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BMS‐180560, an insurmountable inhibitor of angiotensin II‐stimulated responses: comparison with losartan and EXP3174
Author(s) -
Dickinson K.E.J.,
Cohen R.B.,
Skwish S.,
Delaney C.L.,
Serafino R.P.,
Poss M.A.,
Gu Z.,
Ryono D.E.,
Moreland S.,
Powell J.R.
Publication year - 1994
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1994.tb16191.x
Subject(s) - losartan , angiotensin ii , chemistry , medicine , endocrinology , angiotensin ii receptor type 1 , receptor , agonist , contraction (grammar) , antagonist , receptor antagonist , biochemistry
1 This study compares the activity of BMS‐180560 (2‐butyl‐4‐chloro‐1‐[[1‐[2‐(2H‐tetrazol‐5‐yl)phenyl]‐1H‐indol‐4‐yl]methyl]‐1H‐imidazole‐5‐carboxylic acid), an insurmountable angiotensin II (AII) receptor antagonist, with that of losartan and EXP3174 in functional and biochemical models of AII‐receptor activation. 2 BMS‐180560 selectively inhibited [ 125 I]‐Sar 1 Ile 8 AII ([ 125 I]SI‐AII) binding to rat aortic smooth muscle (RASM) cell and rat adrenal cortical AT 1 receptors ( K i = 7.6 ± 1.2 and 18.4 ± 3.9 n m respectively) compared to adrenal cortical AT 2 receptors ( K i = 37.6 ± 1.3 μ m ). The K i values of BMS‐180560 and EXP3174, but not losartan, varied as a function of the BSA concentration used in the assays, indicating that the diacid drugs bound to albumin. 3 BMS‐180560 (3–300 n m ) 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 n m and decreased maximal AII‐stimulated contraction at 1 n m BMS‐180560 by 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 n m . Contraction stimulated by endothelin‐1, noradrenaline, KC1, or the TXA 2 receptor agonist U‐46619 were unaffected by BMS‐180560 (1 n m ). 5 All stimulated the acidification rates of RASM cells as measured by a Cytosensor microphysiometer with an EC 50 of 18 n m . Losartan (30 n m ) shifted the AII concentration‐effect curves in a competitive manner whereas BMS‐180560 (0.01 and 0.1 n m ) decreased the maximum responses by 60 and 75% respectively. Inhibition by losartan and BMS‐180560 could be reversed following washout although recovery took longer for BMS‐180560. 6 In [ 3 H]‐myoinositol‐labelled RASM cells, losartan (30 and 200 n m ), shifted the EC 50 for AII‐stimulated [ 3 H]‐inositol monophosphate formation to higher values, with no change in the maximal response. By contrast, EXP3174 (0.1 to 1 n m ) decreased the maximal response in a concentration‐dependent manner (17–55%). BMS‐180560 (3 and 10 n m ) increased the EC 50 for AII and decreased the maximum response by 30 and 80% respectively. The inhibition by EXP3174 and BMS‐180560 could be reversed by inclusion of losartan (200 n m ) indicating that the inhibition was not irreversible. 7 In conclusion, BMS‐180560 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 number, BMS‐180560 produced insurmountable antagonism of AII‐stimulated second messenger formation, extracellular acidification, and smooth muscle contraction.