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

Non-technical summary Arachidonic acid metabolites called epoxyeicosatrienoic acids (EETs) influence vascular tone and renal tubular sodium and water transport and thus have been implicated in the control of blood pressure. Inhibition of the enzyme soluble epoxide hydrolase (sEH), which reduces EET degradation to the corresponding diols, leads to substantial attenuation of malignant hypertension in a transgenic rat strain harbouring the mouse renin gene particularly via an improvement of renal function. The observed antihypertensive and renoprotective effects of this novel pharmacological approach provide a potentially new direction in antihypertensive therapy. 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 mu mol 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.