ICI 125,211: A new gastric antisecretory agent acting on histamine H2-receptors

The isolated stomach preparation of the mouse: a physiological unit for pharmacological analysis

“…In this study, therefore, basal secretion was recorded for 120 min at which time tiotidine (10-4M) was added to the organ bath and secretion recorded for a further 60 min. Tiotidine was chosen due to its classification as a highly selective histamine H2-receptor antagonist (Yellin et al, 1979) with a pKB of 7.57 . Concentrations of 104 M, more than 3,000 x greater than the KB, had no effect on the noradrenaline interaction with ,Breceptors in the guinea-pig right atrium or on the effects of histamine (HI), acetylcholine (muscarinic) or 5-hydroxytryptamine (5-HT2) on guinea-pig ileum (Yellin et al, 1979).…”

“…Tiotidine was chosen due to its classification as a highly selective histamine H2-receptor antagonist (Yellin et al, 1979) with a pKB of 7.57 . Concentrations of 104 M, more than 3,000 x greater than the KB, had no effect on the noradrenaline interaction with ,Breceptors in the guinea-pig right atrium or on the effects of histamine (HI), acetylcholine (muscarinic) or 5-hydroxytryptamine (5-HT2) on guinea-pig ileum (Yellin et al, 1979). In the present experiments, tiotidine had no effect on basal acid secretion at 120min from stomachs with 12cmH2O or 18 cmH2O intragastric pressures from fed or fasted mice (Figure la,b (Figure 1 a) and from stomachs with 12 cmH2O intragastric pressure from fed mice ( Figure Ib) did not show the initial high rate observed from stomachs with 18 cmH2O intragastric pressure from fed mice.…”

INHIBITION BY THE TETRAMINE DISULPHIDE, BENEXTRAMINE, OF CARDIAC CHRONOTROPIC HISTAMINE H2‐RECEPTOR‐MEDIATED EFFECTS

“…The resulting disulphide bond between (Steinberg & Holland, 1975;Wilson & Broadley, 1980) it slightly potentiates the inotropic effect of histamine on the guineapig left atrium (Figure 1). The competitive H2-receptor blocking drug, cimetidine, antagonizes chronotropic effects of histamine with KB values ranging between 0.21 pM and 0.79 fAM (Brimblecombe, Duncan, Durant, Ganellin, Parsons & Black, 1975;Bradshaw, Brittain, Clitherow, Daly, Jack, Price & Stables, 1979;Yellin, Buck, Gilman, Jones & Wardleworth, 1979;McCulloch, Medgett & Rand, 1979 Unlike cimetidine, benextramine not only shifted the histamine log dose-response curve but also depressed its maximum. The same occurred when benextramine antagonized the noradrenaline effect in the rabbit aorta (Melchiorre et aL, 1978) and the phenylephrine effect in the rabbit atrium (Benfey et aL, 1980), and when the 3-haloalkylamine dibenamine antagonized the adrenaline effect in the rabbit aorta (Furchgott, 1955).…”

The binding of [3H]‐tiotidine to homogenates of guinea‐pig lung parenchyma

“…All of the competition curves were clearly biphasic: a typical example using the H2-antagonist, burimamide, being shown in Figure 5. For each H2-compound, the first phase -3 displacement was studied in detail as this was taken to represent displacement of [3H]-tiotidine from the H2-receptor, occurring over the pharmacologically active concentration range of each competing H2-compound (Black et al, 1972;Black et al, 1973;Brimblecombe et al, 1975;Yellin et al, 1979;Bradshaw et al, 1979;Gajtkowski et al, 1983). Figure 6 shows the first phase displacement of bound [3H]-tiotidine by histamine, burimamide and YMI 1 170, a selective antagonist at histamine H2-receptors (Takeda et al, 1982 (Gajtkowski et al, 1983 (Burkard, 1978;Kendall et al, 1980), where it was later realized that (3H]-cimetidine was in fact labelling an imidazole recognition site which was completely unrelated to the pharmacological receptor (Rising et al, 1980;Smith et al, 1980).…”

“…More recently, results from work with [3H]-cimetidine have suggested a high affinity binding site for this ligand which is unrelated to the pharmacological receptor, but which recognizes the imidazole moiety of this compound (Rising et al, 1980;Smith et al, 1980). [3H]-tiotidine is a more potent H2-antagonist than either ranitidine or cimetidine (Yellin et al, 1979) and has recently been shown to meet the criteria for labelling the H2-receptor in membranes from the guinea-pig cerebral cortex (Gajtkowski et al, 1983).…”