Effects of unfractionated heparin, low molecular weight heparin and r-hirudin on leukocyte adhesion in ischemia/reperfusion.
Activation of the coagulation cascade during myocardial ischemia and reperfusion may contribute to the post-ischemic inflammatory response, mostly via generation of thrombin. We assessed the effect of the anticoagulants unfractionated heparin (UFH), low molecular weight heparin (LMWH) and r-hirudin on leukocyte adhesion and emigration after ischemia and reperfusion in rats. The rat cremaster muscle was prepared for intravital microscopy. One hundred and twenty minutes of ischemia were followed by 90 min of reperfusion. Saline (control), UFH, LMWH or r-hirudin were given 15 min prior to reperfusion and infused for the rest of the observation period. Dosages per kilogram of body weight were (bolus, infusion): saline, 3 ml, 3 ml/h; UFH, 400 IU, 100 IU/h; LMWH, 100 IU, 3 ml/h saline; or r-hirudin, 0.3 mg, 0.15 mg/h. In collecting venules, rolling, adherent, and extravasated leukocytes were counted from recordings of the intravital microscopy. All three anticoagulants similarly attenuated post-ischemic endothelial leukocyte adhesion. In contrast, emigration of leukocytes was only attenuated by r-hirudin. The emigration efficiency of adherent leukocytes (control, 1.21) was unchanged after UFH (1.74), and LMWH (1.51) but decreased after r-hirudin treatment (0.12). The different efficacy of the three anticoagulants in affecting emigration of adherent leukocytes suggests a specific role for the direct thrombin inhibitor r-hirudin in attenuating the post-ischemic inflammatory response. This effect may contribute to the benefits of direct thrombin inhibitors seen in clinical studies after treatment for acute coronary syndromes.
Habazettl
Helmut
H
Department of Physiology, Charité, Campus Benjamin Franklin, Berlin, Germany. habazett@zedat.fu-berlin.de
Lindert
Jens
J
Baeter
Simonida
S
Neumann
Konrad
K
Kuppe
Hermann
H
Kuebler
Wolfgang M
WM
Pries
Axel R
AR
Koster
Andreas
A
D000818:Animals; D002448:Cell Adhesion / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects*; D004727:Endothelium / Q000473:pathology; D005343:Fibrinolytic Agents / Q000008:administration & dosage*; D006493:Heparin / Q000008:administration & dosage*; D006495:Heparin, Low-Molecular-Weight / Q000008:administration & dosage*; D006629:Hirudins / Q000008:administration & dosage*; D007962:Leukocytes / Q000473:pathology; D008297:Male; D017202:Myocardial Ischemia / Q000188:drug therapy* / Q000473:pathology* / Q000503:physiopathology; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy* / Q000473:pathology* / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley
D005343:Fibrinolytic Agents; D006495:Heparin, Low-Molecular-Weight; D006629:Hirudins; D006493:Heparin