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(Circulation. 1999;100:II-335.)
© 1999 American Heart Association, Inc.

Myocardial Protection and Vascular Biology

Recombinant Gene Transfer of Endothelial Nitric Oxide Synthase Augments Coronary Artery Relaxations During Hypoxia

David G. Cable, MD; Vincent J. Pompili, MD; Timothy O’Brien, MD; Hartzell V. Schaff, MD

From the Cardiac Surgical Research Center (D.G.C., H.V.S.), Department of Endocrinology (T.O.), and the Section of Cardiovascular Surgery (D.G.C., H.V.S.), Mayo Clinic and Mayo Foundation, Rochester, Minn; and the Department of Medicine (V.J.P.), The Krannert Institute of Cardiology, Indiana University School of Medicine, Indianapolis.

Correspondence to Hartzell V. Schaff, MD, Section of Cardiovascular Surgery, Mayo Clinic and Mayo Foundation, 200 First St SW, Rochester, MN 55905. E-mail schaff{at}mayo.edu

Background—Coronary arteries respond to hypoxia with transient relaxations, which increases coronary blood flow, in part, by release of nitric oxide. We hypothesized that increased expression of nitric oxide synthase might further augment blood vessel relaxation during hypoxia. The present study examined the effect of adenovirus-mediated transfer of bovine endothelial nitric oxide synthase (eNOS) on hypoxia-induced transient relaxations in canine coronary arteries.

Methods and Results—Paired segments of coronary arteries were exposed to vehicle (phosphate-buffered saline with albumin) or an adenovirus encoding either E coli ß-galactosidase (Ad.CMVLacZ, viral control; 10¹⁰ pfu/mL) or eNOS (Ad.CMVeNOS; 10¹⁰ pfu/mL) for 2 hours at 37°C. Immunohistochemistry with a monoclonal antibody specific for eNOS documented both endothelial and adventitial expression in Ad.CMVeNOS arteries, whereas vehicle and viral controls demonstrated only constitutive expression. Levels of cGMP were increased 5-fold in Ad.CMVeNOS arteries compared with controls. In arteries exposed to Ad.CMVeNOS, maximum contraction to prostaglandin F₂ was reduced compared with viral controls, and this effect was eliminated by pretreatment with a competitive inhibitor of eNOS (N^G-monomethyl-L-arginine, 10^-3 mol/L). Hypoxia-induced transient relaxation (95% N₂-5% CO₂) in Ad.CMVeNOS arteries (45.2±8.8%, n=6) was augmented compared with vehicle (26.3±6.0%) or viral (27.2±7.1%) controls.

Conclusions—Adenovirus-mediated gene transfer of nitric oxide synthase reduces receptor-dependent contractions and augments hypoxia-induced relaxations in canine coronary arteries; this method of augmentation of NO production might be advantageous for reduction of coronary artery vasospasm.

Key Words: arteries • genes • genetics • nitric oxide • hypoxia • ß-galactosidase • ischemia