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

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 pKb value and the shift between the CECs. PD 142893 inhibited the contraction by ET-1 and bigET-1. The pKb-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.