Vol. 279, Issue 6, H3065-H3075, December 2000
Inhibition of coronary thrombosis and local inflammation by a
noncarbohydrate selectin inhibitor
Pierre
Zoldhelyi,
Pamela J.
Beck,
Robert J.
Bjercke,
Judy
C.
Ober,
X.
Hu,
Janice M.
McNatt,
Salman
Akhtar,
Mohammed
Ahmed,
Fred J.
Clubb Jr.,
Zhi-Qiang
Chen,
Richard A. F.
Dixon,
Edward T. H.
Yeh, and
James T.
Willerson
Wafic Said Molecular and Gene Therapy Research Laboratory and
Cullen Cardiovascular Research Laboratory, Texas Heart Institute, St.
Luke's Episcopal Hospital; Texas Biotechnology Corporation; Institute
of Molecular Medicine; and Department of Internal Medicine, University
of Texas-Houston Medical School, Houston, Texas 77030
We tested the hypothesis
that selectin inhibition with blocking antibodies or a
small-molecular-weight inhibitor of L-, P-, and E-selectin,
methoxybenzoylpropionic acid (MBPA), prevents thrombus
formation in a canine coronary Folts' model. Cyclic flow variations
(CFVs) were induced by crush injury and constriction of the left
anterior descending coronary artery in dogs. Systemic infusion of
antibodies to P- and L-selectin abolished CFVs, respectively, in 50%
and 17% of treated dogs [P = not significant (NS)].
The combination of P- and L-selectin antibodies suppressed CFVs in 60%
of treated dogs (P = NS). In contrast, systemic
selectin blockade by intravenous infusion or local adventitial
application of MBPA markedly reduced CFVs and, in addition, reduced
myocardial myeloperoxidase (MPO) activity. We conclude that
inhibition of L-, P-, and E-selectin binding by a
small-molecular-weight, noncarbohydrate compound markedly reduces
arterial thrombosis, whereas systemic 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 suggest that inhibition
of P- and L- selectin may not suffice to prevent thrombus formation in
this model. The role of E-selectin in thrombus formation in this model
awaits further testing.
selectins; platelet inhibition; P-selectin; antithrombotics
