Role of endothelin-1 in cerebral hematoma-induced modification of cerebral vascular reactivity in piglets

Momoh A. Yakubu, Charles Leffler

Research output: Contribution to journalArticle

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Abstract

Endothelin-1 (ET-1) has been implicated in hematoma-induced cerebral vasoconstriction and modification of cerebral microvascular reactivity, particularly attenuation of vasodilation to cAMP-dependent dilators and enhanced vasoconstriction to ET-1. We examined effects of the ET-1 antagonist, BQ-123, on hematoma-induced modification of pial arteriolar responses to ET-1 and iloprost, a cAMP-dependent dilator, in vivo, plus the effects of such treatment on the cortical CSF cAMP. Closed cranial windows were implanted in α-chloralose anesthetized piglets 4 days following cortical subarachnoid injection of: (1) artificial cerebrospinal fluid (aCSF); (2) autologous blood; (3) BQ-123 alone; or (4) BQ-123 in combination with blood. ET-1 in CSF was significantly elevated from 3 in control to 45 fmol/ml 6 h following hematoma, dropping to 24 fmol/ml at 24 h but remaining above control 4 days later (14 fmol/ml). The mean diameters of pial arterioles were reduced 30% 4 days following blood injection. This reduction was prevented by pretreatment with BQ-123. In the control piglets, pial arterioles dose-dependently dilated to topical application of iloprost with increases in diameter of 10%, 16% and 21% at 10-12 M, 10-10 M and 10-8 M, respectively. Iloprost-induced dilation was attenuated by hematoma to 4%, 9% and 14% at 10-12 M, 10-10 M and 10-8 M, respectively. Treating piglets with BQ-123 along with hematoma on day 1 prevented the hematoma-induced attenuation of pial arteriolar dilation to iloprost on day 4 (14%, 21% and 29% at 10-12 M, 10-10 M and 10-8 M, respectively). Conversely, dilation to sodium nitroprusside (SNP) was not different among the groups. Topical ET-1 dilated pial arterioles at 10-12 M and produced dose-dependent constriction at higher doses in the control piglets. The dilation at 10-12 M ET-1 was reversed to constriction 4 days following hematoma and constrictions to higher doses were enhanced. BQ-123 treatment along with hematoma prevented both the loss of low dose dilation and the enhanced vasoconstriction to ET-1. Treatment with BQ-123 alone on day 1 did not affect the dilation to iloprost or constriction to ET-1, 4 days later. The cortical CSF level of cAMP was significantly reduced from 1637 fmol/ml in controls to 294 fmol/ml in piglets with hematoma. Treatment with BQ-123 along with hematoma blocked the reduction in cAMP (3369 fmol/ml). Initial elevation of ET-1 and the subsequent activation of ET(A) receptor may play an important role in hematoma-induced alterations of cerebral vascular reactivity and prolonged cerebral vasoconstriction that occur 4 days later. Thus, cerebral hematoma appears to attenuate iloprost-induced dilation and reduce basal cAMP level 4 days following hematoma via release that involves ET-1 of substance(s) on day 1 of hematoma. This substance(s) may act by inhibiting adenylyl cyclase. These results suggest that ET-1 plays an important role in the blood-induced prolonged cerebral vasoconstriction and altered vasoreactivity that follows cerebral hemorrhage via stimulation of ET(A) receptor.

Original languageEnglish (US)
Pages (from-to)149-156
Number of pages8
JournalBrain Research
Volume734
Issue number1-2
DOIs
StatePublished - Sep 23 1996

Fingerprint

Endothelin-1
Hematoma
Blood Vessels
Iloprost
Dilatation
Vasoconstriction
Constriction
Arterioles
Chloralose
Injections
cyclo(Trp-Asp-Pro-Val-Leu)
Cerebral Hemorrhage
Nitroprusside
Adenylyl Cyclases
Vasodilation
Cerebrospinal Fluid
Therapeutics

All Science Journal Classification (ASJC) codes

  • Neuroscience(all)
  • Molecular Biology
  • Clinical Neurology
  • Developmental Biology

Cite this

Role of endothelin-1 in cerebral hematoma-induced modification of cerebral vascular reactivity in piglets. / Yakubu, Momoh A.; Leffler, Charles.

In: Brain Research, Vol. 734, No. 1-2, 23.09.1996, p. 149-156.

