G-00578-2005.r1 Angiotensin Ii Type 1 Receptors and the Intestinal Microvascular Dysfunction Induced by Ischemia and Reperfusion

The acute phase of intestinal ischemia-reperfusion (I/R) injury is mediated by leukocytes and is characterized by oxidative stress and blood cell recruitment. Upregulation of angiotensin II type 1 receptors (AT1-R) has been implicated in the pathogenesis of conditions associated with oxidative stress. The AT1-R-antagonist Losartan (Los) attenuates leukocyte recruitment following I/R. However, the role of AT1-R in intestinal I/R injury and the associated platelet-leukocyte interactions remains unclear. The objective of this study was to define the contribution of AT1-receptors to I/R-induced blood cell recruitment in intestinal venules. Leukocyte and platelet adhesion were quantified by intravital microscopy in the small bowel of C57Bl/6 (WT) mice exposed to sham operation or 45 min ischemia and 4 h reperfusion. A separate WT group received Los for 7 days before gut I/R (WT-I/R+Los). AT1-R bone marrow chimeras that express AT1-R on the vessel wall but not blood cells also underwent I/R. Platelet and leukocyte adhesion, as well as AT1-R expression in the gut microvasculature were significantly elevated after I/R. All of these responses were attenuated in the WT-I/R+Los group, compared to untreated I/R mice. A comparable abrogation of I/R-induced blood cell adhesion was noted in AT1-R bone marrow chimeras. I/R-induced platelet adhesion was unaltered in mice overexpressing Cu,Zn-SOD, or mice deficient in NAD(P)H oxidase. These data suggest that while gut I/R upregulates endothelial expression of AT1-R, engagement of these angiotensin II receptors on blood cells is more important in eliciting the prothrombogenic and pro-inflammatory state observed in postischemic gut venules, through a superoxide-independent pathway.