effects of ANG II on direct transport; the latter is a consequence of decreasing plasma and tissue levels of the peptide caused by EET-A treatment as observed in the present study.…”

“…Rats were anesthetized with a combination of tiletamine, zolazepam (Zoletil; Virbac SA, Carros Cedex, France; 8 mg/kg) and xylazine (Rometar, Spofa, Czech Republic; 4 mg/kg) intramuscularly, and TA11PA-C40 radiotelemetric probes (Data Sciences International, St. Paul, Minnesota, USA) were implanted for direct BP measurements as described previously [24,26,38,41]. The rats were allowed 10 days to recover before basal BP was recorded, and only animals with stable BP records at the end of this recovery period were used for experiments.…”

“…Samples were extracted, separated by reverse-phase HPLC, and analyzed by negative-mode electrospray ionization and tandem mass spectroscopy as described previously [47–50]. The procedures for blood sampling, the assays of individual components of RAS, and the EET and DHETE assays are routinely employed in our laboratory, and this standardized approach allows us to compare the results with those of our previous studies evaluating the role of the RAS and CYP-dependent metabolites in the pathophysiology of ANG II-dependent form of hypertension [24,26,35]. …”

Soluble epoxide hydrolase: Gene structure, expression and deletion

“…These results point to a role for sEH in the vasculature of the kidney in the maintenance of hypertension. Interestingly, there is no difference in sEH protein expression in the kidney cortex and medulla of transgenic mice with inducible expression of the renin gene when the control and induced groups are compared (Honetschlagerova et al, 2011). Similarly, sEH expression in the kidney did not change in a dietary salt-loading model of hypertension (Sinal et al, 2000).…”

Antihypertensive and renoprotective actions of soluble epoxide hydrolase inhibition in ANG II-dependent malignant hypertension are abolished by pretreatment with L-NAME

“…It has been shown that the approach to increase EETs' tissue levels by preventing their degradation to the biologically inactive dihydroxyeicosatrienoic acids (DHETEs) by soluble epoxide hydrolase (sEH) inhibition displays antihypertensive actions [3–7]. We have recently shown that substantial increase in the level of endogenous EETs in the presence of sEH inhibition markedly attenuate the development of angiotensin II (ANG II)-dependent form of malignant hypertension particularly by the improvement of renal hemodynamics and increased sodium excretion [8,9]. These findings are in accordance with results from previous studies proposing that the EETs-mediated antihypertensive actions are mainly due to their direct vasodilatory effects and their direct influence on renal tubular transport of sodium [1–3,5,6,10].…”