In contrast to acute preparations such as the exteriorized mesentery or the cremaster muscle, chronically instrumented chamber models allow one to study the microcirculation under "physiological" conditions, i.e., in the absence of trauma-induced leukocyte rolling along the venular endothelium. To underscore the importance of studying the naive microcirculation, we implanted titanium dorsal skinfold chambers in hamsters and used intravital fluorescence microscopy to study venular leukocyte rolling in response to ischemia-reperfusion injury or extracorporeal blood circulation. The experiments were performed in chambers that fulfilled all well-established criteria for a physiological microcirculation as well as in chambers that showed various extents of leukocyte rolling due to trauma, hemorrhage, or inflammation. In ideal chambers with a physiological microcirculation (Ͻ30 rolling leukocytes/mm vessel circumference in 30 s), ischemia-reperfusion injury and extracorporeal blood circulation significantly stimulated leukocyte rolling along the venular endothelium and, subsequently, firm leukocyte adhesion. In contrast, both stimuli failed to elicit leukocyte rolling in borderline chambers (30 -100 leukocytes/mm), and in blatantly inflamed chambers with yet higher numbers of rolling leukocytes at baseline (Ͼ100 leukocytes/mm), we observed a paradoxical reduction of leukocyte rolling after ischemia-reperfusion injury or extracorporeal blood circulation. A similar effect was observed when we superfused leukotriene B 4 (LTB4) onto the chamber tissue. The initial increase in leukocyte rolling in response to an LTB 4 challenge was reversed by a second superfusion 90 min later. These observations underscore 1) the benefit of studying leukocyte-endothelial cell interaction in chronically instrumented chamber models and 2) the necessity to strictly adhere to well-established criteria of a physiological microcirculation. leukotriene B 4; animal model; intravital microscopy THE MULTISTEP CONCEPT of leukocyte-endothelial cell interaction proposes early leukocyte tethering and rolling along the endothelial wall followed by firm leukocyte adhesion and transendothelial emigration; each consecutive step involves distinct adhesion molecules and distinct chemoattractant and/or adhesion-promoting mediators (5,21,23,29). It is widely established that leukocyte rolling along the endothelium constitutes a prerequisite for subsequent leukocyte adhesion and emigration (22). However, Kanwar and co-workers (21) identified an enormous redundancy in this system: even an inhibition of leukocyte rolling by Ͼ90% with fucoidin or selectin antagonists exerted no significant effect on subsequent firm leukocyte adhesion.In intact animal organisms, the study of leukocyte-endothelium interaction can be accomplished by intravital microscopy on acutely prepared tissues (e.g., hamster cheek pouch, cremaster muscle, and exteriorized mesentery) or on chronically instrumented tissues [e.g., the dorsal skinfold chamber model in hamsters (10, 28) and mice (27)...