BMS-180560, AN INSURMOUNTABLE INHIBITOR OF ANGIOTENSIN II-STIMULATED RESPONSES - COMPARISON WITH LOSARTAN AND EXP3174

1 This study compares the activity of BMS-180560 utyl-4-chloro-1-[[1-[ 2-(2H-tetrazol-5-yl)phenyl]-1 H-indol-4-yl]methyl]-1H-imidazole-5-carb oxylic acid), an insurmountable angiotensin II (AII) receptor antagoni st, with that of losartan and EXP3174 in functional and biochemical mo dels of AII-receptor activation. 2 BMS-180560 selectively inhibited [I -125]-Sar(1)Ile(8)AII ([I-125]SI-AII) binding to rat aortic smooth mus cle (RASM) cell and rat adrenal cortical AT(1) receptors (K-i = 7.6 +/ - 1.2 and 18.4 +/- 3.9 nM respectively) compared to adrenal cortical A T(2) receptors (K-i = 37.6 +/- 1.3 mu M). The K-i values of BMS-180560 and EXP3174, but not losartan, varied as a function of the BSA concen tration used in the assays, indicating that the diacid drugs bound to albumin. 3 BMS-180560 (3-300 nM) increased the K-D of SI-AII for RASM cell AT(1) receptors. Only at high concentrations of BMS-180560 (300 n M) were B-max values decreased. 4 BMS-180560 inhibited AII-stimulated contraction of rabbit aorta with a calculated K-B = 0.068 +/- 0.048 nM and decreased maximal AII-stimulated contraction at 1 nM BMS-180560 b y 75%. In the presence of 0.1% BSA, a higher K-B value (5.2 +/- 0.92 n M) was obtained. Losartan behaved as a competitive antagonist with a K -B = 2.6 +/- 0.13 nM. Contraction stimulated by endothelin-1, noradren aline, KCl, or the TXA(2) receptor agonist U-46619 were unaffected by BMS-180560 (1 nM). 5 AII stimulated the acidification rates of RASM ce lls as measured by a Cytosensor microphysiometer with an EC(50) of 18 nM. Losartan (30 nM) shifted the AII concentration-effect curves in a competitive manner whereas BMS-180560 (0.01 and 0.1 nM) decreased the maximum responses by 60 and 75% respectively. Inhibition by losartan a nd BMS-180560 could be reversed following washout although recovery to ok longer for BMS-180560. 6 In [H-3]-myoinositol-labelled RASM cells, losartan (30 and 200 nM), shifted the EC(50)) for AII-stimulated [H-3] -inositol monophosphate formation to higher values, with no change in the maximal response. By contrast, EXP3174 (0.1 to 1 nM) decreased the maximal response in a concentration-dependent manner (17-55%). BMS-18 0560 (3 and 10 nM) increased the EC(50) for AII and decreased the maxi mum response by 30 and 80% respectively. The inhibition by EXP3174 and BMS-180560 could be reversed by inclusion of losartan (200 nM) indica ting that the inhibition was not irreversible. 7 In conclusion, BMS-18 0560 is a potent, specific, predominantly competitive, reversible AII receptor antagonist, which displays insurmountable receptor antagonism . At concentrations of BMS-180560 which have no effect on receptor num ber, BMS-180560 produced insurmountable antagonism of AII-stimulated s econd messenger formation, extracellular acidification, and smooth mus cle contraction.