Cerebrovascular characterization of the novel nonpeptide endothelin-A receptor antagonist XXXX .

@entity510 @entity1827 @entity35 @entity2553 @entity15940
Enhanced cerebrovascular resistance under pathologic conditions, like @entity2553 after @entity510 , seems to be caused by the vasocontractile effect of @entity1827 ( @entity1827 ). Therefore, the effect of the novel and ET(A) receptor selective antagonist @entity15940 was characterized by the contraction and relaxation induced by @entity1827 and bigET-1 on @entity35 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 @entity1827 or bigET-1 in the presence of @entity15940 (10(-7)M, 10(-6)M, and 10(-5)M). The effect of @entity15940 was determined by the pA(2) value. The contraction by @entity1827 and bigET-1 was inhibited by @entity15940 in a dose-dependent manner. The pA(2) values for @entity1827 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 @entity1827 were reduced significantly in the presence of @entity15940 . A significant relaxation by @entity1827 or bigET-1 was observed only in the presence of @entity15940 . This relaxation was inhibited by @entity15940 in higher concentrations, with pA(2) values of 5.68 +/- 0.05 ( @entity1827 ) 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 @entity15940 . 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 @entity15940 .
