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(Circulation. 1999;99:1062-1068.)
© 1999 American Heart Association, Inc.

Basic Science Reports

Nonanticoagulant Heparin Prevents Coronary Endothelial Dysfunction After Brief Ischemia-Reperfusion Injury in the Dog

Peter C. Kouretas, MD, PhD; Young D. Kim, MD; Paul A. Cahill, PhD; Adam K. Myers, PhD; Lam N. To, BS; Yi-Ning Wang, MD; James V. Sitzmann, MD; Robert L. Hannan, MD

From the Departments of Surgery (P.C.K., P.A.C., Y.-N.W., J.V.S.), Physiology and Biophysics (P.C.K., P.A.C., A.K.M., L.N.T., J.V.S.), and Anesthesiology (Y.D.K.), Georgetown University Medical Center, Washington, DC, and the Department of Thoracic and Cardiovascular Surgery (R.L.H.), University of Virginia Health Sciences Center, Charlottesville, Va.

Correspondence to Robert L. Hannan, MD, University of Virginia Health Sciences Center, Department of Surgery Box 3501, Charlottesville, VA 22908. E-mail rhannan001{at}aol.com

Background—Coronary endothelial dysfunction after brief ischemia-reperfusion (IR) remains a clinical problem. We investigated the role of heparin and N-acetylheparin, a nonanticoagulant heparin derivative, in modulating coronary endothelial function after IR injury, with an emphasis on defining the role of the nitric oxide (NO)–cGMP pathway in the heparin-mediated effect.

Methods and Results—Male mongrel dogs were surgically instrumented, and the effects of both bovine heparin and N-acetylheparin on coronary endothelial vasomotor function, expressed as percent change from baseline flow after acetylcholine challenge, were studied after 15 minutes of regional ischemia of the left anterior descending artery (LAD) followed by 120 minutes of reperfusion. In dogs treated with placebo (saline), coronary vasomotor function was significantly (P0.03) decreased after 15 and 30 minutes of reperfusion (65±12% and 73±12%) compared with preischemia (103±6%). In contrast, the vasodilatory response to the endothelium-independent vasodilator sodium nitroprusside was maintained during reperfusion. Preischemic administration of both bovine heparin and N-acetylheparin (6.0 mg/kg IV) preserved coronary endothelial function throughout reperfusion. In a parallel group of dogs, nitrate/nitrite (NOx) and cGMP levels in the LAD were measured after treatment and during 15-minute reperfusion. Preischemic administration of N-acetylheparin caused a significant increase in basal NOx and cGMP levels compared with saline controls. Pretreatment with N-acetylheparin also caused a significant increase in NOx and cGMP levels in the LAD after 15 minutes of reperfusion compared with IR alone.

Conclusions—These results suggest that heparin preserves coronary endothelial function after brief IR injury by a mechanism independent of its anticoagulant activity and that the effect of heparin may be mediated in part by activation of the NO-cGMP pathway.

Key Words: endothelium • endothelium-derived factors • heparin • ischemia • reperfusion

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