Invited Symposium: Stroke/Cerebral Vasospasm


Section 1

Section 2

Section 3

Section 4

Section 5


INABIS '98 Home Page Your Session Symposia & Poster Sessions Plenary Sessions Exhibitors' Foyer Personal Itinerary New Search

The Role of Endothelin-1 in Subarachnoid Hemorrhage-Induced Vasospasm

Contact Person: Marolo Zuccarello, MD (zuccarm@uc.edu)


Endothelin (ET)-1 has demonstrated a wide variety of effects throughout the body. Studies have shown effects on bronchial constriction, on the kidneys, even as a potential neurotransmitter.[15,21,27,28] Its effects on the vasculature have been widely studied.[7,23,29] Specifically, ET-1 has been studied with respect to its role in the development of subarachnoid hemorrhage (SAH)-induced vasospasm.

The following is a summary of ET-1 and its role in SAH-induced vasospasm. ET-1 is 21 amino acid peptide.[31] It is synthesized from mRNA, which produces a precursor called prepro-ET-1. This is cleaved into a molecule called big ET-1 by a specific endopeptidase. Big ET-1 is further cleaved into ET-1 by an endopeptidase called ET-converting enzyme.[18,20,26] ET-1 is expressed in a variety of tissues in the brain, including the endothelium, neurons, glial cells, choroid plexus and hypothalamic cells.[8,9,12,16,17,32] ET-1, when injected systemically in rats, causes an initial drop in blood pressure, which is felt to be mediated via stimulation of prostaglandin I2 and endothelin derived relaxing factor release. This drop in blood pressure is quickly followed by a prolonged increase in the blood pressure.[7] This constrictive effect was also demonstrated in the cerebral vasculature.[2,14]

Back to the top.

Role of ET-1 in SAH-Induced Vasospasm

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.

Back to the top.


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.

Back to the top.


