No 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.

Epoxyeicosatrienoic acids (EETs) are endothelium-derived metabolites of arachidonic acid. They relax vascular smooth muscle by membrane hyperpolarization. These actions are inhibited by the EET antagonist, 14,15-epoxyeicosa-5(Z)-enoic acid (14,15-EE5ZE). We synthesized 20-125 iodo-14,15-EE5ZE (20-125 I-14,15-EE5ZE), a radiolabeled EET antagonist, and characterized its binding to cell membranes. 14,15-EET (10 Ϫ9 -10 Ϫ5 M) caused a concentration-related relaxation of the preconstricted bovine coronary artery and phosphorylation of p38 in U937 cells that were inhibited by 20-125

No abstract

The endocannabinoid, N-arachidonylethanolamine (AEA) is accumulated by neurons via a process that has been characterized biochemically but not molecularly. Inhibitors of AEA accumulation have been characterized individually but have not been compared in a single study. Our purpose was to compare the potency of five previously described compounds (AM404, AM1172, VDM11, OMDM-2, and UCM707) both as inhibitors of AEA and N-palmitoylethanolamine (PEA) accumulation by cerebellar granule neurons and as inhibitors of AEA hydrolysis. The compounds all inhibited AEA accumulation; AM404, VDM11 and OMDM-2 with IC(50) values of approximately 5 microM, whereas AM1172 and UCM707 exhibited IC(50) values of 24 and 30 microM, respectively. The compounds also inhibited PEA accumulation; AM404 being the most potent with an IC(50) of 6 microM, whereas the other compounds had IC(50) values in the range of 30-70 microM. All of the compounds potently inhibited AEA hydrolysis by brain membranes; the K(I) values for AM404, VDM11, and UCM707 were less than 1 microM; AM1172 and OMDM-2 exhibited K(I) values of 3 and 10 microM, respectively. The IC(50) values for inhibition of AEA accumulation were compared to the IC(50) values for PEA accumulation and AEA hydrolysis using linear regression. None of the regressions were significant. These data indicate that inhibition of AEA accumulation by neurons is not a result of the inhibition of endocannabinoid hydrolysis and is a process different from the accumulation of PEA. These studies support the hypothesis that the cellular AEA accumulation beyond simple equilibrium between intracellular and extracellular concentrations occurs because AEA binds to an intracellular protein that is not FAAH but that also recognizes the AEA uptake inhibitors.