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(Stroke. 2001;32:2143.)
© 2001 American Heart Association, Inc.

Original Contributions

Protective Effect of Endothelin Type A Receptor Antagonist on Brain Edema and Injury After Transient Middle Cerebral Artery Occlusion in Rats

Yoshiyuki Matsuo, PhD; Shin-ichi Mihara, PhD; Mitsuyoshi Ninomiya, PhD Masafumi Fujimoto, PhD

From the Discovery Research Laboratories, Shionogi and Co, Ltd, Toyonaka, Osaka, Japan.

Correspondence to Yoshiyuki Matsuo, PhD, Discovery Research Laboratories, Shionogi and Co, Ltd, 3-1-1 Futaba-cho, Toyonaka, Osaka 561-0825, Japan. E-mail yoshiyuki.matsuo{at}shionogi.co.jp

Background and Purpose—— Recent evidence strongly suggests that endothelins (ETs) play an important role in the regulation of blood-brain barrier (BBB) functions. The aim of the present study was to evaluate the role of ETs on edema formation and BBB permeability change after cerebral ischemia/reperfusion.

Methods—— We examined the brain tissue ET-1 content and evaluated the time and dose response of the therapeutic effects of the specific ET type A receptor (ET_A) antagonist, S-0139, on brain edema formation, development of infarction, and disruption of BBB after 1 hour of middle cerebral artery occlusion (MCAO) in rats.

Results—— After 1-hour MCAO and reperfusion, the brain ET-1 content did not change during the first 3 hours, increased at 6 hours, and rose almost continuously over 48 hours in the ischemic region as well as in the ischemic rim. Rats infused with S-0139 (0.03 to 1.0 mg/kg per hour) during reperfusion showed dose-dependent and significant attenuation of the increase in brain water content 24 hours after reperfusion. When the infusion of S-0139 was begun after 10 minutes and 1 hour of reperfusion, the brain edema formation and infarct size were significantly attenuated. Furthermore, posttreatment with S-0139 significantly attenuated the increased Evans blue dye-quantified albumin extravasation and improved the mortality of animals after cerebral ischemia/reperfusion.

Conclusions>—— Our data demonstrate that infusion with S-0139, an ET_A antagonist, results in significant reduction of brain injury and plasma extravasation after transient MCAO. Thus, ETs may contribute to cerebral ischemia/reperfusion injury at least partly by increasing the BBB permeability via ET_As.

Key Words: blood-brain barrier • brain edema • brain injuries • cerebral ischemia, focal • endothelins • rats

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