on January 13, 2003
Circulation. 2003
Published online before print January 13, 2003, doi: 10.1161/01.CIR.0000047278.28407.C2
Published online before print January 13, 2003, doi: 10.1161/01.CIR.0000047278.28407.C2
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Submitted on March 21, 2002
From the Vascular Biology Group (S.L.A., F.S.G., X.W., K.H., E.D.M.), Cardiology (S.L.A., D.H.K., M.P., E.D.M., S.M.), Physiology (S.L.A.), and Cardiovascular Surgery (A.K., S.W.), University of Alberta, Edmonton, Canada; the Medical College of Wisconsin, Milwaukee (W.B.C.); and the University of Texas Southwestern Medical School, Dallas (J.R.F.). * To whom correspondence should be addressed. E-mail: sarcher{at}cha.ab.ca.
Background--Left internal mammary arteries (LIMAs) synthesize endothelium-derived hyperpolarizing factor (EDHF), a short-lived K+ channel activator that persists after inhibition of nitric oxide (NO) and prostaglandin synthesis. EDHF hyperpolarizes and relaxes smooth muscle cells (SMCs). The identity of EDHF in humans is unknown. We hypothesized that EDHF (1) is 11,12-epoxyeicosatrienoic acid (11,12-EET); (2) is generated by cytochrome P450-2C, CYP450-2C; and (3) causes relaxation by opening SMC large-conductance Ca2+-activated K+ channels (BKCa). Methods and Results--The identity of EDHF and its mechanism of action were assessed in 120 distal human LIMAs and 20 saphenous veins (SVs) obtained during CABG. The predominant EET synthesized by LIMAs is 11,12-EET. Relaxations to exogenous 11,12-EET and endogenous EDHF are of similar magnitudes. Inhibition of EET synthesis by chemically distinct CYP450 inhibitors (17-octadecynoic acid, N-methylsulfonyl-6-(2-propargyloxyphenyl)hexanamide), or a selective EET antagonist (4,15-epoxyeicosa-5(Z)-enoic acid) impairs EDHF relaxation. 11,12-EET activates a BKCa current and hyperpolarizes LIMA SMCs. Inhibitors of BKCa but not inward-rectifier or small-conductance KCa channels abolish relaxation to endogenous EDHF and exogenous 11,12-EET. BKCa and CYP450-2C mRNA and proteins are more abundant in LIMAs than in SVs, perhaps explaining the lack of EDHF activity of the SV. Laser capture microdissection and quantitative RT-PCR demonstrate that BKCa channels are primarily in vascular SMCs, whereas the CYP450-2C enzyme is present in both the endothelium and SMCs. Conclusions--In human LIMAs, EDHF is 11,12-EET produced by an EDHF synthase CYP450-2C and accounting for
Revised on October 10, 2002
Accepted on October 28, 2002
Endothelium-Derived Hyperpolarizing Factor in Human Internal Mammary Artery Is 11,12-Epoxyeicosatrienoic Acid and Causes Relaxation by Activating Smooth Muscle BKCa Channels
Stephen L. Archer MD*,
40% of net endothelial relaxation. 11,12-EET causes relaxation by activating SMC BKCa channels.
Key words: lasers • ion channels • bypass • cytochromes
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