Effect of delayed cerebral vasospasm on cerebrovascular endothelin A receptor expression and function

Hartmut Vatter M.D., Juergen Konczalla, Stefan Weidauer M.D., Ph.D., Christine Preibisch Ph.D., Michael Zimmermann M.D., Ph.D., Andreas Raabe M.D., Ph.D., and Volker Seifert M.D., Ph.D.
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Object

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 ETA 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 ETA 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 ETA 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 ETA 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 ETA 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 ETA receptors in cases of cerebral vasospasm. The inhibitory potency of clazosentan on this contraction is increased. Furthermore, some evidence for an ETA receptor and an endothelium-dependent vasoactive effect after SAH is provided.

Abbreviations used in this paper:

ACH = acetylcholine; ANOVA = analysis of variance; BA = basilar artery; CEC = concentration effect curve; EC50%K+ = concentration of endothelin-1 that induces half of the reference contraction; Emax = maximum effect; ET = endothelin; MR = magnetic resonance; SAH = subarachnoid hemorrhage; SEM = standard error of the mean; 5-HT = 5-hydroxy-tryptamine.

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Contributor Notes

Address reprint requests to: Hartmut Vatter, M.D., Schleusenweg 2-16, D-60528 Frankfurt am Main, Germany. email: H.Vatter@em.uni-frankfurt.de.
  • 1

    Alabadi JA, , Torregrosa G, , Miranda FJ, , Salom JB, , Centeno JM, & Alborch E: Impairment of the modulatory role of nitric oxide on the endothelin-1-elicited contraction of cerebral arteries: a pathogenetic factor in cerebral vasospasm after subarachnoid hemorrhage?. Neurosurgery 41:245253, 1997

    • Search Google Scholar
    • Export Citation
  • 2

    Alafaci C, , Jansen I, , Arbab MA, , Shiokawa Y, , Svendgaard NA, & Edvinsson L: Enhanced vasoconstrictor effect of endothelin in cerebral arteries from rats with subarachnoid haemorrhage. Acta Physiol Scand 138:317319, 1990

    • Search Google Scholar
    • Export Citation
  • 3

    Beck J, , Raabe A, , Lanfermann H, , Seifert V, & Weidauer S: Tissue at risk concept for endovascular treatment of severe vasospasm after aneurysmal subarachnoid haemorrhage. J Neurol Neurosurg Psychiatry 75:17791781, 2004

    • Search Google Scholar
    • Export Citation
  • 4

    Callera GE, , Montezano AC, , Touyz RM, , Zorn TM, , Carvalho MH, & Fortes ZB, et al. : ETA receptor mediates altered leukocyte-endothelial cell interaction and adhesion molecules expression in DOCA-salt rats. Hypertension 43:872879, 2004

    • Search Google Scholar
    • Export Citation
  • 5

    Chow M, , Dumont AS, & Kassell NF: Endothelin receptor antagonists and cerebral vasospasm: an update. Neurosurgery 51:13331342, 2002

  • 6

    Dumont AS, , Dumont RJ, , Chow MM, , Lin CL, , Calisaneller T, & Ley KF, et al. : Cerebral vasospasm after subarachnoid hemorrhage: putative role of inflammation. Neurosurgery 53:123135, 2003

    • Search Google Scholar
    • Export Citation
  • 7

    Ehrenreich H, & Schilling L: New developments in the understanding of cerebral vasoregulation and vasospasm: the endothelinnitric oxide network. Cleve Clin J Med 62:105116, 1995

    • Search Google Scholar
    • Export Citation
  • 8

    Feger GI, , Schilling L, , Ehrenreich H, & Wahl M: Endothelium-dependent relaxation counteracting the contractile action of endothelin-1 is partly due to ETB receptor activation. Res Exp Med (Berl) 196:327337, 1997

    • Search Google Scholar
    • Export Citation
  • 9

    Findlay JM, & Deagle GM: Causes of morbidity and mortality following intracranial aneurysm rupture. Can J Neurol Sci 25:209215, 1998

  • 10

    Hansen-Schwartz J, , Hoel NL, , Zhou M, , Xu CB, , Svendgaard NA, & Edvinsson L: Subarachnoid hemorrhage enhances endothelin receptor expression and function in rat cerebral arteries. Neurosurgery 52:11881195, 2003

