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

Abstract

Objective The present study was performed to investigate in a model of malignant hypertension if the antihypertensive actions of soluble epoxide hydrolase (sEH) inhibition are nitric oxide (NO)-dependent. Methods ANG II-dependent malignant hypertension was induced through dietary administration for 3 days of the natural xenobiotic indole-3-carbinol (I3C) in Cyp1a1-Ren-2 transgenic rats. Blood pressure (BP) was monitored by radiotelemetry and treatment with the sEH inhibitor [cis-4-[4-(3-adamantan-1-yl-ureido)-cyclohexyl-oxy]-benzoic acid (c-AUCB)] was started 48h before administration of the diet containing I3C. In separate groups of rats, combined administration of the sEH inhibitor and the nonspecific NO synthase inhibitor [Nω-nitro-l-arginine methyl ester (L-NAME)] on the course of BP in I3C-induced and noninduced rats were evaluated. In addition, combined blockade of renin–angiotensin system (RAS) was superimposed on L-NAME administration in separate groups of rats. After 3 days of experimental protocols, the rats were prepared for renal functional studies and renal concentrations of epoxyeicosatrienoic acids (EETs) and their inactive metabolites dihydroxyeicosatrienoic acids (DHETEs) were measured. Results Treatment with c-AUCB increased the renal EETs/DHETEs ratio, attenuated the increases in BP, and prevented the decreases in renal function and the development of renal damage in I3C-induced Cyp1a1-Ren-2 rats. The BP lowering and renoprotective actions of the treatment with the sEH inhibitor c-AUCB were completely abolished by concomitant administration of L-NAME and not fully rescued by double RAS blockade without altering the increased EETs/DHETEs ratio. Conclusion Our current findings indicate that the antihypertensive actions of sEH inhibition in this ANG II-dependent malignant form of hypertension are dependent on the interactions of endogenous bioavailability of EETs and NO.

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

“…Using the same model, we recently showed that development of typical malignant hypertension is not simply the result of RAS overactivity, but also of its perturbed interactions with other vasoactive systems. In particular, we found that the development of ANG II-dependent malignant hypertension in Cyp1a1-Ren-2 transgenic rats is accompanied by decreased intrarenal EET concentrations [26,38,41]. Based on the above considerations, we first decided to employ the model in an attempt to examine if chronic oral administration of EET-A would attenuate the development of ANG II-dependent malignant hypertension.…”

Flaxseed Consumption Reduces Blood Pressure in Patients With Hypertension by Altering Circulating Oxylipins via an α-Linolenic Acid–Induced Inhibition of Soluble Epoxide Hydrolase

“…10 In contrast, the epoxyeicosatrienoic acids (EETs) produced from arachidonic acid are endothelial-derived hyperpolarizing factors that are associated with vasodilation and natriuresis 11,12 and may indirectly propagate vasodilation [13][14][15] by activating endothelial nitric oxide synthase. 16,17 EETs can be rapidly metabolized to dihydroxyeicosatrienoic acids (DHETs) by the enzyme soluble epoxide hydrolase (sEH), resulting in a concomitant loss of vasodilation. 18,19 sEH also converts the protoxins, epoxyoctadecenoic acids, to the dihydroxyoctadecenoic acids, which are potent cytotoxic and proinflammatory metabolites.…”

“…The sEH substrates, EETs, have known vasodilatory actions. [12][13][14][15][16][17][18][19]23 However, because of the short half-life of EETs, 33 these sEH substrates were below the level of detection and it was not . Schematic of proposed α-linolenic acid-induced alterations in the oxylipin profile.…”

“…18,19 sEH also converts the protoxins, epoxyoctadecenoic acids, to the dihydroxyoctadecenoic acids, which are potent cytotoxic and proinflammatory metabolites. [20][21][22] Because products of sEH propagate loss of vascular relaxation and promote inflammation, targeting sEH inhibition pharmacologically has been used successfully to reduce blood pressure, 12,17,23 hypertension-associated renal damage, 17 and infarction size 23 in animal models. The proposed relationship between epoxygenase-derived oxylipins and hypertension is depicted in Figure 1.…”

“…Pharmacological inhibition of sEH has resulted in a reduction of sEH-derived DHETs and blood pressure in animal studies. 17,23,31,32 The potential mechanisms behind the relationship between sEH-derived oxylipins and blood pressure are numerous. The sEH substrates, EETs, have known vasodilatory actions.…”