ADJUNCTIVE SELECTIN BLOCKADE SUCCESSFULLY REDUCES INFARCT SIZE BEYOND THROMBOLYSIS IN THE ELECTROLYTIC CANINE CORONARY-ARTERY MODEL

被引:51
作者
SILVER, MJ
SUTTON, JM
HOOK, S
LEE, P
MALYCKY, JL
PHILLIPS, ML
ELLIS, SG
TOPOL, EJ
NICOLINI, FA
机构
[1] CLEVELAND CLIN FDN,DEPT CARDIOL F15,JOSEPH J JACOBS CTR THROMBOSIS & VASC BIOL,CLEVELAND,OH 44195
[2] CYTEL CORP,SAN DIEGO,CA 92121
关键词
ADHESION MOLECULES; NEUTROPHILS; THROMBOLYSIS; REPERFUSION; SELECTIN;
D O I
10.1161/01.CIR.92.3.492
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Background An adjunctive pharmacological strategy to thrombolytic therapy that is tailored to limit reperfusion injury after thrombolysis could further maximize the unquestioned benefit of restoring flow to ischemic myocardium. Ischemia-reperfusion injury exhibits features characteristic of an acute inflammatory response, including the rapid activation and infiltration of neutrophils. The initial process of neutrophil migration from the circulation to injured tissue is modulated by a group of adhesion molecules called selectins. The purpose of the present study was to assess the efficacy of a selectin blocker (CY 1503) given as an adjunct to thrombolytic therapy to interfere with the inflammatory response after ischemia-reperfusion and subsequently reduce myocardial infarct size in the electrolytic canine model. Methods and Results A fully occlusive thrombus was formed in the left circumflex coronary artery by electrolytic injury in 20 anesthetized open-chest dogs. After occlusion, an infusion of 1 mg/kg recombinant tissue-type plasminogen activator (rTPA) was administered over 20 minutes with either a bolus of placebo or the selectin blocker CY 1503 (40 mg/kg). At the onset of reperfusion, 20 mu g/kg per minute rTPA was administered for 1 hour to prevent reocclusion. After 1 hour of reperfusion, infarct size, myocardial myeloperoxidase activity, and reperfusion arrhythmias were measured. In CY 1503-treated dogs, there was a significant 69% reduction in infarct size when expressed as a percentage of the area at risk (6.7+/-8.4% versus 21.8+/-13.6%; P=.008) and a marked reduction in myeloperoxidase activity (0.014+/-0.009 versus 0.0370+/-0.025 U/min per gram; P=.02) compared with the placebo group. There was no difference between the groups in the occurrence of reperfusion arrhythmias. Conclusions Selectin blockade as an adjunct to rTPA-mediated thrombolysis significantly reduces infarct size and myocardial neutrophil infiltration well beyond thrombolysis alone in the electrolytic canine model. These data suggest that selectin blockade is extremely effective at reducing ischemia-reperfusion injury and myocardial infarct size in this model and that the neutrophil is a potent mediator of ischemia-reperfusion injury.
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页码:492 / 499
页数:8
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  • [41] SIMPSON PJ, 1988, J PHARMACOL EXP THER, V244, P619
  • [42] ILOPROST INHIBITS NEUTROPHIL FUNCTION-INVITRO AND INVIVO AND LIMITS EXPERIMENTAL INFARCT SIZE IN CANINE HEART
    SIMPSON, PJ
    MICKELSON, J
    FANTONE, JC
    GALLAGHER, KP
    LUCCHESI, BR
    [J]. CIRCULATION RESEARCH, 1987, 60 (05) : 666 - 673
  • [43] PROSTACYCLIN PROTECTS ISCHEMIC REPERFUSED MYOCARDIUM IN THE DOG BY INHIBITION OF NEUTROPHIL ACTIVATION
    SIMPSON, PJ
    MITSOS, SE
    VENTURA, A
    GALLAGHER, KP
    FANTONE, JC
    ABRAMS, GD
    SCHORK, MA
    LUCCHESI, BR
    [J]. AMERICAN HEART JOURNAL, 1987, 113 (01) : 129 - 137
  • [44] TEMPORAL RELATION BETWEEN NEUTROPHIL ACCUMULATION AND MYOCARDIAL REPERFUSION INJURY
    SMITH, EF
    EGAN, JW
    BUGELSKI, PJ
    HILLEGASS, LM
    HILL, DE
    GRISWOLD, DE
    [J]. AMERICAN JOURNAL OF PHYSIOLOGY, 1988, 255 (05): : H1060 - H1068
  • [45] ASSAY-METHOD FOR MYELOPEROXIDASE IN HUMAN POLYMORPHONUCLEAR LEUKOCYTES
    SUZUKI, K
    OTA, H
    SASAGAWA, S
    SAKATANI, T
    FUJIKURA, T
    [J]. ANALYTICAL BIOCHEMISTRY, 1983, 132 (02) : 345 - 352
  • [46] VIVALDI MT, 1985, AM J PATHOL, V121, P522
  • [47] WERNS S, 1989, CIRCULATION S2, V80, P113
  • [48] INVIVO NEUTRALIZATION OF P-SELECTIN PROTECTS FELINE HEART AND ENDOTHELIUM IN MYOCARDIAL-ISCHEMIA AND REPERFUSION INJURY
    WEYRICH, AS
    MA, XL
    LEFER, DJ
    ALBERTINE, KH
    LEFER, AM
    [J]. JOURNAL OF CLINICAL INVESTIGATION, 1993, 91 (06) : 2620 - 2629
  • [49] ANTI-P-SELECTIN MONOCLONAL-ANTIBODY ATTENUATES REPERFUSION INJURY TO THE RABBIT EAR
    WINN, RK
    LIGGITT, D
    VEDDER, NB
    PAULSON, JC
    HARLAN, JM
    [J]. JOURNAL OF CLINICAL INVESTIGATION, 1993, 92 (04) : 2042 - 2047
  • [50] EFFECT OF SOME FREE-RADICAL SCAVENGERS ON REPERFUSION INDUCED ARRHYTHMIAS IN THE ISOLATED RAT-HEART
    WOODWARD, B
    ZAKARIA, MNM
    [J]. JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY, 1985, 17 (05) : 485 - 493