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Vascular pathology of large cerebral arteries in experimental subarachnoid hemorrhage: Vasoconstriction, functional CGRP depletion and maintained CGRP sensitivity

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@article{c2bf9c51f369449cbbcd6bbc0eebf07e,
title = "Vascular pathology of large cerebral arteries in experimental subarachnoid hemorrhage: Vasoconstriction, functional CGRP depletion and maintained CGRP sensitivity",
abstract = "Subarachnoid hemorrhage (SAH) is associated with increased cerebral artery sensitivity to vasoconstrictors and release of the perivascular sensory vasodilator CGRP. In the current study the constrictive phenotype and the vasodilatory effects of exogenous and endogenous perivascular CGRP were characterized in detail applying myograph technology to cerebral artery segments isolated from experimental SAH and sham-operated rats. Following experimental SAH, cerebral arteries exhibited increased vasoconstriction to endothelin-1, 5-hydroxytryptamine and U46419. In addition, depolarization-induced vasoconstriction (60mM potassium) was significantly increased, supporting a general SAH-associated vasoconstrictive phenotype. Using exogenous CGRP, we demonstrated that sensitivity of the arteries to CGRP-induced vasodilation was unchanged after SAH. However, vasodilation in response to capsaicin (100nM), a sensory nerve activator used to release perivascular CGRP, was significantly reduced by SAH (P = 0.0079). Because CGRP-mediated dilation is an important counterbalance to increased arterial contractility, a reduction in CGRP release after SAH would exacerbate the vasospasms that occur after SAH. A similar finding was obtained with artery culture (24h), an in vitro model of SAH-induced vascular dysfunction. The arterial segments maintained sensitivity to exogenous CGRP but showed reduced capsaicin-induced vasodilation. To test whether a metabolically stable CGRP analogue could be used to supplement the loss of perivascular CGRP release in SAH, SAX was systemically administered in our in vivo SAH model. SAX treatment, however, induced CGRP-desensitization and did not prevent the development of vasoconstriction in cerebral arteries after SAH.",
keywords = "Artery culture, Basilar artery, CGRP, CGRP analogue, CGRP receptor, Subarachnoid hemorrhage",
author = "Johansson, {Sara Ellinor} and Bahareh Abdolalizadeh and Majid Sheykhzade and Lars Edvinsson and Anette Sams",
note = "Copyright {\circledC} 2019 Elsevier B.V. All rights reserved.",
year = "2019",
doi = "10.1016/j.ejphar.2019.01.007",
language = "English",
volume = "846",
pages = "109--118",
journal = "European Journal of Pharmacology",
issn = "0014-2999",
publisher = "Elsevier BV",

}

RIS

TY - JOUR

T1 - Vascular pathology of large cerebral arteries in experimental subarachnoid hemorrhage

T2 - Vasoconstriction, functional CGRP depletion and maintained CGRP sensitivity

AU - Johansson, Sara Ellinor

AU - Abdolalizadeh, Bahareh

AU - Sheykhzade, Majid

AU - Edvinsson, Lars

AU - Sams, Anette

N1 - Copyright © 2019 Elsevier B.V. All rights reserved.

PY - 2019

Y1 - 2019

N2 - Subarachnoid hemorrhage (SAH) is associated with increased cerebral artery sensitivity to vasoconstrictors and release of the perivascular sensory vasodilator CGRP. In the current study the constrictive phenotype and the vasodilatory effects of exogenous and endogenous perivascular CGRP were characterized in detail applying myograph technology to cerebral artery segments isolated from experimental SAH and sham-operated rats. Following experimental SAH, cerebral arteries exhibited increased vasoconstriction to endothelin-1, 5-hydroxytryptamine and U46419. In addition, depolarization-induced vasoconstriction (60mM potassium) was significantly increased, supporting a general SAH-associated vasoconstrictive phenotype. Using exogenous CGRP, we demonstrated that sensitivity of the arteries to CGRP-induced vasodilation was unchanged after SAH. However, vasodilation in response to capsaicin (100nM), a sensory nerve activator used to release perivascular CGRP, was significantly reduced by SAH (P = 0.0079). Because CGRP-mediated dilation is an important counterbalance to increased arterial contractility, a reduction in CGRP release after SAH would exacerbate the vasospasms that occur after SAH. A similar finding was obtained with artery culture (24h), an in vitro model of SAH-induced vascular dysfunction. The arterial segments maintained sensitivity to exogenous CGRP but showed reduced capsaicin-induced vasodilation. To test whether a metabolically stable CGRP analogue could be used to supplement the loss of perivascular CGRP release in SAH, SAX was systemically administered in our in vivo SAH model. SAX treatment, however, induced CGRP-desensitization and did not prevent the development of vasoconstriction in cerebral arteries after SAH.

AB - Subarachnoid hemorrhage (SAH) is associated with increased cerebral artery sensitivity to vasoconstrictors and release of the perivascular sensory vasodilator CGRP. In the current study the constrictive phenotype and the vasodilatory effects of exogenous and endogenous perivascular CGRP were characterized in detail applying myograph technology to cerebral artery segments isolated from experimental SAH and sham-operated rats. Following experimental SAH, cerebral arteries exhibited increased vasoconstriction to endothelin-1, 5-hydroxytryptamine and U46419. In addition, depolarization-induced vasoconstriction (60mM potassium) was significantly increased, supporting a general SAH-associated vasoconstrictive phenotype. Using exogenous CGRP, we demonstrated that sensitivity of the arteries to CGRP-induced vasodilation was unchanged after SAH. However, vasodilation in response to capsaicin (100nM), a sensory nerve activator used to release perivascular CGRP, was significantly reduced by SAH (P = 0.0079). Because CGRP-mediated dilation is an important counterbalance to increased arterial contractility, a reduction in CGRP release after SAH would exacerbate the vasospasms that occur after SAH. A similar finding was obtained with artery culture (24h), an in vitro model of SAH-induced vascular dysfunction. The arterial segments maintained sensitivity to exogenous CGRP but showed reduced capsaicin-induced vasodilation. To test whether a metabolically stable CGRP analogue could be used to supplement the loss of perivascular CGRP release in SAH, SAX was systemically administered in our in vivo SAH model. SAX treatment, however, induced CGRP-desensitization and did not prevent the development of vasoconstriction in cerebral arteries after SAH.

KW - Artery culture

KW - Basilar artery

KW - CGRP

KW - CGRP analogue

KW - CGRP receptor

KW - Subarachnoid hemorrhage

UR - http://www.scopus.com/inward/record.url?scp=85060703198&partnerID=8YFLogxK

U2 - 10.1016/j.ejphar.2019.01.007

DO - 10.1016/j.ejphar.2019.01.007

M3 - Journal article

VL - 846

SP - 109

EP - 118

JO - European Journal of Pharmacology

JF - European Journal of Pharmacology

SN - 0014-2999

ER -

ID: 56377850