    • Search Google Scholar
    • Export Citation
  • 11

    Hertel F, , Walter C, , Bettag M, & Morsdorf M: Perfusion-weighted magnetic resonance imaging in patients with vasospasm: a useful new tool in the management of patients with subarachnoid hemorrhage. Neurosurgery 56:2835, 2005

    • Search Google Scholar
    • Export Citation
  • 12

    Hino A, , Tokuyama Y, , Kobayashi M, , Yano M, , Weir B, & Takeda J, et al. : Increased expression of endothelin B receptor mRNA following subarachnoid hemorrhage in monkeys. J Cereb Blood Flow Metab 16:688697, 1996

    • Search Google Scholar
    • Export Citation
  • 13

    Hop JW, , Rinkel GJ, , Algra A, & van Gijn J: Case-fatality rates and functional outcome after subarachnoid hemorrhage: a systematic review. Stroke 28:660664, 1997

    • Search Google Scholar
    • Export Citation
  • 14

    Itoh S, , Sasaki T, , Asai A, & Kuchino Y: Prevention of delayed vasospasm by an endothelin ETA receptor antagonist, BQ-123: change of ETA receptor mRNA expression in a canine subarachnoid hemorrhage model. J Neurosurg 81:759764, 1994

    • Search Google Scholar
    • Export Citation
  • 15

    Konczalla J, , Vatter H, , Weidauer S, , Raabe A, & Seifert V: Alteration of the cerebrovascular function of endothelin B receptor after subarachnoidal hemorrhage in the rat. Exp Biol Med (Maywood) 231:10641068, 2006

    • Search Google Scholar
    • Export Citation
  • 16

    Macdonald RL: Management of cerebral vasospasm. Neurosurg Rev 29:179193, 2006

  • 17

    Macdonald RL, , Kakarieka A, , Mayer S, , Pasqualin D, , Ruefenacht D, & Schmiedek P, et al. : Prevention of cerebral vasospasm after aneurysmal subarachnoid hemorrhage with clazosentan, an endothelin receptor antagonist. 9th International Conference on Cerebral Vasospasm June 27–30, 2006 Istanbul Turkey, The Marmara Hotel Abstract Book 2006. (Abstract OP5–3)

    • Search Google Scholar
    • Export Citation
  • 18

    Macdonald RL, , Zhang ZD, , Takahashi M, , Nikitina E, , Young J, & Xie A, et al. : Calcium sensitivity of vasospastic basilar artery after experimental subarachnoid hemorrhage. Am J Physiol Heart Circ Physiol 290:H2329H2336, 2006

    • Search Google Scholar
    • Export Citation
  • 19

    Masaki T: Historical review: Endothelin. Trends Pharmacol Sci 25:219224, 2004

  • 20

    Rabinstein AA, , Pichelmann MA, , Friedman JA, , Piepgras DG, , Nichols DA, & McIver JI, et al. : Symptomatic vasospasm and outcomes following aneurysmal subarachnoid hemorrhage: a comparison between surgical repair and endovascular coil occlusion. J Neurosurg 98:319325, 2003

    • Search Google Scholar
    • Export Citation
  • 21

    Rordorf G, , Koroshetz WJ, , Copen WA, , Gonzalez G, , Yamada K, & Schaefer PW, et al. : Diffusion-and perfusion-weighted imaging in vasospasm after subarachnoid hemorrhage. Stroke 30:599605, 1999

    • Search Google Scholar
    • Export Citation
  • 22

    Roux S, , Breu V, , Giller T, , Neidhart W, , Ramuz H, & Coassolo P, et al. : Ro 61–1790, a new hydrosoluble endothelin antagonist: general pharmacology and effects on experimental cerebral vasospasm. J Pharmacol Exp Ther 283:11101118, 1997

    • Search Google Scholar
    • Export Citation
  • 23

    Roux S, , Loffler BM, , Gray GA, , Sprecher U, , Clozel M, & Clozel JP: The role of endothelin in experimental cerebral vasospasm. Neurosurgery 37:7886, 1995

    • Search Google Scholar
    • Export Citation
  • 24

    Rubanyi GM, & Polokoff MA: Endothelins: molecular biology, biochemistry, pharmacology, physiology, and pathophysiology. Pharmacol Rev 46:325415, 1994

