title: Dissociation of vasospasm and secondary effects of experimental subarachnoid hemorrhage by clazosentan.
abstract: OBJECTIVE
  Endothelin receptor antagonists such as clazosentan decrease large-artery vasospasm after experimental and clinical subarachnoid hemorrhage. We used clazosentan to gain insight into the pathophysiology of subarachnoid hemorrhage by determining if decreasing vasospasm is associated with alleviation of other secondary complications of subarachnoid hemorrhage such as oxidative stress, endothelial nitric oxide synthase dysfunction, microthromboembolism, and neuronal injury.
  
  
  METHODS
  Mice were subjected to subarachnoid hemorrhage by injection of blood into the chiasmatic cistern. They were treated with clazosentan or vehicle by continuous intraperitoneal infusion for 48 hours. Middle cerebral artery vasospasm, superoxide anion radical, peroxynitrite, microthromboemboli, endothelial nitric oxide synthase uncoupling, cerebral blood flow, neuronal injury, and mortality were assessed.
  
  
  RESULTS
  Clazosentan preserved cerebral blood flow, alleviated vasospasm, and decreased mortality but did not affect superoxide anion radical, peroxynitrite, or microthromboemboli in the brain. Endothelial nitric oxide synthase uncoupling and neuronal injury also were not reduced by clazosentan.
  
  
  CONCLUSIONS
  This study shows large-artery vasospasm is pathophysiologically independent of some other effects of subarachnoid hemorrhage. The findings have implications for development of treatments for this disease.
authors: Division of Neurosurgery, St Michael's Hospital, University of Toronto, 30 Bond Street, Toronto, Ontario, Canada, M5B 1W8.
authors: Mohammed
authors: M
authors: Sabri
authors: Jinglu
authors: J
authors: Ai
authors: R Loch
authors: RL
authors: Macdonald
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D004146:Dioxanes / Q000494:pharmacology / Q000627:therapeutic use*; D004195:Disease Models, Animal; D065130:Endothelin A Receptor Antagonists; D051379:Mice; D008822:Mice, Transgenic; D052250:Nitric Oxide Synthase Type III / Q000187:drug effects / Q000502:physiology; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D011725:Pyridines / Q000494:pharmacology / Q000627:therapeutic use*; D011743:Pyrimidines / Q000494:pharmacology / Q000627:therapeutic use*; D012039:Regional Blood Flow / Q000187:drug effects / Q000502:physiology; D013345:Subarachnoid Hemorrhage / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology*; D013449:Sulfonamides / Q000494:pharmacology / Q000627:therapeutic use*; D013777:Tetrazoles / Q000494:pharmacology / Q000627:therapeutic use*; D013923:Thromboembolism / Q000209:etiology / Q000517:prevention & control; D020301:Vasospasm, Intracranial / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology*
chemical_list: D004146:Dioxanes; D065130:Endothelin A Receptor Antagonists; D011725:Pyridines; D011743:Pyrimidines; D013449:Sulfonamides; D013777:Tetrazoles; C109641:clazosentan; D052250:Nitric Oxide Synthase Type III