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Novel Epoxyeicosatrienoic Acid (EET) Analogs Increase Sodium Excretion and Lower Blood Pressure in Hypertension

EETs contribute to electrolyte homeostasis and blood pressure regulation. This has led to the concept that EETs can be therapeutically targeted for cardiovascular diseases. In this study, thirty compounds were synthesized using the pharmacophoric moiety of 14,15‐EET and tested for vasodilatory properties and soluble epoxide hydrolase inhibitory (sEHi) activity. Compounds with vasodilatory activity similar to 14,15‐EET without sEHi activities (IC50 >500 nM) were tested for effects on mean arterial pressure (MAP) in angiotensin (ANG) hypertension and spontaneously hypertensive rats (SHR). EET analogs that had the COOH group replaced with aspartic acid (EET‐A) or a heterocyclic surrogate (EET‐B) attenuated ANG hypertension when administered for 14 days (10 mg/kg/d ip). After the 14‐days, MAP averaged 153±5 (n=6) in vehicle, 134±5 (n=3) in EET‐A, and 106±6 mmHg (n=6, p<0.05) in EET‐B treated ANG hypertension. Next, Na+ excretion (UNa) was determined to assess the contribution of natriuresis to the EET‐B decrease in MAP. EET‐B increased UNa in ANG hypertension (2.7±0.3 vs. 1.9±0.7 mmol/d). In SHR, two‐week EET‐A (n=5) or EET‐B (n=6) treatment also lowered MAP by ~15 mmHg. These data demonstrate that novel EET analogs increase Na+ excretion and lower blood pressure in hypertension supporting the concept that they have potential for therapeutic use in cardiovascular diseases.