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.
Subject(s)
Cerebral Arteries/drug effects , Endothelin A Receptor Antagonists , Endothelin B Receptor Antagonists , Oligopeptides/pharmacology , Vasoconstriction/drug effects , Animals , Basilar Artery/drug effects , Basilar Artery/physiology , Cerebral Arteries/physiology , Dose-Response Relationship, Drug , In Vitro Techniques , Male , Rats , Rats, Sprague-Dawley , Receptor, Endothelin A/physiology , Receptor, Endothelin B/physiology , Vasoconstriction/physiologyABSTRACT
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(-7)M, 10(-6)M, and 10(-5)M). The effect of LU 208075 was determined by the pA(2) value. The contraction by ET-1 and bigET-1 was inhibited by LU 208075 in a dose-dependent manner. The pA(2) 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 pA(2) 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.
Subject(s)
Cerebral Arteries/drug effects , Endothelin Receptor Antagonists , Phenylpropionates/pharmacology , Animals , Basilar Artery/drug effects , Basilar Artery/physiology , Cerebral Arteries/physiology , Dose-Response Relationship, Drug , Humans , In Vitro Techniques , Male , Pyridazines , Rats , Rats, Sprague-Dawley , Receptor, Endothelin A , Receptors, Endothelin/physiology , Vasoconstriction/drug effects , Vasoconstriction/physiology , Vasodilation/drug effects , Vasodilation/physiologyABSTRACT
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.
