Endothelin B Receptor Antagonists Attenuate Subarachnoid Hemorrhage–Induced Cerebral Vasospasm

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Abstract
Background and Purpose —While it has been widely reported that the vasospasm following subarachnoid hemorrhage (SAH) is prevented/reversed by endothelin (ET) receptor antagonists selective for the ET A receptor and by nonselective ET receptor antagonists, ie, antagonists of both the ET A and ET B receptors, there are no reports on the possible attenuation of the spasm by selective ET B receptor antagonists. The purpose of this study was to investigate whether (1) ET B receptor antagonists prevent and reverse SAH-induced spasm and (2) attenuation of the spasm results from blockade of smooth muscle ET B (ET B2 ) receptor–mediated constriction and/or endothelial ET B (ET B1 ) 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 effects of agents on the spasm were determined by angiography after their intracisternal infusion (10 μL/h) by mini osmotic pump. In situ effects of agents on the spasm were determined by direct measurement of vessel diameter after their suffusion in a cranial window. Results —SAH constricted the basilar artery by 30%. Intracisternal infusion with 10 μmol/L BQ788, an ET B1/B2 receptor antagonist, reduced the spasm to 10%. To investigate whether BQ788 prevented the spasm by blockade of ET B1 receptor–mediated ET-1–induced ET-1 release, as opposed to ET B2 receptor–mediated constriction, we tested whether ET B1 receptor blockade also prevented the spasm. Indeed, intracisternal infusion with 10 μmol/L RES-701-1, a selective ET B1 receptor antagonist, reduced the spasm to 10%. Similarly, in situ superfusion with 1 μmol/L BQ788 reversed the spasm by 40%, and 1 μmol/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 relaxed with 0.1 mmol/L phosphoramidon, an ET-converting enzyme inhibitor. Conclusions —These results demonstrate that ET B receptor antagonists prevent and reverse SAH-induced cerebral vasospasm in an animal model. The likely mechanism underlying the attenuation of the spasm is blockade of ET B1 receptor–mediated ET-1–induced ET-1 release of newly synthesized ET-1. These studies provide rationale for the therapeutic use of ET B1 receptor antagonists to relieve the vasospasm following SAH, as well as other pathophysiological conditions involving possible ET-1–induced ET-1 release.