Different effects of clazosentan on consequences of subarachnoid hemorrhage in rats

• Published in: Brain research 2011-05, Vol.1392, p.132-139
• Main Authors: Chen, Gang, Tariq, Asma, Ai, Jinglu, Sabri, Mohammed, Jeon, Hyo-jin, Tang, Elaine J.Y, Lakovic, Katarina, Wan, Hoyee, Macdonald, R. Loch
• Format: Article
• Language: English
• Subjects: Analysis of Variance; animal models; Animals; arteries; Biological and medical sciences; blood; Blood and lymphatic vessels; brain; Cardiology. Vascular system; Caspase 3 - metabolism; cell death; Chi-Square Distribution; Clazosentan; clinical trials; Dioxanes - therapeutic use; Disease Models, Animal; Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous; drugs; Electric Stimulation; Endothelin; Fibrinogen - metabolism; Fluoresceins; hemorrhage; Hippocampus - physiopathology; In Situ Nick-End Labeling; In Vitro Techniques; intravenous injection; jugular vein; Long-term potentiation; Long-Term Potentiation - physiology; Male; Medical sciences; mortality; Neurology; neurons; Organic Chemicals; Phosphopyruvate Hydratase - metabolism; Pyridines - therapeutic use; Pyrimidines - therapeutic use; Rats; Rats, Sprague-Dawley; relative risk; risk reduction; Subarachnoid hemorrhage; Subarachnoid Hemorrhage - drug therapy; Subarachnoid Hemorrhage - pathology; Subarachnoid Hemorrhage - physiopathology; Sulfonamides - therapeutic use; Tetrazoles - therapeutic use; Vascular diseases and vascular malformations of the nervous system; Vasospasm; Vasospasm, Intracranial - drug therapy; Vasospasm, Intracranial - etiology
• ISSN: 0006-8993; 1872-6240
• DOI: 10.1016/j.brainres.2011.03.068

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, 10 mg/kg bolus, or vehicle control was administered 1 h after SAH intravenously, followed by a continuous infusion (1 mg/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.