Naotsugu Horikawa, Yoshikazu Kuribayashi, Natsuko Itoh, Mizue Nishioka,
Kazuki Matsui*, Nobuko Kawamura and Naohito Ohashi
Sumitomo Pharmaceuticals Research Division, 1-98, Kasugadenaka 3-chome,
Konohana-ku, Osaka 554-0022, Japan
*Corresponding author. FAX: +81-6-6466-5287
E-mail: kmatsui@sumitomopharm.co.jp
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-(aminoiminomethyl)-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«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.
Keywords: Na+/H+ exchanger, Cerebral ischemia,
Endothelial cell, Cerebral blood flow, Blood-brain barrier
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