title: The inhibitory effect of HOE 731 in isolated rabbit gastric glands.
abstract: HOE 731, a substituted thienoimidazole derivative, was studied on [14C] aminopyrine uptake and oxygen consumption in isolated rabbit gastric glands. HOE 731 caused a concentration-dependent inhibition of [14C]aminopyrine uptake during histamine and dbcAMP stimulation. The inhibition during dbcAMP stimulation was in accordance with its proton-pump inhibiting properties, which has already been reported. (Herling et al., Gastroenterology 96: A206, 1989). IC50 values were during histamine stimulation 0.8 +/- 0.3 microM and during dbcAMP stimulation 1.3 +/- 0.4 microM. The inhibition was reversible after addition of dithioerythritol and was of a non-competitive type. Omeprazole caused similar inhibitory effects in the same concentration-range. During time-course studies in glands, the inhibitory effect on [14C]aminopyrine uptake of 0.1 microM HOE 731 already appeared after 10 min of incubation but decreased with increasing incubation time, while 0.1 microM omeprazole caused an unchanged inhibition which started after 30 min of incubation. The concentration of 3 microM of HOE 731 and omeprazole caused a comparable constant inhibition. After pre-incubation for 135 min under basal conditions with subsequent stimulation of the glands with dbcAMP, the inhibitory effect of 10 microM HOE 731 also decreased in contrast to omeprazole. During stimulation for 4 hr, the inhibition of both compounds remained constant. In oxygen consumption studies HOE 731, at 100 microM, caused a strong inhibition down to basal values. This inhibitory effect could be prevented totally when 10 mM imidazole was added to neutralize the acidic compartment of the parietal cell during stimulation. It is concluded that HOE 731 needs acid-activation like omeprazole to inhibit the proton pump, but probably due to its chemical differences (stability, pH for conversion of HOE 731 to its active form) it shows a different inhibitory profile (faster transformation into its active moiety with faster onset of a partially reversible inhibition) as compared to omeprazole.
authors.affiliation: HOECHST AG, Frankfurt/Main Federal Republic of Germany.
authors.forename: A W
authors.initials: AW
authors.lastname: Herling
authors.forename: M
authors.initials: M
authors.lastname: Becht
authors.forename: H J
authors.initials: HJ
authors.lastname: Lang
authors.forename: K H
authors.initials: KH
authors.lastname: Scheunemann
authors.forename: K
authors.initials: K
authors.lastname: Weidmann
authors.forename: T
authors.initials: T
authors.lastname: Scholl
authors.forename: R
authors.initials: R
authors.lastname: Rippel
mesh_terms: D000249:Adenosine Monophosphate / Q000031:analogs & derivatives; D000251:Adenosine Triphosphatases / Q000037:antagonists & inhibitors; D000632:Aminopyrine / Q000378:metabolism; D000818:Animals; D004226:Dithioerythritol; D005744:Gastric Acid / Q000378:metabolism*; D005753:Gastric Mucosa / Q000187:drug effects* / Q000378:metabolism; D017506:H(+)-K(+)-Exchanging ATPase; D007093:Imidazoles / Q000494:pharmacology*; D066298:In Vitro Techniques; D009853:Omeprazole / Q000494:pharmacology; D010101:Oxygen Consumption; D011817:Rabbits
chemical_list: D007093:Imidazoles; D000632:Aminopyrine; D000249:Adenosine Monophosphate; D004226:Dithioerythritol; D000251:Adenosine Triphosphatases; D017506:H(+)-K(+)-Exchanging ATPase; D009853:Omeprazole