Effect of delayed cerebral vasospasm on cerebrovascular endothelin A receptor expression and function.
OBJECTIVE
The key role in the development of cerebral vasospasm after subarachnoid hemorrhage (SAH) is increasingly assigned to endothelin (ET)-1. Constriction of the cerebrovasculature by ET-1 is mainly mediated by the ET(A) receptor but is putatively altered during the development of cerebral vasospasm. Therefore, the aim in the present study was to characterize these alterations, with the emphasis on the ET(A) receptor.


METHODS
Cerebral vasospasm was induced using the rat double-hemorrhage model and proven by perfusion weighted magnetic resonance imaging. Rats were killed on Day 5 after SAH, and immunohistochemical staining for ET(A), receptors was performed. The isometric force of basilar artery ring segments with (E+, control group) and without (E-, SAH group) endothelial function was measured. Concentration effect curves (CECs) for ET-1 were constructed by cumulative application in the absence and presence of the selective ET(A) receptor antagonist clazosentan (10(-8) or 10(-7) M).


RESULTS
The CEC for E+ segments was significantly shifted to the left after SAH by a factor of 3.7, whereas maximum contraction was unchanged. In E- segments, the CECs were not shifted during cerebral vasospasm but the maximum contraction was significantly enhanced. The inhibitory potency of clazosentan yielded a pA2 value of 8.6 +/- 0.2. Immunohistochemical staining of the smooth-muscle layer showed no significant increase of ET(A) receptor expression, but positive staining occurred in the endothelial space after SAH.


CONCLUSIONS
The present data indicate an enhanced contractile effect of the smooth-muscle ET(A) receptors in cases of cerebral vasospasm. The inhibitory potency of clazosentan on this contraction is increased. Furthermore, some evidence for an ET(A) receptor and an endothelium-dependent vasoactive effect after SAH is provided.
Vatter
Hartmut
H
Department of Neurosurgery, Johann Wolfgang Goethe-University, Frankfurt am Main, Germany. H.Vatter@em.uni-frankfurt.de
Konczalla
Juergen
J
Weidauer
Stefan
S
Preibisch
Christine
C
Zimmermann
Michael
M
Raabe
Andreas
A
Seifert
Volker
V
D000818:Animals; D001488:Basilar Artery / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D004146:Dioxanes / Q000008:administration & dosage / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D065130:Endothelin A Receptor Antagonists; D007150:Immunohistochemistry; D007537:Isometric Contraction / Q000187:drug effects; D008279:Magnetic Resonance Imaging; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism; D011725:Pyridines / Q000008:administration & dosage / Q000494:pharmacology; D011743:Pyrimidines / Q000008:administration & dosage / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D044022:Receptor, Endothelin A / Q000235:genetics / Q000502:physiology*; D013345:Subarachnoid Hemorrhage / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D013449:Sulfonamides / Q000008:administration & dosage / Q000494:pharmacology; D013777:Tetrazoles / Q000008:administration & dosage / Q000494:pharmacology; D013997:Time Factors; D020301:Vasospasm, Intracranial / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology*
D004146:Dioxanes; D065130:Endothelin A Receptor Antagonists; D011725:Pyridines; D011743:Pyrimidines; D044022:Receptor, Endothelin A; D013449:Sulfonamides; D013777:Tetrazoles; C109641:clazosentan