Research output: Contribution to journalArticle

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title = "Role of endothelin-1 in cerebral hematoma-induced modification of cerebral vascular reactivity in piglets",
abstract = "Endothelin-1 (ET-1) has been implicated in hematoma-induced cerebral vasoconstriction and modification of cerebral microvascular reactivity, particularly attenuation of vasodilation to cAMP-dependent dilators and enhanced vasoconstriction to ET-1. We examined effects of the ET-1 antagonist, BQ-123, on hematoma-induced modification of pial arteriolar responses to ET-1 and iloprost, a cAMP-dependent dilator, in vivo, plus the effects of such treatment on the cortical CSF cAMP. Closed cranial windows were implanted in α-chloralose anesthetized piglets 4 days following cortical subarachnoid injection of: (1) artificial cerebrospinal fluid (aCSF); (2) autologous blood; (3) BQ-123 alone; or (4) BQ-123 in combination with blood. ET-1 in CSF was significantly elevated from 3 in control to 45 fmol/ml 6 h following hematoma, dropping to 24 fmol/ml at 24 h but remaining above control 4 days later (14 fmol/ml). The mean diameters of pial arterioles were reduced 30{\%} 4 days following blood injection. This reduction was prevented by pretreatment with BQ-123. In the control piglets, pial arterioles dose-dependently dilated to topical application of iloprost with increases in diameter of 10{\%}, 16{\%} and 21{\%} at 10-12 M, 10-10 M and 10-8 M, respectively. Iloprost-induced dilation was attenuated by hematoma to 4{\%}, 9{\%} and 14{\%} at 10-12 M, 10-10 M and 10-8 M, respectively. Treating piglets with BQ-123 along with hematoma on day 1 prevented the hematoma-induced attenuation of pial arteriolar dilation to iloprost on day 4 (14{\%}, 21{\%} and 29{\%} at 10-12 M, 10-10 M and 10-8 M, respectively). Conversely, dilation to sodium nitroprusside (SNP) was not different among the groups. Topical ET-1 dilated pial arterioles at 10-12 M and produced dose-dependent constriction at higher doses in the control piglets. The dilation at 10-12 M ET-1 was reversed to constriction 4 days following hematoma and constrictions to higher doses were enhanced. BQ-123 treatment along with hematoma prevented both the loss of low dose dilation and the enhanced vasoconstriction to ET-1. Treatment with BQ-123 alone on day 1 did not affect the dilation to iloprost or constriction to ET-1, 4 days later. The cortical CSF level of cAMP was significantly reduced from 1637 fmol/ml in controls to 294 fmol/ml in piglets with hematoma. Treatment with BQ-123 along with hematoma blocked the reduction in cAMP (3369 fmol/ml). Initial elevation of ET-1 and the subsequent activation of ET(A) receptor may play an important role in hematoma-induced alterations of cerebral vascular reactivity and prolonged cerebral vasoconstriction that occur 4 days later. Thus, cerebral hematoma appears to attenuate iloprost-induced dilation and reduce basal cAMP level 4 days following hematoma via release that involves ET-1 of substance(s) on day 1 of hematoma. This substance(s) may act by inhibiting adenylyl cyclase. These results suggest that ET-1 plays an important role in the blood-induced prolonged cerebral vasoconstriction and altered vasoreactivity that follows cerebral hemorrhage via stimulation of ET(A) receptor.",
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N2 - Endothelin-1 (ET-1) has been implicated in hematoma-induced cerebral vasoconstriction and modification of cerebral microvascular reactivity, particularly attenuation of vasodilation to cAMP-dependent dilators and enhanced vasoconstriction to ET-1. We examined effects of the ET-1 antagonist, BQ-123, on hematoma-induced modification of pial arteriolar responses to ET-1 and iloprost, a cAMP-dependent dilator, in vivo, plus the effects of such treatment on the cortical CSF cAMP. Closed cranial windows were implanted in α-chloralose anesthetized piglets 4 days following cortical subarachnoid injection of: (1) artificial cerebrospinal fluid (aCSF); (2) autologous blood; (3) BQ-123 alone; or (4) BQ-123 in combination with blood. ET-1 in CSF was significantly elevated from 3 in control to 45 fmol/ml 6 h following hematoma, dropping to 24 fmol/ml at 24 h but remaining above control 4 days later (14 fmol/ml). The mean diameters of pial arterioles were reduced 30% 4 days following blood injection. This reduction was prevented by pretreatment with BQ-123. In the control piglets, pial arterioles dose-dependently dilated to topical application of iloprost with increases in diameter of 10%, 16% and 21% at 10-12 M, 10-10 M and 10-8 M, respectively. Iloprost-induced dilation was attenuated by hematoma to 4%, 9% and 14% at 10-12 M, 10-10 M and 10-8 M, respectively. Treating piglets with BQ-123 along with hematoma on day 1 prevented the hematoma-induced attenuation of pial arteriolar dilation to iloprost on day 4 (14%, 21% and 29% at 10-12 M, 10-10 M and 10-8 M, respectively). Conversely, dilation to sodium nitroprusside (SNP) was not different among the groups. Topical ET-1 dilated pial arterioles at 10-12 M and produced dose-dependent constriction at higher doses in the control piglets. The dilation at 10-12 M ET-1 was reversed to constriction 4 days following hematoma and constrictions to higher doses were enhanced. BQ-123 treatment along with hematoma prevented both the loss of low dose dilation and the enhanced vasoconstriction to ET-1. Treatment with BQ-123 alone on day 1 did not affect the dilation to iloprost or constriction to ET-1, 4 days later. The cortical CSF level of cAMP was significantly reduced from 1637 fmol/ml in controls to 294 fmol/ml in piglets with hematoma. Treatment with BQ-123 along with hematoma blocked the reduction in cAMP (3369 fmol/ml). Initial elevation of ET-1 and the subsequent activation of ET(A) receptor may play an important role in hematoma-induced alterations of cerebral vascular reactivity and prolonged cerebral vasoconstriction that occur 4 days later. Thus, cerebral hematoma appears to attenuate iloprost-induced dilation and reduce basal cAMP level 4 days following hematoma via release that involves ET-1 of substance(s) on day 1 of hematoma. This substance(s) may act by inhibiting adenylyl cyclase. These results suggest that ET-1 plays an important role in the blood-induced prolonged cerebral vasoconstriction and altered vasoreactivity that follows cerebral hemorrhage via stimulation of ET(A) receptor.

