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A potent and selective soluble epoxide hydrolase inhibitor improves angiotensin II‐induced hypertension
Author(s) -
Ishimoto Tsuyoshi,
Morita Kazuhiro,
Iwahashi Yuki,
Fujikawa Naoto,
Sato Mariko,
Kakinuma Hiroyuki,
Hirano Hitomi,
Shimaoka Takashi,
Kanno Hideo,
Tsubata Kenji,
Muramatsu Makoto,
Miyata Noriyuki
Publication year - 2006
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.20.5.a1109-a
Subject(s) - epoxide hydrolase 2 , chemistry , ic50 , pharmacology , angiotensin ii , in vivo , potency , nitric oxide , renin–angiotensin system , in vitro , enzyme , blood pressure , biochemistry , endocrinology , medicine , receptor , biology , microbiology and biotechnology , organic chemistry
Soluble epoxide hydrolase (sEH) participates in the metabolism of epoxyeicosatrienoic acids (EETs), and pharmacological inhibition of the enzyme is considered as a novel approach to improve hypertension. In vitro assay with cytosol fraction prepared from human liver, we have discovered sEH inhibitors, Anilide Derivative (AD) and Benzimidazole Derivative (BD), from our chemical library. These compounds completely inhibited sEH‐catalyzed the conversion of trans‐stilbene oxide (AD, IC 50 =4.5 nM; BD, IC 50 =28 nM) and 14,15‐EET (AD, IC 50 =121 nM; BD, IC 50 =50 nM) to their corresponding diols, but had little inhibition for cycloxygenase‐1 and 5‐lipoxygenase. BD also showed a strong inhibition on recombinant human sEH activity with the IC 50 value of 19 nM. To clarify the potency of BD in vivo, we investigated the hypotensive effect of BD in angiotensin II‐induced hypertensive rats. Subcutaneous implantation of osmotic pump filled with angiotensin II exhibited the elevation in systolic blood pressure up to 170 mmHg, whereas, given BD to these rats (60mg/kg/day, po) reduced the rise in blood pressure to 140 mmHg. In conclusion, we have discovered potent and selective inhibitors of sEH that may be useful for treating hypertension.