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(Stroke. 1998;29:1924-1929.)
© 1998 American Heart Association, Inc.

Original Contributions

Endothelin B Receptor Antagonists Attenuate Subarachnoid Hemorrhage–Induced Cerebral Vasospasm

Mario Zuccarello, MD; Riccardo Boccaletti, MD; Alberto Romano, MD; Robert M. Rapoport, PhD

From the Departments of Neurosurgery (M.Z., R.B., A.R.) and Pharmacology and Cell Biophysics (R.B., R.M.R.), University of Cincinnati College of Medicine, and Veterans Affairs Medical Center, Cincinnati, Ohio.

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.

Editorial Comment

J. Paul Muizelaar, MD, PhD, Guest Editor

Department of Neurosurgery, University of California, Davis Sacramento, California

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