Characterization of the potent combined endothelin(A/B)-antagonist PD 142893 on cerebral vessels.
A disturbed balance between endothelin (ET)-1 and nitric oxide (NO) seems to play a key role in the development of delayed cerebral vasospasm following subarachnoidal hemorrhage. Therefore, the effect of PD 142893 one of the first potent ET(A)- and ET(B)-receptor antagonists was characterized on the contraction and relaxation induced by ET-1 and bigET-1 on rat basilar artery (BA). Concentration-effect curves (CECs) were constructed by cumulative application of ET-1 or big ET-1 on BA ring segments with (E+) and without (E-) functionally intact endothelium. The effect of PD 142893 was determined by the modified pK(b) value and the shift between the CECs. PD 142893 inhibited the contraction by ET-1 and bigET-1. The pK(b)-values were for ET-1: 5.17 (E+) and 5.15 (E-) and for big ET-1: 5.34 (E+) and 5.57 (E-), respectively. A significant relaxation of pre-contracted segments by ET-1 or big ET-1 was neither observed in the presence nor in the absence of the receptor antagonist. The present data suggest a competitive inhibition of the ET(A)-receptor mediated contraction of cerebral arteries by PD 142893. The ET(B)-dependent relaxation of the cerebrovasculature is inhibited by PD 142893 at least in a comparable amount of contraction.
Zimmermann
Michael
M
Department of Neurosurgery, Johann Wolfgang Goethe-University, Frankfurt, Germany. Michael.Zimmermann@em.uni-frankfurt.de
Vatter
Hartmut
H
Weyrauch
Edda
E
Lange
Bettina N
BN
Krishnan
René
R
Raabe
Andreas
A
Seifert
Volker
V
D000818:Animals; D001488:Basilar Artery / Q000187:drug effects / Q000502:physiology; D002536:Cerebral Arteries / Q000187:drug effects* / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D065130:Endothelin A Receptor Antagonists; D065131:Endothelin B Receptor Antagonists; D066298:In Vitro Techniques; D008297:Male; D009842:Oligopeptides / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D044022:Receptor, Endothelin A / Q000502:physiology; D044023:Receptor, Endothelin B / Q000502:physiology; D014661:Vasoconstriction / Q000187:drug effects* / Q000502:physiology
D065130:Endothelin A Receptor Antagonists; D065131:Endothelin B Receptor Antagonists; D009842:Oligopeptides; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; C076213:PD 142893