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.
OBJECTIVE
The disturbed balance between nitric oxide and endothelin (ET)-1 in the cerebrovasculature seems to play a major role in the development of cerebral vasospasm after subarachnoid hemorrhage. Endothelin-1 represents the contractile part in this balance. In addition to the prevailing ET(A) receptor-dependent contractile effect, ET-1 also has ET(B) receptor-mediated vasodilatory attributes. The aim of the present study was to define the actual selectivity of clazosentan, the first putative highly ET(A) receptor-selective antagonist clinically proven to be effective in the treatment of vasospasm in the cerebrovasculature.


METHODS
Rat basilar artery ring segments with endothelial function were used for the measurement of isometric force. Concentration effect curves were constructed by cumulative application of sarafotoxin S6c, ET-1, or big ET-1 in the presence or absence of clazosentan (10(-9) to 10(-6) M) after a precontraction was induced by prostaglandin F2alpha. The inhibition by clazosentan was estimated by the value of the affinity constant (pA2). The relaxation induced by sarafotoxin S6c, ET-1, and big ET-1 was inhibited in a competitive manner by clazosentan, yielding pA2 values of 7.1, 6.7, and 6.5, respectively. The selectivity to the ET(A) receptor in the cerebrovascular system was approximately two logarithmic units.


CONCLUSIONS
The present investigation shows a competitive inhibition of ET(B) receptor-mediated relaxation in cerebral vessels by clazosentan in therapeutically relevant concentrations. Thus, additional clinical trials should be undertaken to evaluate clazosentan concentrations in cerebrospinal fluid. Furthermore, the present data may be taken to describe the pharmacological properties for an ET receptor antagonist specifically tailored for the treatment of pathological conditions of impaired cerebral blood flow.
Vatter
Hartmut
H
Department of Neurosurgery, Johann Wolfgang Goethe University, Frankfurt am Main. H.Vatter@em.uni-frankfurt.de
Zimmermann
Michael
M
Tesanovic
Veronika
V
Raabe
Andreas
A
Seifert
Volker
V
Schilling
Lothar
L
D000818:Animals; D001488:Basilar Artery / Q000187:drug effects / Q000502:physiology; D004347:Drug Interactions; D065131:Endothelin B Receptor Antagonists; D019332:Endothelin-1 / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D010455:Peptides / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D044023:Receptor, Endothelin B / Q000378:metabolism; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects*; D020301:Vasospasm, Intracranial / Q000188:drug therapy*; D014757:Viper Venoms / Q000494:pharmacology
D065131:Endothelin B Receptor Antagonists; D019332:Endothelin-1; D010455:Peptides; D044023:Receptor, Endothelin B; D014662:Vasoconstrictor Agents; D014757:Viper Venoms; C057354:sarafotoxins s6