Vascular pathology of large cerebral arteries in experimental subarachnoid hemorrhage: Vasoconstriction, functional CGRP depletion and maintained CGRP sensitivity
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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.
|Journal||European Journal of Pharmacology|
|Number of pages||10|
|Publication status||Published - 5 Mar 2019|
Copyright © 2019 Elsevier B.V. All rights reserved.
- 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid/pharmacology, Animals, Calcitonin Gene-Related Peptide/pharmacology, Capsaicin/pharmacology, Cerebral Arteries/drug effects, Endothelin-1/pharmacology, Male, Models, Animal, Rats, Rats, Sprague-Dawley, Serotonin/pharmacology, Subarachnoid Hemorrhage/pathology, Vasoconstriction/drug effects, Vasoconstrictor Agents/pharmacology, Vasodilation/drug effects, Vasodilator Agents/pharmacology