CHANGES IN THE CEREBROVASCULAR EFFECTS OF ENDOTHELIN-1 AND NICARDIPINE AFTER EXPERIMENTAL SUBARACHNOID HEMORRHAGE

THE ROLE OF endothelium-related factors in the pathogenesis of cerebra l vasospasm after subarachnoid hemorrhage (SAH) has gained interest si nce the discovery of endothelin-1 (ET-1). We have examined, before and after SAH, the responsiveness of the cerebrovascular bed of the goat to ET-1, the sources of Ca2+ in ET-1-induced responses, and the abilit y of the Ca2+ entry blocker nicardipine to counteract them. Before SAH , injection of ET-1 into the cerebral circulation increased cerebrovas cular resistance, thereby producing dose-dependent reductions in cereb ral blood flow (CBF), which were prevented by nicardipine. In isolated middle cerebral arteries, ET-1 induced concentration-dependent contra ctions, which were equally inhibited in Ca2+-free medium (without or w ith ethylene glycol tetraacetic acid) and by the Ca2+ entry blocker ni cardipine. On the third day after SAH, CBF was reduced by 28% and cere brovascular resistance increased by 39%. At the same time, both ET-1-i nduced reductions in CBF and the constricting effects of ET-1 in vitro were enhanced. The ability of nicardipine to increase CBF and to inhi bit the effects of ET-1 was impaired as a result of reduced dependence of cerebral arteries on extracellular Ca2+. On the seventh day after SAH, CBF and cerebrovascular resistance returned to control values, an d effects of ET-1 became normal. It is suggested that the hyperreactiv ity to ET-1 of the cerebrovascular bed induced by SAH could have a rol e in the development of vasospasm, which could reduce the vascular eff ects of Ca2+ entry blockers after SAH.