Protective effect of endothelin type A receptor antagonist on brain edema and injury after transient middle cerebral artery occlusion in rats.
OBJECTIVE
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(A)s.
Matsuo
Y
Y
Discovery Research Laboratories, Shionogi and Co, Ltd, Toyonaka, Osaka, Japan. yoshiyuki.matsuo@shionogi.co.jp
Mihara Si
Ninomiya
M
M
Fujimoto
M
M
D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000502:physiology; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001923:Brain Chemistry; D001929:Brain Edema / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D002109:Caffeic Acids / Q000008:administration & dosage*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000378:metabolism; D016232:Endothelins / Q000378:metabolism / Q000494:pharmacology; D020244:Infarction, Middle Cerebral Artery / Q000150:complications / Q000188:drug therapy* / Q000473:pathology; D002546:Ischemic Attack, Transient / Q000150:complications / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D018696:Neuroprotective Agents / Q000008:administration & dosage*; D009828:Oleanolic Acid / Q000008:administration & dosage* / Q000031:analogs & derivatives; D009195:Peroxidase / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D044022:Receptor, Endothelin A; D015427:Reperfusion Injury / Q000209:etiology / Q000517:prevention & control; D015996:Survival Rate; D013997:Time Factors; D014867:Water / Q000032:analysis / Q000378:metabolism
D002109:Caffeic Acids; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D016232:Endothelins; D018696:Neuroprotective Agents; D044022:Receptor, Endothelin A; C086421:S 0139; D014867:Water; D009828:Oleanolic Acid; D009195:Peroxidase