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.