It has been shown that
hypercholesterolemia (HCh) exaggerates the microvascular dysfunction that is elicited by
ischemia and reperfusion (I/R). The objective of this study was to determine whether
oxidants contribute to the exaggerated inflammatory responses and enhanced
albumin leakage observed in HCh rat mesenteric venules exposed to I/R (10 minutes of
ischemia and 30 minutes of reperfusion). Intravital videomicroscopy was used to quantify the number of adherent and emigrated leukocytes,
albumin extravasation, platelet-leukocyte aggregation in postcapillary venules, and the degranulation of adjacent mast cells. Oxidation of the
fluorochrome dihydrorhodamine 123 (DHR) was used to monitor
oxidant production by venular endothelium. I/R was shown to elicit an increased DHR oxidation in venules of both control and HCh rats, with the latter group exhibiting a significantly larger response. Treatment with either
oxypurinol or
superoxide dismutase largely prevented the leukocyte recruitment, platelet-leukocyte aggregation, mast cell degranulation, and enhanced DHR oxidation elicited by I/R in HCh rats. The enhanced
albumin leakage was reduced by
superoxide dismutase but not by
oxypurinol. These results indicate that HCh amplifies the
oxidant stress elicited by I/R and that interventions that blunt the
oxidant stress effectively attenuate the leukocyte, platelet, and mast cell activation that result from I/R.