THE KININ B-1 RECEPTOR ANTAGONIST DES-ARG(9)-[LEU(8)]BRADYKININ - AN ANTAGONIST OF THE ANGIOTENSIN AT(1) RECEPTOR WHICH ALSO BINDS TO THE AT(2) RECEPTOR

1 Agonists and antagonists of kinin B-1 and B-2 receptors were evaluat ed in vitro for their effects against angiotensin II (AII)-induced con tractile responses in the rabbit aorta and for their binding propertie s to angiotensin AT(1) and AT(2) receptors from purified membrane of r at liver and lamb uterus respectively. 2 In aortic rings, the kinin B- 1 receptor antagonist, des-Arg(9)-[leu(8)]bradykinin (BK) (3-100 mu M) caused a concentration-dependent decrease in sensitivity and a depres sion of the maximum response to AII. Des-Arg(10)-[Leu(9)]kallidin (KD) , des-Arg(9)-BK, des-Arg(10)-KD, BK or KD at 3 mu M had no effect agai nst AII-induced contractions. 3 Des-Arg(9)-[Leu(8)]BK (3 or 100 mu M) did not affect contractions of aortic rings to histamine, potassium ch loride, endothelin-1, 5-hydroxytryptamine, noradrenaline and the throm boxane A(2)-mimetic, U46619. 4 Des-Arg(9)-[Leu(8)]BK displaced [I-125] -Sar(1)-AII binding to the AT(1) subtype in rat liver membranes with a K-i value of 1.1 +/- 0.4 mu M. Values of K-i for des-Arg(9)-BK and KD were 45 +/- 13 mu M and 25 +/- 22 mu M, respectively. The other kinin derivatives des-Arg(10)-KD, BK and des-Arg(10)-[Leu(9)]KD at concentr ations up to 100 mu M did not bind to the AT(1) receptor. 5 All the ki nin derivatives except BK bound to AT(2) receptors in lamb uterus memb ranes. Values of K-i for des-Arg(9)-[Leu(8)]BK, des-Arg(10)-[Leu(9)]KD , des-Arg(9)-BK, des-Arg(10)-KD and KD were 0.3 +/- 0.1, 0.7 +/- 0.1, 1.2 +/- 0.3, 1.5 +/- 0.3 and 7.0 +/- 1.6 mu M, respectively. 6 In conc lusion, des-Arg(9)-[Leu(8)]BK is an insurmountable antagonist of AII-i nduced contractions in the rabbit aorta and also binds with a relative ly high affinity to AT(1) and AT(2) receptors in isolated membrane fra ctions. These additional properties of des-Arg(9)-[Leu(8)]BK should be considered when it is used as an antagonist to characterize kinin B-1 receptors.