AB - Endothelin-1 (ET-1) has been implicated in hematoma-induced cerebral vasoconstriction and modification of cerebral microvascular reactivity, particularly attenuation of vasodilation to cAMP-dependent dilators and enhanced vasoconstriction to ET-1. We examined effects of the ET-1 antagonist, BQ-123, on hematoma-induced modification of pial arteriolar responses to ET-1 and iloprost, a cAMP-dependent dilator, in vivo, plus the effects of such treatment on the cortical CSF cAMP. Closed cranial windows were implanted in α-chloralose anesthetized piglets 4 days following cortical subarachnoid injection of: (1) artificial cerebrospinal fluid (aCSF); (2) autologous blood; (3) BQ-123 alone; or (4) BQ-123 in combination with blood. ET-1 in CSF was significantly elevated from 3 in control to 45 fmol/ml 6 h following hematoma, dropping to 24 fmol/ml at 24 h but remaining above control 4 days later (14 fmol/ml). The mean diameters of pial arterioles were reduced 30% 4 days following blood injection. This reduction was prevented by pretreatment with BQ-123. In the control piglets, pial arterioles dose-dependently dilated to topical application of iloprost with increases in diameter of 10%, 16% and 21% at 10-12 M, 10-10 M and 10-8 M, respectively. Iloprost-induced dilation was attenuated by hematoma to 4%, 9% and 14% at 10-12 M, 10-10 M and 10-8 M, respectively. Treating piglets with BQ-123 along with hematoma on day 1 prevented the hematoma-induced attenuation of pial arteriolar dilation to iloprost on day 4 (14%, 21% and 29% at 10-12 M, 10-10 M and 10-8 M, respectively). Conversely, dilation to sodium nitroprusside (SNP) was not different among the groups. Topical ET-1 dilated pial arterioles at 10-12 M and produced dose-dependent constriction at higher doses in the control piglets. The dilation at 10-12 M ET-1 was reversed to constriction 4 days following hematoma and constrictions to higher doses were enhanced. BQ-123 treatment along with hematoma prevented both the loss of low dose dilation and the enhanced vasoconstriction to ET-1. Treatment with BQ-123 alone on day 1 did not affect the dilation to iloprost or constriction to ET-1, 4 days later. The cortical CSF level of cAMP was significantly reduced from 1637 fmol/ml in controls to 294 fmol/ml in piglets with hematoma. Treatment with BQ-123 along with hematoma blocked the reduction in cAMP (3369 fmol/ml). Initial elevation of ET-1 and the subsequent activation of ET(A) receptor may play an important role in hematoma-induced alterations of cerebral vascular reactivity and prolonged cerebral vasoconstriction that occur 4 days later. Thus, cerebral hematoma appears to attenuate iloprost-induced dilation and reduce basal cAMP level 4 days following hematoma via release that involves ET-1 of substance(s) on day 1 of hematoma. This substance(s) may act by inhibiting adenylyl cyclase. These results suggest that ET-1 plays an important role in the blood-induced prolonged cerebral vasoconstriction and altered vasoreactivity that follows cerebral hemorrhage via stimulation of ET(A) receptor.

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