gms | German Medical Science

56. Jahrestagung der Deutschen Gesellschaft für Neurochirurgie e. V. (DGNC)
3èmes journées françaises de Neurochirurgie (SFNC)

Deutsche Gesellschaft für Neurochirurgie e. V.
Société Française de Neurochirurgie

07. bis 11.05.2005, Strasbourg

Cerebrovascular characterization of clazosentan, the first non-peptide Endothelin-receptor antagonist clinically effective for the treatment of cerebral vasospasm

Zerebrovaskuläre Charakterisierung von Clazosentan, dem ersten nicht-peptidischen Endothelin Rezeptorantagonisten, für den eine klinische Wirksamkeit zur Behandlung des zerebralen Vasospasmus nachgewiesen wurde

Meeting Abstract

  • corresponding author H. Vatter - Klinik für Neurochirurgie, Johann Wolfgang Goethe Universität, Frankfurt
  • M. Zimmermann - Klinik für Neurochirurgie, Johann Wolfgang Goethe Universität, Frankfurt
  • V. Tesanovic - Klinik für Neurochirurgie, Johann Wolfgang Goethe Universität, Frankfurt
  • A. Raabe - Klinik für Neurochirurgie, Johann Wolfgang Goethe Universität, Frankfurt
  • V. Seifert - Klinik für Neurochirurgie, Johann Wolfgang Goethe Universität, Frankfurt
  • L. Schilling - Klinik für Neurochirugie, Abtl. Neurochirurgische Forschung, Fakultät für Klinische Medizin Mannheim, Universität Heidelberg

Deutsche Gesellschaft für Neurochirurgie. Société Française de Neurochirurgie. 56. Jahrestagung der Deutschen Gesellschaft für Neurochirurgie e.V. (DGNC), 3èmes journées françaises de Neurochirurgie (SFNC). Strasbourg, 07.-11.05.2005. Düsseldorf, Köln: German Medical Science; 2005. Doc11.05.-13.07

Die elektronische Version dieses Artikels ist vollständig und ist verfügbar unter: http://www.egms.de/de/meetings/dgnc2005/05dgnc0245.shtml

Veröffentlicht: 4. Mai 2005

© 2005 Vatter et al.
Dieser Artikel ist ein Open Access-Artikel und steht unter den Creative Commons Lizenzbedingungen (http://creativecommons.org/licenses/by-nc-nd/3.0/deed.de). Er darf vervielf&aauml;ltigt, verbreitet und &oauml;ffentlich zug&aauml;nglich gemacht werden, vorausgesetzt dass Autor und Quelle genannt werden.


Gliederung

Text

Objective

The disturbed balance between nitric oxide (NO) and Endothelin (ET)-1 in the cerebrovasculature seems to play a major role in the development of cerebral vasospasm (CVS) after subarachnoid hemorrhage (SAH). ET-1 represents the contractile part in this balance. Besides the prevailing ET(A)-receptor dependent contractile effect ET-1 has also ET(B)-receptor mediated vasodilatory attributes. Aim of the present study was, therefore, to provide the pharmacological properties and the actual receptor selectivity in the cerebrovasculature of clazosentan, the first putatively ET(A)-receptor selective antagonist, which was clinically proven for the treatment of CVS.

Methods

Isometric force measurements were performed in rat basilar artery (BA) ring segments with (E+) and without (E-) endothelial function. Concentration effect curves (CEC) were constructed by cumulative application of ET-1 on segments under resting tension and ET-1 or sarafotoxin S6c (S6c) after precontraction with prostaglandin F2α in the presence or absence of clazosentan (10-9M - 10-6M). The inhibitory potency of clazosentan was determined by the pA2-value.

Results

The CECs for ET-1 were shifted to the right in the presence of clazosentan dose dependently and in a parallel manner, which indicates competitive antagonism. The pA2-values for ET-1 were 7.8 (E+) and 8.6 (E-). The relaxation by ET-1 and S6c was also inhibited in a competitive manner by clazosentan, yielding pA2-values of 6.7 and 7.1, respectively. The selectivity to the ET(A)-receptor in the cerebrovascular system was, therefore, approximately two logarithmic units.

Conclusions

The present investigations characterize clazosentan as a potent competitive antagonist on the ET(A)-receptor mediated constriction of the cerebrovasculature by ET-1. However, an additional competitive inhibition of ET(B)-receptor mediated relaxation in cerebral vessels by clazosentan in therapeutically relevant concentrations is suggested by the present results. These functional data may also be used to define an in vitro profile of an ET-receptor antagonist with a high probability of clinical efficacy.