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Ether epoxyeicosatrienoic acid (EET) analogs lower blood pressure when administered in‐vivo to the spontaneously hypertensive rats
Author(s) -
Elmarakby Ahmed A.,
Falck John R.,
Imig John D.
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.479.44
Subject(s) - epoxide hydrolase 2 , ether , chemistry , in vivo , blood pressure , carboxylic acid , spontaneously hypertensive rat , stereochemistry , pharmacology , epoxyeicosatrienoic acid , enzyme , biochemistry , medicine , organic chemistry , arachidonic acid , biology , microbiology and biotechnology
Epoxyeicosatrienoic acids (EETs) play an important role in the regulation of vascular tone. EETs rapidly degrade in‐vivo by the soluble epoxide hydrolase (sEH) enzyme. Using the pharmacophoric moiety of EET, ether EET analogs were designed with improved solubility and resistance to auto‐oxidation and metabolism by sEH. We tested the blood pressure lowering effects of these analogs in an established model of hypertension, the spontaneously hypertensive rats (SHR) using telemetry. Initially, 11,12–ether EET‐8‐ZE failed to lower blood pressure in 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 with a blood pressure lowering effect when injected at 3 mg/day in SHR for 5 days (MAP Δ change at day 2 of injection was −8± 1.3 for treated and 1±1.3 mmHg in control SHR). Amidation of the carboxylic group with lysine amino acid produced another analog with a 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.