New sialyl-Lewis-X analogues antagonize leukocyte-induced ischemia-reperfusion arrhythmia--a mapping study

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.

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.

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.

Sialyl-Lewis-X analogues (Hoe934553, Hoe943644) can antagonize PMN infiltration and PMN-induced VF in the course of ischemia and reperfusion.