Nonanticoagulant heparin prevents coronary endothelial dysfunction after brief ischemia-reperfusion injury in the dog

Background-Coronary endothelial dysfunction after brief ischemia-reperfusio n (IR) remains a clinical problem. We investigated the role of heparin and N-acetylheparin, a nonanticoagulant heparin derivative, in modulating coron ary 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 a cetylcholine challenge, were studied after 15 minutes of regional ischemia of the left anterior descending artery (LAD) followed by 120 minutes of rep erfusion, In dogs treated with placebo (saline), coronary vasomotor functio n was significantly (P less than or equal to 0.03) decreased after 15 and 3 0 minutes of reperfusion (65+/-12% and 73+/-12%) compared with preischemia (103+/-6%). In contrast, the vasodilatory response to the endothelium-indep endent 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. I n a parallel group of dogs, nitrate/nitrite (NOx) and cGMP levels in the LA D were measured after treatment and during 15-minute reperfusion, Preischem ic administration of N-acetylheparin caused a significant increase in basal NOx and cGMP levels compared with saline controls. Pretreatment with N-ace tylheparin 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 endotheli al function after brief IR injury by a mechanism independent of its anticoa gulant activity and that the effect of heparin may be mediated in part by a ctivation of the NO-cGMP pathway.