Inhibition of coronary thrombosis and local inflammation by a noncarbohydrate selectin inhibitor

We tested the hypothesis that selectin inhibition with blocking antibodies or a small-molecular-weight inhibitor of L-, P-, and E-selectin, methoxyben zoylpropionic acid (MBPA), prevents thrombus formation in a canine coronary Folts' model. Cyclic flow variations (CFVs) were induced by crush injury a nd constriction of the left anterior descending coronary artery in dogs. Sy stemic infusion of antibodies to P- and L- selectin abolished CFVs, respect ively, in 50% and 17% of treated dogs [P = not significant (NS)]. The combi nation of P- and L- selectin antibodies suppressed CFVs in 60% of treated d ogs (P = NS). In contrast, systemic selectin blockade by intravenous infusi on or local adventitial application of MBPA markedly reduced CFVs and, in a ddition, reduced myocardial myeloperoxidase (MPO) activity. We conclude tha t inhibition of L-, P-, and E-selectin binding by a small-molecular-weight, noncarbohydrate compound markedly reduces arterial thrombosis, whereas sys temic administration of antibodies to L- and P- selectin fail to reproduce this antithrombotic effect. These results underscore the role of selectins in the pathogenesis of arterial thrombosis under high shear stress and sugg est that inhibition of P- and L- selectin may not suffice to prevent thromb us formation in this model. The role of E-selectin in thrombus formation in this model awaits further testing.