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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.

AbstractOBJECT:
The central role of endothelin (ET)-1 in the development of cerebral vasospasm after subarachnoid hemorrhage is indicated by the successful treatment of this vasospasm in several animal models by using selective ET(A) receptor antagonists. Clazosentan is a selective ET(A) receptor antagonist that provides for the first time clinical proof that ET-1 is involved in the pathogenesis of cerebral vasospasm. The aim of the present investigation was, therefore, to define the pharmacological properties of clazosentan that affect ET(A) receptor-mediated contraction in the cerebrovasculature.
METHODS:
Isometric force measurements were performed in rat basilar artery (BA) ring segments with (E+) and without (E-) endothelial function. Concentration effect curves (CECs) were constructed by cumulative application of ET-1 or big ET-1 in the absence or presence of clazosentan (10(-9), 10(-8), and 10(-7) M). The inhibitory potency of clazosentan was determined by the value of the affinity constant (pA2). The CECs for contraction induced by ET-1 and big ET-1 were shifted to the right in the presence of clazosentan in a parallel dose-dependent manner, which indicates competitive antagonism. The pA2 values for ET-1 were 7.8 (E+) and 8.6 (E-) and the corresponding values for big ET-1 were 8.6 (E+) and 8.3 (E-).
CONCLUSIONS:
The present data characterize clazosentan as a potent competitive antagonist of ET(A) receptor-mediated constriction of the cerebrovasculature by ET-1 and its precursor big ET-1. 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.
AuthorsHartmut Vatter, Michael Zimmermann, Veronika Tesanovic, Andreas Raabe, Lothar Schilling, Volker Seifert
JournalJournal of neurosurgery (J Neurosurg) Vol. 102 Issue 6 Pg. 1101-7 (Jun 2005) ISSN: 0022-3085 [Print] United States
PMID16028770 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Endothelin A Receptor Antagonists
  • Peptides
  • Receptor, Endothelin A
Topics
  • Animals
  • Basilar Artery (drug effects, physiology)
  • Dose-Response Relationship, Drug
  • Endothelin A Receptor Antagonists
  • In Vitro Techniques
  • Male
  • Peptides (pharmacology)
  • Rats
  • Rats, Sprague-Dawley
  • Receptor, Endothelin A (metabolism)
  • Vasoconstriction (drug effects)
  • Vasospasm, Intracranial (drug therapy)

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