Abstract
Adhesion of leukocytes to the vascular endothelium hallmarks a key event in neutrophil-mediated organ injury after ischemia-reperfusion. The autacoid adenosine has been shown to inhibit activated neutrophil function and to interfere with leukocyte-endothelial adherence. Its therapeutic use in ischemia-reperfusion, however, has been limited by severe cardiovascular side effects. We therefore investigated the effects of the adenosine kinase inhibitor GP515 in vivo on hepatic leukocyte-endothelial interactions in a rat model of hemorrhagic hypotension and resuscitation, using intravital microscopy. Rats were pretreated with either GP515 (0.25 mg/kg) or saline in a randomized and blinded manner and subjected to pressure-controlled hemorrhagic hypotension at a mean arterial pressure of 40 mmHg for 60 min followed by 5 h of resuscitation. Five hours after resuscitation in saline-treated animals, firm leukocyte-sinusoidal adhesion was strongly enhanced in the periportal and midzonal sublobular regions, and sinusoidal diameters were also markedly reduced. Compared with saline treatment, GP515 significantly attenuated shock and resuscitation-induced leukocyte adhesion in both sublobular regions. Moreover, although GP515 did not signific...Continue Reading
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