Increased expression of endothelin B receptor mRNA following subarachnoid hemorrhage in monkeys

Abstract

These studies tested the hypothesis that the cerebral vasospasm that follows subarachnoid hemorrhage (SAH) is due to alterations in endothelin (ET) and ET receptor expression. Eight monkeys underwent cerebral angiography and induction of SAH. Angiography was repeated 7 days later to confirm the presence of cerebral vasospasm, and animals were killed. RNA was isolated from right (vasospastic) and left (control) side middle cerebral arteries and surrounding cerebral cortex. The levels of prepro (PP) ET-1 (ppET-1) and ppET-3 and ET(A) and ET(B) receptor mRNAs were determined using a quantitative reverse transcriptase polymerase chain reaction-based assay. ET- 1 peptide was also measured in CSF at baseline and after 7 days. Specific agonist binding to ET(A) and ET(B) receptors in both middle cerebral arteries and in surrounding brain cortex was measured in three animals by autoradiographic binding assays. Levels of ET(B) receptor mRNA were 3.4 ± 2.2-fold higher in the right than in the left cerebral arteries (p < 0.01). There were no significant differences in the levels of ppET-1, ppET-3, or ETA receptor mRNA in cerebral arteries. ET-1 peptide was not elevated in CSF. Levels of ET(A) and ET(B) receptor mRNAs were 2.6 ± 1.1- and 2.1 ± 1.3- fold higher, respectively, in the right than in the left cerebral cortex, while the level of ppET-3 mRNA was 2.1 ± 1.0-fold lower. There were no differences in ppET-1 mRNA levels between right and left cerebral cortex. Binding to ET(A) and ET(B) receptors in cerebral arteries and cortex did not differ significantly between right and left sides. These results do not support the hypothesis that overexpression of ET-1 is the principal cause of vasospasm, but rather they suggest that SAH causes complex changes in the ET system that together are responsible for the cellular response to SAH.