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 ETA and ETB 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 ETA and ETB receptors in both middle cerebral arteries and in surrounding brain cortex was measured in three animals by autoradiographic binding assays. Levels of ETB 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 ETA and ETB 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 ETA and ETB 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 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.

Endothelin-1 Regulates Astrocyte Proliferation and Reactive Gliosis via a JNK/c-Jun Signaling Pathway

“…Expression of ET-1 and its receptors (ET-Rs) is strongly upregulated in astrocytes after brain injury (Jiang et al, 1993;Zhang et al, 1994;Hino et al, 1996;Nie and Olsson, 1996;Rogers et al, 1997;Sakurai-Yamashita et al, 1997;Baba, 1998). Astrocytes are autocrine targets of ET-1 action, which results in increased cell proliferation (Lazarini et al, 1996;Hasselblatt et al, 2001Hasselblatt et al, , 2003Rogers et al, 2003;Desai et al, 2004).…”

Source and cause of endothelin-1 release to cerebrospinal fluid after subarachnoid hemorrhage

“…In a primate model of vasospasm, the initial transient ischemia related to SAH from the ruptured intracranial aneurysm does not occur, and no more than 5% of animals with vasospasm develop delayed ischemic neurological deficits, [13] potentially explaining why we and others [19] did not observe an increase in CSF ET-1 levels with this model, in contrast to the findings in patients. [11,48] Our results suggest that the increased CSF ET-1 levels observed in patients after rupture of an intracranial aneurysm and in patients with clinical symptoms of vasospasm [11,14,48,49] are not solely responsible for the development of vasospasm; rather, they result from ischemia occurring after SAH.…”

“…[9,11,14,19,24,33,37,40,[47][48][49] This controversial [5,19] hypothesis is supported by a delayed onset of long-lasting spasm of the intracranial vessels produced by intracisternal administration of ET-1, [3,47] by an increase in ET-1 levels in CSF after SAH in humans, [11,14,48,49] and by a decrease in the incidence of vasospasm after use of ET-1 receptor antagonists. [8,23,34,38,57] Astrocytes, neurons, and pituitary cells produce ET-1.…”

“…[31,46] One of the potential oxyhemoglobin-related mechanisms of vasospasm is the release of endothelin-1 (ET-1), [3,33,37] a potent endothelium-derived vasoconstricting agent, [21,55] into the cerebrospinal fluid (CSF) after SAH. [3,11,14,15,19,21,25,33,[47][48][49] Not only are astrocytes, neurons, and pituitary cells a normal source of extraluminal ET-1, [10,17,26,29,56] but endothelial [9,24,40] and smooth-muscle [24] cells also release ET-1 when stimulated by oxyhemoglobin [9,24,40] or thrombin. [10 ] Because an increase in the levels of ET-1 in CSF has been described in patients with cerebral vasospasm and delayed ischemic neurological deficits after SAH, [11,14,48,49] the production of ET-1 may also be induced by ischemia.…”

Induction of housekeeping gene expression after subarachnoid hemorrhage in dogs

“…The levels of mRNA for these genes has been assumed to be stable in some prior studies (Hino et al, 1996a;Sayama et al, 1998;Ohkuma et al, 1999;Onda et al, 1999;Suzuki et al, 1999;Ono et al, 2000;Miyagi et al, 2000;Aihara et al, 2001). If housekeeping gene mRNA increases, then genes reported to have increased expression might actually have been increased even more.…”