  1. Alabadi JA, Salom JB, Torregrosa G, Miranda FJ, Jover T, Alborch E: Changes in the cerebrovascular effects of endothelin-1 and nicardipine after experimental subarachnoid hemorrhage. Neurosurgery 33: 707-715, 1993.2.
  2. Asano T, Ikegaki I, Susuki Y, Satoh S, Shibuya M: endothelin and the production of vasospasm in dogs. Biochem Biophys Res Commun 159: 1345-1351, 1989.3.
  3. Caner HH, Kwan AL, Arthur A, Jeng AY, Lappe RW, Kassell NF, Lee KS: Systemic administration of an inhibitor of endothelin-converting enzyme for attenuation of cerebral vasospasm following experimental subarachnoid hemorrhage. J Neurosurg 85: 917-922, 1996.4.
  4. Clozel M, Watanabe H: BQ-123, a peptidic endothelin receptor antagonist, prevents the early cerebral vasospasm following subarachnoid hemorrhage after intracisternal but not intravenous injection. Life Sci 52: 825-834, 1993.5.
  5. Clozel M, Breu V, Gray GA, Kalina B, Loffler BM, Burri K, Cassal JM, Hirth G, Muller M, Neidhart W, Ramuz H: Pharmacological characterization of bosetan, a new potent orally active nonpeptidic endothelin receptor antagonist. J Pharmacol Exp Ther 270: 228-235, 1994.6.
  6. Cocks T, Malta E, King S, Woods R, Angus J: Oxyhemoglobin increases the production of endothelin-1 by endothelial cells in culture. Eur J Pharmacol 196: 177-182, 1991.7.
  7. De Nucci G, Thomas R, D'Orleans-Juste P, Antunes E, Walder C, Warner TD, Vane JR: Pressor effects of circulating endothelin are limited by its removal in the pulmonary circulation and by the release of prostacyclin and endothelium-derived relaxing factor. Proc Natl Acad Sci USA 85: 9797-9800, 1988.8.
  8. Ehrenreich H, Anderson RW, Fox CH, Rieckmann P, Hoffman GS, Travis WD, Coligan JE, Kehrl JH, Fauci AS: Endothelins, peptides with potent vasoactive properties, are produced by human macrophages. J Exp Med 172: 1741-1748, 1990.9.
  9. Ehrenreich H, Kehrl JH, Anderson W, Rieckmann P, Vitkovic L, Colian JE, Fauci AS: A vasoactive peptide, endothelin-3, is produced by and specifically binds to primary astrocytes. Brain Res 538: 54-58, 1991.10.
  10. Ehrenreich H, Lange M, Near KA, Anneser F, Schoeller LAC, Schmid R, Winkler PA, Kehrl JH, Schmiedek P, Goebel FD: Long-term monitoring of immunoreactive endothelin-1 and endothelin-3 in ventricular cerebrospinal fluid, plasma and 24-h urine of patients with subarachnoid hemorrhage. Res Exp Med (Berl) 192: 257-268, 1992.11.
  11. Fujimori A, Yanagisawa M, Saito A, Goto K, Masaki T, Mima T, Takakura K, Shigeno T: Endothelin in plasma and cerebrospinal fluid of patients with subarachnoid hemorrhage. Lancet 336: 633, 1989 (letter).12.
  12. Giaid A, Gibson SJ, Ibrahim NBN, Legon S, Bloom SR, Yanagisawa M, Masaki T, Varndell IM, Polak JM: Endothelin-1, an endothelium-derived peptide, is expressed in neurons of the human spinal cord and the dorsal root ganglia. Proc Natl Acad Sci USA 86: 7634-7638, 1989.13.
  13. Kasuya H, Weir BKA, White DM, Stefanson K: Mechanism of oxyhemoglobin-induced release of endothelin-1 from cultured vascular endothelial cells and smooth muscle cells. J Neurosurg 79: 892-898, 1993.14.
  14. Kobayashi H, Hayashi M, Kobayashi S, Kabuto M, Handa Y, Kawano H: Effect of endothelin on the canine basilar artery. Neurosurgery 27: 57-361, 1990.15.
  15. Lagente V, Chabrier PE, Mencia-Huerta JA, Braquet P: Aerosol administration of endothelin induces bronchoconstriction in the guinea pig. Biochem Biophys Res Cummun 158: 625-632, 1989.16.
  16. Lee ME, de la Monte SM, Ng SC, Bloch DB, Quertermous T: Expression of the potent vasoconstrictor endothelin in the human central nervous system. J Clin Invest 86: 141-147, 1990.17.
  17. MacCumber MW, Ross CA, Snyder SH: Endothelin in brain: Receptors, mitogenesis, and biosynthesis in glial cells. Proc Natl Acad Sci USA 87: 2359-2363, 1990.18.
  18. McMahon EG, Fok KF, Moore WM, Smith CE, Siegel NR, Trapani AJ: In vitro and in vivo activity of chymotrypsin activited big-endothelin (porcine 1-40). Biochem Biophys Res Commun 161: 406-413, 1989.19.
  19. Masaoka H, Susuki R, Hirata Y, Emori T, Marumo F, Hirakawa K: Raised plasma endothelin in aneurysmal subarachnoid hemorrhage. Lancet 336: 1402, 1989 (letter).20.
