Microvasospasms After Experimental Subarachnoid Hemorrhage Do Not Depend on Endothelin A Receptors.

Abstract

Perturbations in cerebral microcirculation (eg, microvasospasms) and reduced neurovascular communication determine outcome after subarachnoid hemorrhage (SAH). ET-1 (endothelin-1) and its receptors have been implicated in the pathophysiology of large artery spasms after SAH; however, their role in the development of microvascular dysfunction is currently unknown. Here, we investigated whether inhibiting ET_A (endothelin A) receptors can reduce microvasospasms after experimentally induced SAH. SAH was induced in male C57BL/6 mice by filament perforation of the middle cerebral artery. Three hours after SAH, a cranial window was prepared and the pial and parenchymal cerebral microcirculation was measured in vivo using two-photon microscopy before, during, and after administration of the ET_A receptor inhibitor clazosentan. In separate experiments, the effect of clazosentan treatment on neurological outcome was measured 3 days after SAH. Clazosentan treatment had no effect on the number or severity of SAH-induced cerebral microvasospasms nor did it affect neurological outcome. Our results indicate that ET_A receptors, which mediate large artery spasms after SAH, do not seem to play a role in the development of microarterial spasms, suggesting that posthemorrhagic spasms are mediated by distinct mechanisms in large and small cerebral vessels. Given that cerebral microvessel dysfunction is a key factor for outcome after SAH, further research into the mechanisms that underlie posthemorrhagic microvasospasms is urgently needed.