Heparinoids with low anticoagulant potency attenuate postischemic endothelial cell dysfunction.
OBJECTIVE
Although standard heparin has been demonstrated to reduce endothelial cell dysfunction in acute ischemia-reperfusion injury, its mechanism of action remains unknown. We hypothesized that heparin's salutary endothelial effects are independent of its conventional anticoagulant activity and are not caused by nonspecific polyanion effects.


METHODS
Isolated rat hindlimbs were perfused at constant pressure with an albumin-enriched crystalloid buffer. After 60 minutes of normothermic ischemia, endothelial function was assessed by measurement of endothelial-dependent vasodilation by log increment infusion of acetylcholine. Endothelial-independent vasodilation was measured by exposure to nitroprusside. Some groups were pretreated with heparinoids possessing minimal or intermediate anticoagulant activity.


RESULTS
Treatment with heparinoids with low anticoagulant activity significantly increased endothelial-dependent vasodilation when compared with the nontreated ischemic group and were statistically indistinguishable from the nonischemic control. Treatment with dextran sulfate, a randomly sulfated polymer with size and charge characteristics similar to heparin, did not change postischemic vasodilation. Endothelial-independent vasodilation was largely unaffected by ischemia-reperfusion or drug treatment.


CONCLUSIONS
A heparinoid with negligible antithrombin-binding activity (Astenose) attenuated postischemic endothelial dysfunction, suggesting that its mechanism of action was independent of anticoagulant activity. Failure of dextran sulfate to be protective implied that the effect was not caused by nonspecific polyanion action.
Sternbergh
W C
WC
Department of Surgery, Medical College of Virginia, Richmond.
Sobel
M
M
Makhoul
R G
RG
D000208:Acute Disease; D000818:Animals; D000925:Anticoagulants / Q000494:pharmacology / Q000627:therapeutic use; D002809:Chondroitin Sulfates / Q000494:pharmacology / Q000627:therapeutic use; D003871:Dermatan Sulfate / Q000494:pharmacology / Q000627:therapeutic use; D016264:Dextran Sulfate / Q000494:pharmacology / Q000627:therapeutic use; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000503:physiopathology; D006493:Heparin / Q000494:pharmacology / Q000627:therapeutic use*; D006497:Heparan Sulfate / Q000494:pharmacology / Q000627:therapeutic use; D006614:Hindlimb / Q000098:blood supply*; D066298:In Vitro Techniques; D007511:Ischemia / Q000188:drug therapy; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000503:physiopathology / Q000517:prevention & control*; D014664:Vasodilation / Q000187:drug effects
D000925:Anticoagulants; D002809:Chondroitin Sulfates; D003871:Dermatan Sulfate; D016264:Dextran Sulfate; D006493:Heparin; D006497:Heparan Sulfate; C092386:astenose; C035838:danaparoid