Development of Epoxyeicosatrienoic Acid Analogs with in Vivo Anti-Hypertensive Actions

Abstract

Epoxyeicosatrienoic acids (EETs) contribute importantly to the regulation of vascular tone and blood pressure control. The purpose of this study was to develop stable EET analogs and test their in vivo blood pressure lowering effects in hypertensive rats. Using the pharmacophoric moiety of EETs, ether EET analogs were designed with improved solubility and resistance to auto-oxidation and metabolism by soluble epoxide hydrolase. Ether EET analogs were chosen based on their ability to dilate afferent arterioles and subsequently tested for blood pressure lowering effects in rodent models of hypertension. Initially, 11,12-ether-EET-8-ZE failed to lower blood pressure in angiotensin hypertension or spontaneously hypertensive rats (SHR). Esterification of the carboxylic group of 11,12-ether-EET-8-ZE prevented blood pressure increase in SHR when injected at 2 mg/day for 12 days (MAP Δ change at day 8 of injection was −0.3 ± 2 for treated and 12 ± 1 mmHg for control SHR). Amidation of the carboxylic group with aspartic acid produced another EET analog (NUDSA) with a blood pressure lowering effect when injected at 3 mg/day in SHR for 5 days. Amidation of the carboxylic group with lysine amino acid produced another analog with minimal blood pressure lowering effect. These data suggest that esterification of the carboxylic group of 11,12-ether-EET-8-ZE produced the most effective ether-EET analog in lowering blood pressure in SHR and provide the first evidence to support the use of EET analogs in treatment of cardiovascular diseases.

Functional characterization of cytochrome P450-derived epoxyeicosatrienoic acids in adipogenesis and obesity

“…Administration of NUDSA, an EET analog conducive to repeated dosing in vivo ( 13 ), also signifi cantly attenuated HFD-evoked weight gain ( Fig. 8A ) compared with vehicletreated controls without affecting average food consumption (16.1 ± 0.8 g/week/mouse vs. 17.5 ± 1.2 g/week/ mouse, respectively, P = 0.468).…”

“…The stable EET analog 14,15-epoxyeicosa-8(Z)-enoic acid (14,15-EE-8(Z)-E) and CYP epoxygenase inhibitor N-(methylsulfonyl)-2-(2-propynyloxy)-benzenehexanamide (MS-PPOH) were purchased from Cayman Chemical (Ann Arbor, MI). The stable EET analogs (S)-2-(11-(nonyloxy) undec-8(Z)-enamido)succinic acid (NUDSA) and (S)-2-(13-(3-butylureido) tridec-8(Z)-enamido)succinic acid (EET-A, sodium salt) were synthesized by Dr. John Falck (University of Texas Southwestern, TX) ( 13,14 ).…”

The Cyp2c44 Epoxygenase Regulates Epithelial Sodium Channel Activity and the Blood Pressure Responses to Increased Dietary Salt

“…The recognition of altered tubular transport in hypertensive Cyp2c44 KO mice offers new approaches for the understanding of mechanism(s) by which the kidney regulates sodium excretion and blood pressure. Furthermore, the data presented: (a) provide an experimental foundation for future studies of the functional roles of the CYP2C8 and CYP2C9 epoxygenases in human hypertension and (b) suggest that maneuvers designed to up-regulate kidney CYP2C epoxygenase expression and/or efforts to develop stable EET functional analogs (26,50) could serve as a basis for the development of novel antihypertensive therapies. In summary, it is expected that these studies will stimulate efforts to develop novel CYP2C/EET-based, antihypertensive drugs and strategies for the early detection and diagnosis of hypertension.…”

“…It is therefore of importance that the current methods for drug evaluation take into consideration the potential physiological and/or pathophysiological consequences of interfering with the activity and/or expression of P450s involved in endogenous metabolic pathways. This and other published studies (21,25,50) should influence current views of the roles played by the P450 enzyme system from that of vehicles for drug disposition and/or activation to that of active participants in the biosynthesis of physiologically important mediators of cell and organ function.…”

Anti-inflammatory ω-3 endocannabinoid epoxides

“…Epoxyeicosanoid EETs are generated from AA by CYP epoxygenases (41) and have recently been demonstrated to exert potent anti-inflammatory effects in vitro and in vivo (53). Notably, stable EET analogs have been developed for the treatment of cardiovascular disease and inflammation via interaction with the putative EET receptor (54). Endocannabinoids also have been shown to contain anti-inflammatory and anticancer properties.…”