New Sialyl-Lewis-X Analogues Antagonize Leukocyte-Induced Ischemia-Reperfusion Arrhythmia - A Mapping Study[*]

Abstract

Background: Arrhythmia during ischemia and reperfusion is still an intriguing problem in cardiovascular medicine. Leukocytes infiltrating the ischemic region play an important pathophysiological role. The effects of soluble sialyl-Lewis-X analogues Hoe934553 and Hoe943644, which may inhibit leukocyte-endothelial interaction, were investigated. Methods: Isolated rabbit hearts were perfused with Tyrode solution according to the Langendorff technique. Polymorphic neutrophilic granulocytes (PMN) were isolated from autologous peripheral blood. After 60 min equilibration PMN (n = 7) or vehicle (n = 7) were infused with or without concomitant treatment with Hoe934553 (n = 6) and Hoe943644 (n = 6). Five minutes after the start of the PMN infusion the left descending coronary artery was occluded for 30 min followed by 30 min of reperfusion. Activation and repolarization waves were recorded at 256 sites using a computerized mapping system. Results: Ventricular fibrillation (VF) in 4/7 PMN-treated hearts was found, while in PMN-free hearts no VF occurred. Treatment with Hoe934553 and Hoe943644 completely prevented VF. PMN largely enhanced the dispersion of action potential duration during reperfusion. This PMN effect was completely prevented by both drugs. Myeloperoxidase assay showed reduced activity in Hoe934553 and Hoe943644 treated hearts. Conclusions: Sialyl-Lewis-X analogues (Hoe934553, Hoe943644) can antagonize PMN infiltration and PMN-induced VF in the course of ischemia and reperfusion.

Leukocyte - PMN - heart - selectin - arrhythmia - adhesion

References

• 1 Mullane K M, Young M. The contribution of neutrophil activation and changes in endothelial function to myocardial ischemia-reperfusion injury. Yellon DM, Jennings RB The Pathophysiology of Reperfusion and Reperfusion Injury. New York; Raven Press 1992: 13-33
• 2 Palluy O, Morliere L, Gris J C, Bonne C, Modat G. Hypoxia/reoxygenation stimulates endothelium to promote neutrophil adhesion.  Free Radical Biology & Med. 1992;  13 21-30
• 3 Yoshida N, Granger D N, Anderson D C, Rothlein R, Lane C, Kvietys P R. Anoxia/reoxygenation-induced neutrophil adherence to cultured endothelial cells.  Am J Physiol. 1992;  262 1891-1898
• 4 Sheridan F M, Dauber I M, McMurty I F, Lesnefsky E J, Horwitz L D. Role of leukocytes in coronary vascular endothelial injury due to ischemia and reperfusion.  Circ Res. 1991;  69 1566-1574
• 5 Engler R L, Dahlgren M D, Morris D D, Perterson M A, Schmid-Schönbein G. Role of leukocytes in response to acute myocardial ischemia and reflow in dogs.  Am J Physiol. 1986;  251 314-322
• 6 Dhein S, Schott M, Gottwald E, Müller A, Klaus W. The contribution of neutrophils to reperfusion arrhythmias and a possible role of antiadhesive pharmacological substances.  Cardiovasc Res. 1995;  30 881-889
• 7 Sato N, Endo T, Kiuchi K, Hayakawa H. Effects of a thromboxane synthetase inhibitor, Y-20811, on infarct size, neutrophil accumulation and arrhythmias after coronary artery occlusion and reperfusion in dogs.  J Cardiovasc Pharmacol. 1993;  21 353-361
• 8 Toki Y, Hieda N, Okumurak K, Hashimoto H, Ito T, Ogawa K, Satake T. Myocardial salvage by a novel thromboxane A2-synthetase inhibitor in a canine coronary occlusion-reperfusion model.  Drug Res. 1988;  38 224-227
• 9 Jones S P, Trocha S D, Strange M B, Granger D N, Kevil C G, Bullard D C, Lefer D J. Leukocyte and endothelial cell adhesion molecules in a chronic murine model of myocardial reperfusion injury.  Am J Physiol. 2000;  279 2196-2201
• 10 Kretzschmar G, Sprengard U, Kunz H, Bartnik E, Schmidt W, Toepfer A, Hörsch B, Krause M, Seiffge D. Oligosaccharide recognition by selectins: synthesis and biological activity of multivalent sialyl-Lewis-X ligands.  Tetrahedon. 1995;  51 13015-13030
• 11 Dhein S, Müller A, Gerwin R, Klaus W. Comparative study on the proarrhythmic effects of some class I antiarrhythmic agents.  Circulation. 1993;  87 617-631
• 12 Dhein S, Müller A, Klaus W. Nifedipine antagonizes ouabain-induced ST-segment changes and derangement of epicardial activation pattern in isolated rabbit hearts.  Int J Cardiol. 1990;  29 163-172
• 13 Coronel R, Fiolet J WT, Wilms-Schopman F JG, Schaapherder A FM, Johnson T A, Gettes L S, Janse M J. Distribution of extracellular potassium and its relation to electrophysiologic changes during acute myocardial ischemia in the isolated perfused porcine heart.  Circulation. 1988;  77 1125-1138
• 14 Wilde A AM, Escande D, Schumacher C A, Thuringer D, Mestre M, Fiolet J WT, Janse M J. Potassium accumulation in the globally ischemic mammalian heart.  Circ Res. 1990;  67 835-843
• 15 Spach M S, Josephson M E. Initiating reentry. The role of nonuniform anisotropy in small circuits.  J Cardiovasc Electrophysiol. 1994;  5 182-209
• 16 Massey D, Minnich B N, Burt J M. Arachidonic acid and lipoxygenase metabolites uncouple neonatal rat cardiac myocyte pairs.  Am J Physiol. 1992;  263 494-501
• 17 Mullane K M, Westlin W, Kraemer R. Activated neutrophils release mediators that may contribute to myocardial injury and dysfunction associated with ischemia and reperfusion.  Ann NY Acad Sci. 1988;  524 103-121
• 18 Shandelya S ML, Kuppusamy P, Weisfeldt M L, Zweier J L. Evaluation of the role of polymorphonuclear leukocytes on contractile function in myocardial reperfusion injury.  Circulation. 1993;  87 536-546
• 19 Zacharowski K, Otto M, Hafner G, Marsh Jr H C, Thiemermann C. Reduction of myocardial infarct size with sCR1sLe(x), an alternatively glycosylated form of human soluable complement receptor type 1 (sCR1), possessing sialyl Lewis X.  Br J Pharmacol. 1999;  128 945-952
• 20 Schermerhorn M L, Tofukuji M, Khoury P R, Phillips L, Hickey P R, Sellke F W, Mayer Jr J E, Nelson D P. Sialyl Lewis oligosaccharide preserves cardiopulmonary and endothelial function after hypothermic circulatory arrest in lambs.  J Thorac Cardiovasc Surg. 2000;  120 230-237

1 This paper was presented at the 32nd annual meeting of The German Society for Thoracic and Cardiovascular Surgery, Leipzig, February 23 - 26, 2003