Reduction of Myocardial Infarct Size in the Rabbit by a Carbohydrate Analog of Sialyl Lewis(x).
BACKGROUND: Available data suggest that the accumulation of neutrophils within the myocardium following an ischemic event plays an important role in the pathogenesis of myocardial ischemia/reperfusion injury. It is of interest, therefore, to develop pharmacologic agents designed to inhibit neutrophil adhesion to the endothelium. METHODS AND RESULTS: A synthetic carbohydrate analog to the P-selectin ligand sialyl Lewis(x) (sLe(x)) was evaluated for its ability to protect the myocardium from ischemia/reperfusion injury. Open chest anesthetized rabbits were subjected to 30 minutes occlusion of the left circumflex artery followed by 5 hours of reperfusion. Vehicle or sLe(x) analog (10 mg/kg) was administered intravenously before the onset of reperfusion and every hour during the reperfusion period. Myocardial infarct size in rabbits treated with the sLe(x) analog (10 mg/kg) was administered intravenously before the onset of reperfusion and every hour during the reperfusion period. Myocardial infarct size in rabbits treated with the sLe(x) analog was significantly reduced when compared to rabbits treated with vehicle (28 +/- 9% vs 57 +/- 10% of the area at risk, p <.05). The compound did not alter circulating neutrophil counts or myocardial oxygen demand as determined by the rate-pressure product. Furthermore, neutrophil accumulation within the ischemic region was decreased by 44% (P <.05) in the hearts of animals receiving sLe(x) analog as compared to vehicle. CONCLUSIONS: Carbohydrate derivatives of sLe(x) may be effective in reducing the degree of myocardial injury after ischemia/reperfusion.
Kilgore
KS
Department of Pharmacology, Glycomed, Inc., Ann Arbor, Michigan, USA
Park
JL
Chi
L
Musser
JH
Date
V
Abbas
S
Lucchesi
BR