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Effects of EXRD 4605, a soluble epoxide hydrolase inhibitor, on angiotensin II dependent hypertension in rodents
Author(s) -
Weldon Steven M,
Matera Damian,
Kerr Steven,
Berger Valentina,
Ingraham Richard,
DeLeon Rodney,
Madwed Jeffrey B,
Kabcenell Alisa
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.479.33
Subject(s) - epoxide hydrolase 2 , ex vivo , chemistry , angiotensin ii , vasodilation , endocrinology , renin–angiotensin system , medicine , blood pressure , pharmacology , enzyme , in vitro , biochemistry
EETs are vasoactive AA metabolites generated by the CYP450 enzymatic pathway. EETs exhibit vasodilation in vitro and can be further metabolized to their less active diols, DHET by soluble epoxide hydrolase, sEH. Angiotensin II induces sEH expression in rodents. We examined the effects of EXRD4605 (EX), a sEH inhibitor, on angiotensin II‐induced vascular and blood pressure (BP) responses in rodents. EX is a potent inhibitor of human (Kd=2 nM) and mouse (0.4 nM) sEH and exhibits a cellular ED 50 of 2.4 nM. EX induces dose‐responsive (25%–175%) increases in gracilis muscle arteriolar diameters that is blocked in the presence of the CYP inhibitor miconazole. Administration of ang II (100–1000 ng/kg, IV) in anesthetized mice induces acute BP increases (25%–53%) that are blunted (29%*–32%*p<0.05) by pre‐treatment with EX (30 mg/kg). We hypothesized the attenuation of the BP increase is the result of increased EET by EX pretreatment. EX had no effect in sEH gene deleted mice suggesting the role of sEH in this response. In mice with established hypertension (angII 1 mg/kg/d), EX (10 mg/kg) reduced BP from 136 to 117* mmHg compared to 139 mmHg to 142 mmHg in vehicle control. We conclude that pharmacological inhibition of sEH with EX induces vasodilation in resistance vessels ex vivo and attenuates ang II‐dependent hypertension in vivo . These data support sEH as an intriguing target for blood pressure regulation and hypertension.