Increased levels of endothelin (ET)-1 and bigET-1 may be responsible for enhanced cerebroarterial resistance under pathologic conditions. Therefore, the effect of LU 208075, a novel ET(A)-selective receptor antagonist was determined. The aim of the study was to investigate in vitro the inhibitory effect of LU 208075 on ET-1 and bigET-1 induced contraction and relaxation in rat basilar artery segments. Segments with (E+) and without (E-) endothelium were prepared for the measurement of isometric force. Concentration-effect curves (CECs) were constructed by cumulative application of ET-1 or bigET-1. The shift of the CECs in the presence of LU 208075 against the control curve was determined. Relaxation was investigated on precontracted segments, calculated in percentage decrease of precontraction and compared by the pD(2) and E(max). ET-1 and bigET-1 induced contraction was dose dependently inhibited by LU 208075. Shifts of the CECs in the presence of LU 208075 (10(-6) M and 10(-5) M) were for ET-1 (1) in E+: 4.4 and 19.7; (2) in E-: 8.1 and 60.4 and for bigET-1 (3) in E+: 10.8 and (4) in E-: 26.0 respectively. LU 208075 (10(-5) M) completely inhibited bigET-1-induced contraction. Relaxation by ET-1 or bigE-1 was only observed in the presence of LU 208075. CECs were shifted to the right by LU 208075 (10(-5) M) by a factor of 24 (ET-1) and 4.5 (bigET-1). E(max) values were 45+/-18% and 51+/-15% (ET-1; in the presence of 10(-5) and 10(-6) M LU 208075 respectively), and 56+/-20% and 49+/-17% (bigET-1; in the presence of 10(-5) and 10(-6) M LU 208075 respectively). The data suggests a competitive ET(A)-receptor inhibition by LU 208075. The enhanced inhibitory effect on bigET-1-induced contraction could indicate an additional inhibitory effect on endothelin-converting enzyme activity. The pronounced effect on E-vessels and the inhibition of relaxation may suggest an ET(B) receptor affinity.
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