Reduction of Myocardial Infarct Size in the Rabbit by a Carbohydrate Analog of Sialyl Lewisx

Abstract

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.

Inhibitory effect of SM-20550, an Na + /H + exchange inhibitor, on accumulation of leukocytes in ischemia and reperfusion

“…4). This observation is consistent with previous reports (Kilgore et al 1996(Kilgore et al , 1998, in which neutrophil accumulation in the area-at-risk was observed during the 30 min of myocardial ischemia and 5 h of reperfusion in a similar rabbit model. SM-20550 attenuated the neutrophil accumulation in the area-at-risk without affecting the level of neutrophils in the non-ischemic area (Fig.…”

Antagonism of Selectin-Dependent Adhesion of Human Eosinophils and Neutrophils by Glycomimetics and Oligosaccharide Compounds

“…GM2296, fucose-carbon-glycyrrhetinic acid, was constructed to contain the necessary carboxylic acid and a carbon fucoside, and would be expected to have the ability to flex enough to fit all three selectins. Although in vivo data with these compounds are limited, both GM1380 and GM1292 have been shown in vivo to reduce myocardial infarct size in a rabbit ischemia model (35,36).…”

Cryptococcal capsular glucuronoxylomannan reduces ischaemia‐related neutrophil influx

“…Although a considerable number of these studies showed a clear effect on infarct size [29][30][31][32][33][34], some reports, however, failed to show any effect of antineutrophil measures on reperfusion injury [62][63][64]. infarct size).…”

“…Whereas an inflammatory response normally benefits the host by eliminating host invaders, in the case of ischaemia it is directed against the host-tissue and will contribute to further tissue injury [26]. In addition, it has been demonstrated in animal models that neutrophil depletion and several types of antineutrophil therapy reduce infarct size in postischaemic reperfusion injury [29][30][31][32][33][34]. In addition, it has been demonstrated in animal models that neutrophil depletion and several types of antineutrophil therapy reduce infarct size in postischaemic reperfusion injury [29][30][31][32][33][34].…”

“…The early influx of neutrophils reaches its peak 2-6 h after restoration of the blood flow of ischaemic myocardium [27,28] and has been directly correlated to infarct size [27]. In addition, it has been demonstrated in animal models that neutrophil depletion and several types of antineutrophil therapy reduce infarct size in postischaemic reperfusion injury [29][30][31][32][33][34].…”