title: Targeted over-expression of endothelin-1 in astrocytes leads to more severe brain damage and vasospasm after subarachnoid hemorrhage.
abstract: BACKGROUND
  Endothelin-1 (ET-1) is a potent vasoconstrictor, and astrocytic ET-1 is reported to play a role in the pathogenesis of cerebral ischemic injury and cytotoxic edema. However, it is still unknown whether astrocytic ET-1 also contributes to vasogenic edema and vasospasm during subarachnoid hemorrhage (SAH). In the present study, transgenic mice with astrocytic endothelin-1 over-expression (GET-1 mice) were used to investigate the pathophysiological role of ET-1 in SAH pathogenesis.
  
  
  RESULTS
  The GET-1 mice experienced a higher mortality rate and significantly more severe neurological deficits, blood-brain barrier breakdown and vasogenic edema compared to the non-transgenic (Ntg) mice following SAH. Oral administration of vasopressin V1a receptor antagonist, SR 49059, significantly reduced the cerebral water content in the GET-1 mice. Furthermore, the GET-1 mice showed significantly more pronounced middle cerebral arterial (MCA) constriction after SAH. Immunocytochemical analysis showed that the calcium-activated potassium channels and the phospho-eNOS were significantly downregulated, whereas PKC-α expression was significantly upregulated in the MCA of the GET-1 mice when compared to Ntg mice after SAH. Administration of ABT-627 (ETA receptor antagonist) significantly down-regulated PKC-α expression in the MCA of the GET-1 mice following SAH.
  
  
  CONCLUSIONS
  The present study suggests that astrocytic ET-1 involves in SAH-induced cerebral injury, edema and vasospasm, through ETA receptor and PKC-mediated potassium channel dysfunction. Administration of ABT-627 (ETA receptor antagonist) and SR 49059 (vasopressin V1a receptor antagonist) resulted in amelioration of edema and vasospasm in mice following SAH. These data provide a strong rationale to investigate SR 49059 and ABT-627 as therapeutic drugs for the treatment of SAH patients.
authors.forename: Patrick K K
authors.initials: PK
authors.lastname: Yeung
authors.forename: Jiangang
authors.initials: J
authors.lastname: Shen
authors.forename: Stephen S M
authors.initials: SS
authors.lastname: Chung
authors.affiliation: Department of Anatomy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China. skchung@hkucc.hku.hk.
authors.forename: Sookja K
authors.initials: SK
authors.lastname: Chung
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000378:metabolism*; D004195:Disease Models, Animal; D019332:Endothelin-1 / Q000378:metabolism*; D007150:Immunohistochemistry; D051379:Mice; D008822:Mice, Transgenic; D044022:Receptor, Endothelin A / Q000378:metabolism; D013345:Subarachnoid Hemorrhage / Q000150:complications / Q000378:metabolism* / Q000473:pathology*; D015854:Up-Regulation; D020301:Vasospasm, Intracranial / Q000209:etiology / Q000378:metabolism
chemical_list: D019332:Endothelin-1; D044022:Receptor, Endothelin A