  20. Matsumura Y, Ikegawa R, Tsukahara Y, Takaoka M, Morimoto S: Conversion of big endothelin-1 to endothelin-1 by two types of metalloproteinases derived from porcine aortic endothelial cells. FEBS Lett 272: 166-172, 1990.21.
  21. Miller WL, Redfield MM, Burnett JC: Integrated cardiac, renal, and endocrine actions of endothelin. J Clin Invest 83: 317-320, 1989.22.
  22. Mima T, Yanagisawa M, Shigeno T, Saito A, Goto K, Takakura K,Masaki T: Endothelin acts in feline and canine cerebral arteries from the adventitial side. Stroke 20: 1553-1556, 1989.23.
  23. Papadopoulos S, Gilbert L, Webb C, Amato C: Characterization of contractile responses to endothelin in human cerebral arteries: Implications for cerebral vasospasm. Neurosurgery 26: 810-815,1990.24.
  24. Shinyama H, Uchida T, Kido H, Hayashi K, Watanabe M, Matsumura Y, Ikegawa R, Takaoka M, Morimoto S: Phosphoramidon inhibits the conversion of intracisternally administrated big endothelin to endothelin-1. Biochem Biophys Res Commun 178: 24-30, 1991.25.
  25. Susuki R, Masaoka E, Hirata H, Marumo F, Isotani E, Hirakawa K: The role of endothelin-1 in the origin of cerebral vasospasm in patients with aneurysmal subarachnoid hemorrhage. J Neurosurg 77: 96-100, 1992.26
  26. Takaoka M, Takenobu Y, Miyata Y, Ikegawa R, Matsumura Y, Morimoto S: Pepsin, an aspartic protease, converts porcine big endothelin to 21-residue endothelin. Biochem Biophys Res Commun 166: 436-442, 1990.27.
  27. Touvay C, Vilain B, Pons F, Chabrier PE, Mencia-Huerta JM,Braquet P: Bronchopulmonary and vascular effect of endothelin in the guinea pig. Eur J Pharmacol 176: 23-33, 1990.28.
  28. Wiklund NP, Ohln A, Cederqvist B: Adrenergic neuromodulation by endothelin in guinea pig artery. Neurosci Lett 101: 269-273, 1989.29.
  29. Yamamati T, Johshita H, Takaku F, Ohno H, Susuki N, Matsumoto H, Fugino M: Endothelin family in human plasma and cerebrospinal fluid. J Clin Endocrinol Metab 71: 1611-1615, 1990.30.
  30. Yamaura I, Tani E, Maeda Y, Minami N, Shindo H: Endothelin-1 of canine basilar artery. J Neurosurg 76: 99-105, 1992.31.
  31. Yanagisawa M, Kurihara H, Kimura S, Tomobe Y, Kabayashi M, Mitsui Y, Yazaki Y, Goto K, Masaki T: A novel potent vasoconstrictor peptide produced by the vascular endothelial cells. Nature 332: 411-415, 1988.32.
  32. Yoshizawa T, Shimni O, Giaid A, Yanagisawa M, Gibson SJ, Kimura S, Uchiyama Y, Polak JM, Masaki T, Kanazawa I: Endothelin: A novel peptide in the posterior pituitary system. Science 247: 462-464, 1990.33.
  33. Zuccarello M, Boccaletti R, Rapoport RM: Endothelin ETB receptor-mediated constriction in the rabbit basilar artery. Eur J Pharmacol 350: R7-R9, 1998.34.
  34. Zuccarello M, Boccaletti R, Rapoport RM: Endothelin ETB1 receptor-mediated relaxation of rabbit basilar artery. Eur J Pharmacol 357: 67-71, 1998.35.
  35. Zuccarello M, Soattin GB, Lewis AI, Breu V, Hallak H, Rapoport RM: Prevention of subarachnoid hemorrhage-induced cerebral vasospasm by oral administration of endothelin receptor antagonists. J Neurosurg 84: 503-507, 1996.36.
  36. Zuccarello M, Boccaletti R, Rapoport RM: Endothelium-derived nitric oxide regulates endothelin A versus endothelin B receptor-mediated constriction in rabbit basilar artery in situ. Stroke 29: 323A, 1998.37.
  37. Zuccarello M, Boccaletti R, Romano A, Rapoport RM: Endothelin B receptor antagonists attenuate subarachnoid hemorrhage-induced cerebral vasospasm. Stroke 29: 1924-1929,1998.38.
  38. Zuccarello M, Lewis AI, Rapoport RM: Endothelin ETA and ETB receptors in subarachnoid hemorrhage-induced cerebral vasospasm. Eur J Pharmacol 259: R1-R2, 199439.
  39. Zuccarello M, Romano A, Passalacqua M, Rapoport RM: Endothelin-1-induced endothelin-1 release causes cerebral vasospasm in vivo. J Pharm Pharmacol 47:702, 1995

Back to the top.

Back to the top.

| Discussion Board | Previous Page | Your Symposium |
Jonathan D. Sherman, MD; Robert M. Rapoport, PhD; Marlo Zuccarello, MD; (1998). The Role of Endothelin-1 in Subarachnoid Hemorrhage-Induced Vasospasm. Presented at INABIS '98 - 5th Internet World Congress on Biomedical Sciences at McMaster University, Canada, Dec 7-16th. Invited Symposium. Available at URL http://www.mcmaster.ca/inabis98/zhang/sherman0594/index.html
© 1998 Author(s) Hold Copyright