title: Different effects of clazosentan on consequences of subarachnoid hemorrhage in rats.
abstract: One of the major complications after subarachnoid hemorrhage (SAH) is angiographic vasospasm in the large arteries at the base of the brain. However, a clinical trial of clazosentan demonstrated a 65% relative risk reduction in angiographic vasospasm but no effect on mortality or clinical outcome, raising questions about the role of angiographic vasospasm played in outcome after SAH. The purpose of this study was to determine if reducing or reversing angiographic vasospasm with clazosentan reduced other secondary complications such as microthromboembolism, loss of long-term potentiation (LTP) and neuronal cell death in a rat model of SAH. SAH in rats was created by injection of 300 μl non-heparinized autologous blood into the pre-chiasmatic cistern. Clazosentan, 10mg/kg bolus, or vehicle control was administered 1h after SAH intravenously, followed by a continuous infusion (1mg/kg/h) into the jugular vein using an osmotic pump. Rats treated with clazosentan had less large-artery vasospsam compared to vehicle-treated controls. However, clazosentan did not prevent the formation of microthromboemboli, neuronal cell death and degeneration and loss of LTP, suggesting there is a dissociation between large-artery angiographic vasospasm and other secondary complications of SAH. This result suggests that alleviation of angiographic vasospasm alone may not be sufficient to prevent other secondary complications or that off-target drug effects after systemic administration of clazosentan counteract the beneficial effects on angiographic vasospasm.
authors.affiliation: Division of Neurosurgery, Labatt Family Centre of Excellence in Brain Injury and Trauma Research, Keenan Research Centre in the Li Ka Shing Knowledge, St Michael's Hospital, Toronto M5B 1W8, Ontario, Canada.
authors.forename: Gang
authors.initials: G
authors.lastname: Chen
authors.forename: Asma
authors.initials: A
authors.lastname: Tariq
authors.forename: Jinglu
authors.initials: J
authors.lastname: Ai
authors.forename: Mohammed
authors.initials: M
authors.lastname: Sabri
authors.forename: Hyo-Jin
authors.initials: HJ
authors.lastname: Jeon
authors.forename: Elaine J Y
authors.initials: EJ
authors.lastname: Tang
authors.forename: Katarina
authors.initials: K
authors.lastname: Lakovic
authors.forename: Hoyee
authors.initials: H
authors.lastname: Wan
authors.forename: R Loch
authors.initials: RL
authors.lastname: Macdonald
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D053148:Caspase 3 / Q000378:metabolism; D016009:Chi-Square Distribution; D004146:Dioxanes / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004558:Electric Stimulation; D005340:Fibrinogen / Q000378:metabolism; D005452:Fluoresceins; D006624:Hippocampus / Q000503:physiopathology; D020287:In Situ Nick-End Labeling; D066298:In Vitro Techniques; D017774:Long-Term Potentiation / Q000502:physiology; D008297:Male; D009930:Organic Chemicals; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D011725:Pyridines / Q000627:therapeutic use*; D011743:Pyrimidines / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013345:Subarachnoid Hemorrhage / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology*; D013449:Sulfonamides / Q000627:therapeutic use*; D013777:Tetrazoles / Q000627:therapeutic use*; D020301:Vasospasm, Intracranial / Q000188:drug therapy / Q000209:etiology
chemical_list: D004146:Dioxanes; D005452:Fluoresceins; D009930:Organic Chemicals; D011725:Pyridines; D011743:Pyrimidines; D013449:Sulfonamides; D013777:Tetrazoles; C435731:fluoro jade; C109641:clazosentan; D005340:Fibrinogen; D053148:Caspase 3; D010751:Phosphopyruvate Hydratase