ENDOTHELIN-B RECEPTOR ANTAGONISTS ATTENUATE SUBARACHNOID HEMORRHAGE-INDUCED CEREBRAL VASOSPASM

Background and Purpose-While it has been widely reported that the vaso spasm following subarachnoid hemorrhage (SAH) is prevented/reversed by endothelin (ET) receptor antagonists selective for the ETA receptor a nd by nonselective ET receptor antagonists, ie, antagonists of both th e ETA and ETB receptors, there ore no reports on the possible attenuat ion of the spasm by selective ETB receptor antagonists. The purpose of this study was to investigate whether (1) ET, receptor antagonists pr event and reverse SAM-induced spasm and (2) attenuation of the spasm r esults from blockade of smooth muscle ETB (ETB2) receptor-mediated con striction and/or endothelial ETB (ETBI) receptor-mediated ET-1-induced ET-1 release. Methods-SAH-induced spasm of the rabbit basilar artery was induced with the use of a double: hemorrhage model. In vivo effect s of agents on the spasm were determined by angiography after their in tracisternal infusion (10 mu L/h) by mini osmotic pump. In situ effect s of agents on the spasm were determined by direct measurement of vess el diameter after their suffusion in a cranial window. Results-SAH con stricted the basilar artery by 30%. Intracisternal infusion with 10 mu mol/L BQ788, an ETB1/B2 receptor antagonist, reduced the spasm to 10% . To investigate whether BQ788 prevented the spasm by blockade of ETB1 receptor-mediated ET-1-induced ET-1 release, as opposed to ETB2 recep tor-mediated constriction, we tested whether ETB1 receptor blockade al so prevented the spasm. Indeed, intracisternal infusion with 10 mu mol /L RES-701-1, a selective ETB1 receptor antagonist, reduced the spasm to 10%. Similarly, in situ superfusion with 1,mu mol/L BQ788 reversed the spasm by 40%, and 1 mu mol/L RES-701-1 reversed the spasm by 50%. However, both BQ788 and RES-701-1 enhanced by 40% to 50% the 3 nmol/L ET-1-induced constriction elicited in spastic vessels previously relax ed with 0.1 mmol/L phosphoramidon, an ET-converting enzyme inhibitor. Conclusions-These results demonstrate that ETB receptor antagonists pr event and reverse SAH-induced cerebral vasospasm in an animal model. T he likely mechanism underlying the attenuation of the spasm is blockad e of ETB1 receptor-mediated ET-1-induced ET-1 release of newly synthes ized ET-1. These studies provide rationale for the therapeutic use of ETB1 receptor antagonists to relieve the vasospasm following SAH, as w ell as other pathophysiological conditions involving possible ET-1-ind uced ET-1 release.