    • Search Google Scholar
    • Export Citation
  • 25

    Salom JB, , Torregrosa G, & Alborch E: Endothelins and the cerebral circulation. Cerebrovasc Brain Metab Rev 7:131152, 1995

  • 26

    Schilling L, , Vatter H, , Mursch K, , Ehrenreich H, & Schmiedek P: Characterization of the contractile and relaxant action of the endothelin-1 precursor, big endothelin-1, in the isolated rat basilar artery. Peptides 21:9199, 2000

    • Search Google Scholar
    • Export Citation
  • 27

    Solenski NJ, , Haley EC Jr, , Kassell NF, , Kongable G, , Germanson T, & Truskowski L, et al. : Medical complications of aneurysmal subarachnoid hemorrhage: a report of the multicenter, cooperative aneurysm study. Participants of the Multicenter Cooperative Aneurysm Study. Crit Care Med 23:10071017, 1995

    • Search Google Scholar
    • Export Citation
  • 28

    Solomon RA, , Antunes JL, , Chen RY, , Bland L, & Chien S: Decrease in cerebral blood flow in rats after experimental subarachnoid hemorrhage: a new animal model. Stroke 16:5864, 1985

    • Search Google Scholar
    • Export Citation
  • 29

    Stanimirovic DB, , Bertrand N, , McCarron R, , Uematsu S, & Spatz M: Arachidonic acid release and permeability changes induced by endothelins in human cerebromicrovascular endothelium. Acta Neurochir Suppl (Wien) 60:7175, 1994

    • Search Google Scholar
    • Export Citation
  • 30

    Vajkoczy P, , Meyer B, , Weidauer S, , Raabe A, , Thome C, & Ringel F, et al. : Clazosentan (AXV-034343), a selective endothelin A receptor antagonist, in the prevention of cerebral vasospasm following severe aneurysmal subarachnoid hemorrhage: results of a randomized, double-blind, placebo-controlled, multicenter phase IIa study. J Neurosurg 103:917, 2005

    • Search Google Scholar
    • Export Citation
  • 31

    Van Rossum JM: Cumulative dose-response curves. II. Technique for the making of dose-response curves in isolated organs and the evaluation of drug parameters. Arch Int Pharmacodyn Ther 143:299330, 1963

    • Search Google Scholar
    • Export Citation
  • 32

    Vatter H, , Weidauer S, , Dias S, , Preibisch C, , Ngone S, & Raabe A, et al. : Persistence of the nitric oxide-dependent vasodilator pathway of cerebral vessels after experimental subarachnoid hemorrhage. Neurosurgery 60:179188, 2007

    • Search Google Scholar
    • Export Citation
  • 33

    Vatter H, , Weidauer S, , Konczalla J, , Dettmann E, , Zimmermann M, & Raabe A, et al. : Time course in the development of cerebral vasospasm after experimental subarachnoid hemorrhage: clinical and neuroradiological assessment of the rat double hemorrhage model. Neurosurgery 58:11901197, 2006

    • Search Google Scholar
    • Export Citation
  • 34

    Vatter H, , Zimmermann M, , Seifert V, & Schilling L: Experimental approaches to evaluate endothelin-A receptor antagonists. Methods Find Exp Clin Pharmacol 26:277286, 2004

    • Search Google Scholar
    • Export Citation
  • 35

    Vatter H, , Zimmermann M, , Tesanovic V, , Raabe A, , Schilling L, & Seifert V: Cerebrovascular characterization of clazosentan, the first nonpeptide endothelin receptor antagonist clinically effective for the treatment of cerebral vasospasm. Part I: inhibitory effect on endothelin(A) receptor-mediated contraction. J Neurosurg 102:11011107, 2005

    • Search Google Scholar
    • Export Citation
  • 36

    Vatter H, , Zimmermann M, , Tesanovic V, , Raabe A, , Seifert V, & Schilling L: Cerebrovascular characterization of clazosentan, the first nonpeptide endothelin receptor antagonist shown to be clinically effective for the treatment of cerebral vasospasm. Part II: effect on endothelin(B) receptor-mediated relaxation. J Neurosurg 102:11081114, 2005

    • Search Google Scholar
    • Export Citation
  • 37

    Zimmermann M, & Seifert V: Endothelin and subarachnoid hemorrhage: an overview. Neurosurgery 43:863876, 1998

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