Cerebrovascular Characterization of the Novel Nonpeptide Endothelin-A Receptor Antagonist LU 208075

Abstract

Enhanced cerebrovascular resistance under pathologic conditions, like cerebral vasospasm after subarachnoid hemorrhage, seems to be caused by the vasocontractile effect of endothelin-1 (ET-1). Therefore, the effect of the novel and ET(A) receptor selective antagonist LU 208075 was characterized by the contraction and relaxation induced by ET-1 and bigET-1 on rat basilar artery. Basilar artery ring segments with (E+) and without (E−) functionally intact endothelium were prepared to measure the isometric force. Concentration–effect curves were constructed by cumulative application of ET-1 or bigET-1 in the presence of LU 208075 (10−7M, 10−6M, and 10−5M). The effect of LU 208075 was determined by the pA2 value. The contraction by ET-1 and bigET-1 was inhibited by LU 208075 in a dose-dependent manner. The pA2 values for ET-1 and for bigET-1 were 6.51 ± 0.39 (E+) and 6.67 ± 0.43 (E−), and 7.03 ± 0.32 (E+) and 7.24 ± 0.31 (E−) respectively. The E(max) values for bigET-1 but not for ET-1 were reduced significantly in the presence of LU 208075. A significant relaxation by ET-1 or bigET-1 was observed only in the presence of LU 208075. This relaxation was inhibited by LU 208075 in higher concentrations, with pA2 values of 5.68 ± 0.05 (ET-1) and 5.50 ± 0.39 (bigET-1). The current data correlate with a competitive inhibition of ET(A) receptor-mediated contraction and relaxation, caused by ET(B) receptor activation on cerebral vessels by LU 208075. The selectivity for the ET(A) receptor was approximately sevenfold. Furthermore, the results may suggest an inhibition of the functional ET-converting enzyme activity by LU 208075.