From bench-to-bedside in catastrophic cerebrovascular disease: development of drugs targeting the endothelin axis in subarachnoid hemorrhage-related vasospasm

Survivors of aneurysmal subarachnoid hemorrhage (SAH) may suffer functional dependence, cognitive impairment, and mood disorders. Cerebral vasospasm and delayed cerebral ischemia are associated with poor outcome in SAH and have been the subjects of intense investigation for decades. Recently a series of clinical trials was performed in SAH patients using an endothelin receptor antagonist. The results of these trials emphasize the disconnect between attenuation of cerebral vasospasm and improvement in functional outcome. The purpose of this review article is to evaluate the utilization of animal models for the development of drugs targeting the endothelin pathway in SAH and, given the recent endothelin receptor antagonist clinical trial results and lessons from the ischemic neuroprotection field, reflect on an alternative approach to in vivo preclinical drug testing in SAH.