Na+/H+ Exchange Inhibitor SM-20220 Improves Endothelial Dysfunction Induced by Ischemia-Reperfusion

Abstract

Endothelial cells play an important role in the physiologic homeostasis of the cerebral circulation. Previously, we showed that the Na+/H+ exchanger (NHE) inhibitor SM-20220 (N-(aminoimino-methyl)-1-methyl-1H-indole-2-carboxamide methanesulfonate) improved ischemic brain injury. In this study, we investigated the effect of SM-20220 on cerebrovascular dysfunction after ischemia-reperfusion, focusing on the kinds of dysfunction that involved endothelial function. In cultured bovine brain microvascular endothelial cells (BBMCs), the IC50 value for the NHE activity of SM-20220 was 4 x 10(-8) M. SM-20220 also reduced the cell injury induced by hypoxia/aglycemia-reoxygenation in BBMCs, with statistical significance at 10(-7) M (P<0.05). Next, the effect of SM-20220 on disruption of the blood-brain barrier and cerebral blood flow were evaluated using transient middle cerebral artery (MCA) occlusion models. Intravenous infusion of SM-20220 (0.4 mg/kg per hour for 1 h) attenuated the extravasation of Evans blue, a blood-brain barrier disruption indicator, into cerebral tissue on the day after transient ischemia (P<0.05). The occlusion of the MCA decreased the cerebral blood flow in the MCA territory by about 20%, and only about 45% of the preischemic value was recovered at 1-h reperfusion. A bolus injection of SM-20220 (1 mg/kg, i.v.) improved the postischemic hypoperfusion by about 75%, without causing changes in the systemic blood pressure. These results indicate that the protective effect of NHE inhibitor on ischemic brain injury may be at least partially mediated by the prevention of endothelial dysfunction.