Leukocytes play a key role in
ischemia-reperfusion-induced tissue
injuries. It has been suggested that blocking the Na+/H+ exchanger improves ischemic
injuries such as
stroke. In this study, we investigated the effect of the Na+/H+ exchanger inhibitor
SM-20220 (N-[aminoiminomethyl]- 1-methyl-1H-
indole-2-carboxamide
methanesulfonate) on leukocyte-endothelial cell interactions during
ischemia-reperfusion.
SM-20220 (0.3-1.0 mg/kg i.v.) given after
ischemia significantly attenuated the leukocyte adhesion in the mesenteric postcapillary venules that was induced by transient superior mesenteric artery occlusion. At 60 min after reperfusion, the numbers of adherent leukocytes in groups treated with vehicle or
SM-20220 (0.3 mg/kg) were 15.1+/-2.9 cells/100 microm/3 min and 3.0+/-0.7 cells/100 microm/3 min (p < 0.01), respectively. In a transient
middle cerebral artery occlusion model, i.v. infusion of
SM-20220 (0.4 mg/kg per hour) for 1 h, beginning 1 h after the start of occlusion, significantly reduced both the
infarct size and the increase in brain
myeloperoxidase activity, compared with the vehicle group (p < 0.01 and p < 0.05, respectively). In summary, this is the first evidence that the leukocyte adhesion to the endothelium that is induced by
ischemia-reperfusion is attenuated by the inhibition of Na+/H+ exchanger activity in vivo. Our results suggest that Na+/H+ exchanger inhibitors may prevent
ischemia-reperfusion injuries such as
stroke partly through the attenuation of leukocyte-endothelial cell interactions.