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(Hypertension. 2005;46:607.)
© 2005 American Heart Association, Inc.

Original Articles

Contribution of 20-HETE to Augmented Myogenic Constriction in Coronary Arteries of Endothelial NO Synthase Knockout Mice

An Huang; Dong Sun; Changdong Yan; John R. Falck; Gabor Kaley

From the Department of Physiology (A.H., D.S., C.Y., G.K.), New York Medical College, Valhalla; and Department of Biochemistry (J.R.F.), University of Texas, Southwestern Medical Center, Dallas.

Correspondence to An Huang, MD, PhD, Department of Physiology, New York Medical College, Valhalla, NY 10595. E-mail an_huang{at}nymc.edu

Previous studies suggested an important role for 20-HETE in the regulation of myogenic responses. Thus, pressure–diameter relationships were investigated in isolated, cannulated coronary arteries (100µm) from male endothelial NO synthase knockout (eNOS-KO) and wild-type (WT) mice. All arteries constricted in response to step increases in perfusate pressure from 20 to 100 mm Hg. This constriction was significantly enhanced from 40 to 100 mm Hg in arteries of eNOS-KO compared with those of WT mice. For example, at 60 and 100 mm Hg, respectively, the normalized diameter (expressed as a percentage of the corresponding passive diameter) of arteries of eNOS-KO mice was 10% and 12% smaller than that of WT mice. Removal of the endothelium did not significantly affect the responses of vessels from either strain of mice. However, N-methylsulfonyl-12,12-dibromododec-11-enamide (5x10^–6 M), an inhibitor of cytochrome P-450 (CYP)/-hydroxylase, significantly attenuated the greater myogenic constriction of arteries from eNOS-KO mice by 12% at each pressure step but did not significantly affect responses of those from WT mice, leading to a comparable myogenic response in the 2 strains. Western blot analysis demonstrated a comparable CYP4A protein content in coronary arteries of the 2 strains of mice. However, production of 20-HETE, measured by fluorescent high-performance liquid chromatography assay was 2.7-fold greater in eNOS-KO compared to WT mice. Thus, as a function of eNOS deficiency, the enhanced coronary artery constriction to pressure is attributable to an increased activity of -hydroxylase, which, consequently, increases the synthesis of 20-HETE in vascular smooth muscle.

Key Words: constriction • nitric oxide • coronary artery disease