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 - 2019/3/5
Y1 - 2019/3/5
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 (60 mM 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 (100 nM), 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 (24 h), 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 (60 mM 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 (100 nM), 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 (24 h), 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 - 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid/pharmacology
KW - Animals
KW - Calcitonin Gene-Related Peptide/pharmacology
KW - Capsaicin/pharmacology
KW - Cerebral Arteries/drug effects
KW - Endothelin-1/pharmacology
KW - Male
KW - Models, Animal
KW - Rats
KW - Rats, Sprague-Dawley
KW - Serotonin/pharmacology
KW - Subarachnoid Hemorrhage/pathology
KW - Vasoconstriction/drug effects
KW - Vasoconstrictor Agents/pharmacology
KW - Vasodilation/drug effects
KW - Vasodilator Agents/pharmacology
U2 - 10.1016/j.ejphar.2019.01.007
DO - 10.1016/j.ejphar.2019.01.007
M3 - Journal article
C2 - 30653947
SN - 0014-2999
VL - 846
SP - 109
EP - 118
JO - European Journal of Pharmacology
JF - European Journal of Pharmacology
ER -