Systemic administration of the endothelin-A receptor antagonist TBC 11251 attenuates cerebral vasospasm after experimental subarachnoid hemorrhage

Dose study and review of endothelin-based therapies in the literature on cerebral vasospasm

John E. Wanebo, Adam Arthur, Hunter G. Louis, Kim West, Neal F. Kassell, Kevin S. Lee, Gregory A. Helm

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Abstract

OBJECTIVE: Increasing evidence implicates endothelin (ET)-1 in the pathophysiological development of cerebral vasospasm. This study examined the ability of TBC 11251 (TBC), a new ET(A) receptor antagonist, to prevent vasospasm in a rabbit model of subarachnoid hemorrhage (SAH). METHODS: Eighty-five New Zealand White rabbits were assigned to 1 of 10 groups. SAH was induced by injecting autologous blood into the cisterna magna. The treatment groups were as follows: 1)control (no SAH), 2) SAH alone, 3) SAH plus vehicle every 12 hours (BID), 4) SAH plus 5 mg/kg TBC BID, 5) SAH plus 10 mg/kg TBC BID, 6) SAH plus 20 mg/kg TBC BID, 7) SAH plus vehicle at 24 and 36 hours after SAH (24/36), 8) SAH plus 5 mg/kg TBC 24/36, 9) SAH plus 10 mg/kg TBC 24/36, and 10) SAH plus 20 mg/kg TBC 24/36. Animals were killed 48 hours after SAH, by perfusion-fixation, and then basilar arteries were histologically prepared and their cross-sectional areas were measured. RESULTS: The mean basilar artery cross-sectional area was constricted from 0.332 mm2 in the control group to 0.131 mm2 in the SAH alone group, 0.132 in the vehicle 24/36 group, and 0.125 in the vehicle BID group. All groups treated with TBC showed an increase in cross-sectional luminal basilar artery area, relative to the vehicle-treated groups. The 5 mg/kg TBC BID group exhibited a mean basilar artery area of 0.217 mm2, and the 10 mg/kg TBC BID group showed a mean basilar artery area of 0.240 mm2; both groups were statistically improved, compared with the vehicle-treated groups (P < 0.05). No side effects were seen, and there were no differences in the mean arterial pressures between drug- and vehicle-treated groups. CONCLUSION: These findings demonstrate that systemic administration of the ET(A) receptor antagonist TBC significantly attenuates cerebral vasospasm after SAH, thus providing additional support for the role of ET-1 in vasospasm.

Original languageEnglish (US)
Pages (from-to)1409-1418
Number of pages10
JournalNeurosurgery
Volume43
Issue number6
StatePublished - Dec 1 1998
Externally publishedYes

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Intracranial Vasospasm
Endothelins
Subarachnoid Hemorrhage
Basilar Artery
Therapeutics
Endothelin A Receptor Antagonists
sitaxsentan
Endothelin-1
Cisterna Magna
Rabbits

All Science Journal Classification (ASJC) codes

  • Surgery
  • Clinical Neurology

Cite this

Systemic administration of the endothelin-A receptor antagonist TBC 11251 attenuates cerebral vasospasm after experimental subarachnoid hemorrhage : Dose study and review of endothelin-based therapies in the literature on cerebral vasospasm. / Wanebo, John E.; Arthur, Adam; Louis, Hunter G.; West, Kim; Kassell, Neal F.; Lee, Kevin S.; Helm, Gregory A.

In: Neurosurgery, Vol. 43, No. 6, 01.12.1998, p. 1409-1418.

Research output: Contribution to journalArticle

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title = "Systemic administration of the endothelin-A receptor antagonist TBC 11251 attenuates cerebral vasospasm after experimental subarachnoid hemorrhage: Dose study and review of endothelin-based therapies in the literature on cerebral vasospasm",
abstract = "OBJECTIVE: Increasing evidence implicates endothelin (ET)-1 in the pathophysiological development of cerebral vasospasm. This study examined the ability of TBC 11251 (TBC), a new ET(A) receptor antagonist, to prevent vasospasm in a rabbit model of subarachnoid hemorrhage (SAH). METHODS: Eighty-five New Zealand White rabbits were assigned to 1 of 10 groups. SAH was induced by injecting autologous blood into the cisterna magna. The treatment groups were as follows: 1)control (no SAH), 2) SAH alone, 3) SAH plus vehicle every 12 hours (BID), 4) SAH plus 5 mg/kg TBC BID, 5) SAH plus 10 mg/kg TBC BID, 6) SAH plus 20 mg/kg TBC BID, 7) SAH plus vehicle at 24 and 36 hours after SAH (24/36), 8) SAH plus 5 mg/kg TBC 24/36, 9) SAH plus 10 mg/kg TBC 24/36, and 10) SAH plus 20 mg/kg TBC 24/36. Animals were killed 48 hours after SAH, by perfusion-fixation, and then basilar arteries were histologically prepared and their cross-sectional areas were measured. RESULTS: The mean basilar artery cross-sectional area was constricted from 0.332 mm2 in the control group to 0.131 mm2 in the SAH alone group, 0.132 in the vehicle 24/36 group, and 0.125 in the vehicle BID group. All groups treated with TBC showed an increase in cross-sectional luminal basilar artery area, relative to the vehicle-treated groups. The 5 mg/kg TBC BID group exhibited a mean basilar artery area of 0.217 mm2, and the 10 mg/kg TBC BID group showed a mean basilar artery area of 0.240 mm2; both groups were statistically improved, compared with the vehicle-treated groups (P < 0.05). No side effects were seen, and there were no differences in the mean arterial pressures between drug- and vehicle-treated groups. CONCLUSION: These findings demonstrate that systemic administration of the ET(A) receptor antagonist TBC significantly attenuates cerebral vasospasm after SAH, thus providing additional support for the role of ET-1 in vasospasm.",
author = "Wanebo, {John E.} and Adam Arthur and Louis, {Hunter G.} and Kim West and Kassell, {Neal F.} and Lee, {Kevin S.} and Helm, {Gregory A.}",
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T1 - Systemic administration of the endothelin-A receptor antagonist TBC 11251 attenuates cerebral vasospasm after experimental subarachnoid hemorrhage

