The presence of ET-1 in the plasma and CSF of normal subjects and patients with SAH both with and without vasospasm has been studied. Masaoka, et al, found that when compared with normal subjects, the plasma concentrations of ET-1 in patients with SAH was significantly higher.

In addition, in those patients with SAH-induced vasospasm, the plasma concentrations of ET-1 were higher than in those patients with SAH but without vasospasm.[19] Fugimori, et al, also discovered that in all patients with SAH, those with vasospasm had significantly higher levels of ET-1 in the plasma during the period from 8-14 days after SAH when compared to those patients without vasospasm.

Fugimori, et al, however, failed to find a significant difference in the CSF levels of ET-1.[11] Ehrenreich, et al, demonstrated a peak in the CSF levels of ET-1 in patients with SAH-induced vasospasm, and that this peak coincided with the onset of vasospasm. This peak was absent in those patients with SAH who failed to develop vasospasm.[10] Susuki, et al, had similar findings of ET-1 levels in CSF of patients with SAH.[25]

These findings are clinical evidence that ET-1 has some role in SAH-induced vasospasm. The stimulus for production of ET-1 in SAH was investigated in experimental models. Oxyhemoglobin and methemoglobin were both found to be associated with the production of ET-1.[6,13]

Studies reveal a possible protein kinase C and a cyclic adenosine monophosphate-dependent pathway for oxyhemoglobin's effect of increased ET-1 production. This pathway most likely leads to an increase in ET-1 mRNA production and hence ET-1 production.[13] ET-1 intracisternal infusion leads to a significant vasoconstriction in experimental animals.[2] This is in contrast to studies which reveal that intravertebral artery injection of ET-1 fails to induce a vasoconstriction.[22] Elevated CSF ET-1 levels could also be reproduced via SAH models, as could vasospasm.[30] In SAH models, a hyperreactivity to ET-1 was also noted.[1] Calcium-free mediums and calcium entry blockers significantly reduced the amount of vasoconstriction induced by ET-1, indicating the importance of the role of calcium in ET-1 induced constriction.[1] A variety of compounds have been developed which aid in the study of ET-1 and its role in vasospasm. Inhibitors of ET-1 production are one major class of these compounds. Phosphoramidon and CGS 26303, compounds which inhibit the ET converting enzyme, are two compounds in this class.[3,24] The other class of compounds is the ET-1 receptor antagonists. A variety of these have been developed which have varying specificity for the three major ET-1 receptors involved in vasospasm. These receptors are the ETA receptor and the ETB1 and ETB2 receptor. Among the most used ET-1 receptor antagonists are: BQ123, BQ610, PD155080, and SB209670, ETA receptor antagonists; Bosentan (RO 47-0203) an ETA and ETB receptor antagonist; BQ788, an ETB receptor antagonist; and RES-701-1, an ETB1 receptor antagonist.[4,5,33-39] Use of these compounds has led to elucidation of the role of ET-1 and the ET-1 receptors in the role of SAH-induced vasospasm. In the past five years, our laboratory has investigated the role of ET-1 in SAH-induced cerebral vasospasm utilizing a rabbit model of SAH. First, we suggested that the ET-1-dependent vasospasm was mediated by ETA receptor activation as well as ETB receptor activation.

This suggestion was supported by the in situ demonstration that vasospasm of the rabbit basilar artery was only partially reversed by a selective ETA receptor antagonist, and subsequent addition of an ETA/B receptor antagonist was required to induce complete relaxation.[38] Similar findings were also found in an in vivo rabbit model of SAH where the use of Bosentan, an ETA/B receptor antagonist, effectively prevented the onset of vasospasm.[35] If there are evidences to support the involvement of smooth muscle ETB receptors in the mechanism of endothelin -induced constriction and in the development of vasospasm,[33] the role of endothelial ETB receptor is still unclear.

Using our rabbit basilar artery in situ model, we recently demonstrated the presence of endothelin ETB1 receptors.[34] We also recently suggested that endothelial ETB receptor activation maintains the spasm by the further release of ET-1.[39] This important finding was based on the demonstration that intracisternal infusion of ET-1, and the cessation of the infusion, still induced ET-1-dependent spasm of the rabbit basilar artery. Lending support to the possibility that endothelial ETB receptor activation causes further ET-1 release of newly synthesized ET-1 is our recent demonstration that ETB receptor antagonists (BQ788 and RES-701-1) prevent and reverse SAH-induced cerebral vasospasm in rabbits.

In summary, our proposed working model of the role of ET-1 in SAH-induced cerebral vasospasm is the following: In response to SAH, numerous factors (i.e. serotonin, hemoglobin, ATP, hypoxia, etc.) act on the endothelium o cause the initial release of endothelin. ET-1 then induces (1) spasm through the activation of smooth muscle ETA and ETB2 receptors; (2) further ET-1 release through the activation of endothelial ETB1 receptors; and (3) nitric oxide (NO) release through activation of endothelial ETB1 receptors. While NO release under normal physiological conditions inhibits both the magnitude of ET-1 constriction and ET-1-induced ET-1 release, initially after SAH these negative modulatory effects are inhibited by the presence of hemoglobin(Hb).

Thus, once ET-1-induced ET-1 release is established, the spasm no longer is dependent on the presence of Hb, which results in chronic ET-1-dependent vasospasm.

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