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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2009;29:54.)
© 2009 American Heart Association, Inc.

Integrative Physiology/Experimental Medicine

Interaction Between P450 Eicosanoids and Nitric Oxide in the Control of Arterial Tone in Mice

Hantz C. Hercule; Wolf-Hagen Schunck; Volkmar Gross; Jasmin Seringer; Fung Ping Leung; Steven M. Weldon; Andrey Ch. da Costa Goncalves; Yu Huang; Friedrich C. Luft; Maik Gollasch

From the Charité Campus Buch, Franz Volhard Clinic/ECRC and HELIOS Klinikum-Berlin, Nephrology/Intensive Care Section, Charité Campus Virchow (H.C.A., J.S., M.G.), and Max Delbrück Center for Molecular Medicine, Berlin, Germany (W.-H.S., V.G., A.Ch.daC.G.); the Department of Physiology, the Chinese University of Hong Kong, China (P.L., Y.H.); and Cardiovascular Disease, Boehringer Ingelheim Pharmaceuticals Inc, Ridgefield, Conn (S.M.W.).

Correspondence to Maik Gollasch, MD, PhD, Charité University Medicine, Campus Virchow, Nephrology/Intensive Care Section, Augustenburger Platz 1, 13353 Berlin, Germany. E-mail maik.gollasch{at}charite.de

Objective— Epoxyeicosatrienoic acids (EETs) serve as endothelial-derived hyperpolarizing factors (EDHF), but may also affect vascular function by other mechanisms. We identified a novel interaction between EETs and endothelial NO release using soluble epoxide hydrolase (sEH) –/– and +/+ mice.

Methods and Results— EDHF responses to acetylcholine in pressurized isolated mesenteric arteries were neither affected by the sEH inhibitor, N-adamantyl-N'-dodecylurea (ADU), nor by sEH gene deletion. However, the EDHF responses were abolished by catalase and by apamin/charybdotoxin (ChTx), but not by iberiotoxin, nor by the cytochrome P450 inhibitor PPOH. All four EETs (order of potency: 8,9-EET >14,15-EET5,6-EET >11,12-EET) and all 4 dihydroxy derivatives (14,15-DHET8,9-DHET11,12-DHET >5,6-DHET) produced dose-dependent vasodilation. Endothelial removal or L-NAME blocked 8,9-EET and 14,15-DHET-dependent dilations. The effects of apamin/ChTx were minimal. 8,9-EET and 14,15-DHET induced NO production in endothelial cells. ADU (100 µg/mL in drinking water) lowered blood pressure in angiotensin II–infused hypertension, but not in L-NAME–induced hypertension. Blood pressure and EDHF responses were similar in L-NAME–treated sEH +/+ and –/– mice.

Conclusions— Our data indicate that the EDHF response in mice is caused by hydrogen peroxide, but not by P450 eicosanoids. Moreover, P450 eicosanoids are vasodilatory, largely through their ability to activate endothelial NO synthase (eNOS) and NO release.

Key Words: eicosanoids • soluble epoxide hydrolase • NO synthase • L-NAME • EDRF

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