Endothelin B receptor antagonists attenuate subarachnoid hemorrhage-induced cerebral vasospasm

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.

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 microL/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.

SAH constricted the basilar artery by 30%. Intracisternal infusion with 10 micromol/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 micromol/L RES-701-1, a selective ET(B1) receptor antagonist, reduced the spasm to 10%. Similarly, in situ superfusion with 1 micromol/L BQ788 reversed the spasm by 40%, and 1 micromol/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.

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.