Characterization of the potent combined endothelin(A/B)-antagonist PD 142893 on cerebral vessels

Neurol Res. 2004 Sep;26(6):692-7. doi: 10.1179/016164104225015967.

Abstract

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.

Publication types

  • Comparative Study

MeSH terms

  • Animals
  • Basilar Artery / drug effects
  • Basilar Artery / physiology
  • Cerebral Arteries / drug effects*
  • Cerebral Arteries / physiology
  • Dose-Response Relationship, Drug
  • Endothelin A Receptor Antagonists*
  • Endothelin B Receptor Antagonists*
  • In Vitro Techniques
  • Male
  • Oligopeptides / pharmacology*
  • Rats
  • Rats, Sprague-Dawley
  • Receptor, Endothelin A / physiology
  • Receptor, Endothelin B / physiology
  • Vasoconstriction / drug effects*
  • Vasoconstriction / physiology

Substances

  • Endothelin A Receptor Antagonists
  • Endothelin B Receptor Antagonists
  • Oligopeptides
  • Receptor, Endothelin A
  • Receptor, Endothelin B
  • PD 142893