Background-Simvastatin, a 3-hydroxy-methylglutaryl coenzyme A reductase inhibitor, has been shown to lower serum cholesterol levels in clinical use. Moreover, statins exert beneficial effects in vascular diseases by inhibition of leukocyte rolling, adherence, and transmigration. The aim of this study was to determine if pretreatment with simvastatin attenuates Staphylococcus aureus ␣-toxin-induced increase in leukocyte-endothelial interactions during exotoxemia. Methods and Results-The effects of simvastatin on leukocyte-endothelial cell interactions were observed by intravital microscopy in the rat mesenteric microcirculation. Simvastatin (50 or 100 g/kg) was administered 18 hours before the study. Activation of microcirculation was induced by bolus administration of 40 g/kg S aureus ␣-toxin. Exotoxemia resulted in a significant and time-dependent increase in leukocyte rolling, adherence, and transmigration of leukocytes as well as P-selectin expression on the intestinal vascular endothelium. Pretreatment with simvastatin significantly inhibited exotoxin-induced leukocyte rolling from 71Ϯ10 to 14Ϯ4.7 cells/min (PϽ0.01) and adherence from 14Ϯ3.5 to 0.4Ϯ0.2 cells (PϽ0.01). In addition, simvastatin pretreatment significantly inhibited transmigration of leukocytes from 10.5Ϯ1.2 to 4.2Ϯ0.9 (PϽ0.05) cells. Immunohistochemical detection of endothelial cell adhesion molecule P-selectin showed a 50% decrease in endothelial cell surface expression after simvastatin treatment. Furthermore, simvastatin treatment resulted in enhanced expression of endothelial cell NO synthase III in the intestinal microcirculation. Conclusions-These results demonstrate that simvastatin interferes with exotoxin-induced leukocyte-endothelial cell interactions, which may be relevant in various infectious diseases. Statin treatment may offer a new therapeutic strategy for these clinical conditions.

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Background and purpose: The Na þ /H þ exchange (NHE) inhibitor cariporide is known to ameliorate ischaemia/reperfusion (I/R) injury by reduction of cytosolic Ca 2 þ overload. Leukocyte activation and infiltration also mediates I/R injury but whether cariporide reduces I/R injury by affecting leukocyte activation is unknown. We studied the effect of cariporide on thrombin and I/R induced leukocyte activation and infiltration models and examined P-selectin expression as a potential mechanism for any identified effects. Experimental approach: An in vivo rat mesenteric microcirculation microscopy model was used with stimulation by thrombin (0.5 m ml À1 ) superfusion or ischaemia (by haemorrhagic shock for 60 min) and reperfusion (90 min). Key results: Treatment with cariporide (10 mg kg À1 i.v.) significantly reduced leukocyte rolling, adhesion and extravasation after thrombin exposure. Similarly, cariporide reduced leukocyte rolling (54 ± 6.2 to 2.4 ± 1.0 cells min À1 , Po0.01), adherence (6.3±1.9 to 1.2±0.4 cells 100 mm À1 , Po0.01) and extravasation (9.1±2.1 to 2.4±1.1 cells per 20 Â 100 mm perivascular space, Po0.05), following haemorrhagic shock induced systemic ischaemia and reperfusion. The cell adhesion molecule Pselectin showed a profound decrease in endothelial expression following cariporide administration in both thrombin and I/R stimulated groups (35.4 ± 3.2 vs 14.2 ± 4.1% P-selectin positive cells per tissue section, Po0.01). Conclusions and implications:The NHE inhibitor cariporide is known to limit reperfusion injury by controlling Ca 2 þ overload but these data are novel evidence for a vasculoprotective effect of NHE inhibition at all levels of leukocyte activation, an effect which is likely to be mediated at least in part by a reduction of P-selectin expression.

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