T2 - Dose study and review of endothelin-based therapies in the literature on cerebral vasospasm

AU - Wanebo, John E.

AU - Arthur, Adam

AU - Louis, Hunter G.

AU - West, Kim

AU - Kassell, Neal F.

AU - Lee, Kevin S.

AU - Helm, Gregory A.

PY - 1998/12/1

Y1 - 1998/12/1

N2 - OBJECTIVE: Increasing evidence implicates endothelin (ET)-1 in the pathophysiological development of cerebral vasospasm. This study examined the ability of TBC 11251 (TBC), a new ET(A) receptor antagonist, to prevent vasospasm in a rabbit model of subarachnoid hemorrhage (SAH). METHODS: Eighty-five New Zealand White rabbits were assigned to 1 of 10 groups. SAH was induced by injecting autologous blood into the cisterna magna. The treatment groups were as follows: 1)control (no SAH), 2) SAH alone, 3) SAH plus vehicle every 12 hours (BID), 4) SAH plus 5 mg/kg TBC BID, 5) SAH plus 10 mg/kg TBC BID, 6) SAH plus 20 mg/kg TBC BID, 7) SAH plus vehicle at 24 and 36 hours after SAH (24/36), 8) SAH plus 5 mg/kg TBC 24/36, 9) SAH plus 10 mg/kg TBC 24/36, and 10) SAH plus 20 mg/kg TBC 24/36. Animals were killed 48 hours after SAH, by perfusion-fixation, and then basilar arteries were histologically prepared and their cross-sectional areas were measured. RESULTS: The mean basilar artery cross-sectional area was constricted from 0.332 mm2 in the control group to 0.131 mm2 in the SAH alone group, 0.132 in the vehicle 24/36 group, and 0.125 in the vehicle BID group. All groups treated with TBC showed an increase in cross-sectional luminal basilar artery area, relative to the vehicle-treated groups. The 5 mg/kg TBC BID group exhibited a mean basilar artery area of 0.217 mm2, and the 10 mg/kg TBC BID group showed a mean basilar artery area of 0.240 mm2; both groups were statistically improved, compared with the vehicle-treated groups (P < 0.05). No side effects were seen, and there were no differences in the mean arterial pressures between drug- and vehicle-treated groups. CONCLUSION: These findings demonstrate that systemic administration of the ET(A) receptor antagonist TBC significantly attenuates cerebral vasospasm after SAH, thus providing additional support for the role of ET-1 in vasospasm.

AB - OBJECTIVE: Increasing evidence implicates endothelin (ET)-1 in the pathophysiological development of cerebral vasospasm. This study examined the ability of TBC 11251 (TBC), a new ET(A) receptor antagonist, to prevent vasospasm in a rabbit model of subarachnoid hemorrhage (SAH). METHODS: Eighty-five New Zealand White rabbits were assigned to 1 of 10 groups. SAH was induced by injecting autologous blood into the cisterna magna. The treatment groups were as follows: 1)control (no SAH), 2) SAH alone, 3) SAH plus vehicle every 12 hours (BID), 4) SAH plus 5 mg/kg TBC BID, 5) SAH plus 10 mg/kg TBC BID, 6) SAH plus 20 mg/kg TBC BID, 7) SAH plus vehicle at 24 and 36 hours after SAH (24/36), 8) SAH plus 5 mg/kg TBC 24/36, 9) SAH plus 10 mg/kg TBC 24/36, and 10) SAH plus 20 mg/kg TBC 24/36. Animals were killed 48 hours after SAH, by perfusion-fixation, and then basilar arteries were histologically prepared and their cross-sectional areas were measured. RESULTS: The mean basilar artery cross-sectional area was constricted from 0.332 mm2 in the control group to 0.131 mm2 in the SAH alone group, 0.132 in the vehicle 24/36 group, and 0.125 in the vehicle BID group. All groups treated with TBC showed an increase in cross-sectional luminal basilar artery area, relative to the vehicle-treated groups. The 5 mg/kg TBC BID group exhibited a mean basilar artery area of 0.217 mm2, and the 10 mg/kg TBC BID group showed a mean basilar artery area of 0.240 mm2; both groups were statistically improved, compared with the vehicle-treated groups (P < 0.05). No side effects were seen, and there were no differences in the mean arterial pressures between drug- and vehicle-treated groups. CONCLUSION: These findings demonstrate that systemic administration of the ET(A) receptor antagonist TBC significantly attenuates cerebral vasospasm after SAH, thus providing additional support for the role of ET-1 in vasospasm.

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