title: 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.
abstract: OBJECTIVE
  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.
authors: Department of Neurosurgery, Johann Wolfgang Goethe University, Frankfurt am Main. H.Vatter@em.uni-frankfurt.de
authors: Hartmut
authors: H
authors: Vatter
authors: Michael
authors: M
authors: Zimmermann
authors: Veronika
authors: V
authors: Tesanovic
authors: Andreas
authors: A
authors: Raabe
authors: Lothar
authors: L
authors: Schilling
authors: Volker
authors: V
authors: Seifert
mesh_terms: D000818:Animals; D001488:Basilar Artery / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D065130:Endothelin A Receptor Antagonists; D066298:In Vitro Techniques; D008297:Male; D010455:Peptides / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D044022:Receptor, Endothelin A / Q000378:metabolism; D014661:Vasoconstriction / Q000187:drug effects*; D020301:Vasospasm, Intracranial / Q000188:drug therapy*
chemical_list: D065130:Endothelin A Receptor Antagonists; D010455:Peptides; D044022:Receptor, Endothelin A