Reversible inhibition of rat gastric H+/K+-ATPase by T-330, 2-[2-dimethylaminobenzyl)sulfinyl]-1-(3-methylpyridine-2-yl)imidazole.
The effect of 2-[(2-dimethylaminobenzyl)sulfinyl]-1-(3-methylpyridine-2-yl)imidazole (T-330), on rat gastric H+/K+-ATPase was studied in vitro and in vivo in comparison with the irreversible proton pump inhibitor omeprazole. T-330 and omeprazole inhibited rat gastric H+/K+-ATPase at pH 6.1, and their IC50 values were 75 microM and 4.6 microM, respectively. Recovery from the T-330-inhibited H+K/+-AtPase activity was effected by beta-mercaptoethanol at concentrations above 10 microM, whereas significant recovery from the inhibition by omeprazole required 100 mM. When intraduodenally administered, T-330 (0.6-10 mg/kg) induced a more potent yet shorter-lasting inhibition of both gastric H+/K+ -ATPase activity and gastric acid secretion than did omeprazole (2.5-40 mg/kg). Recovery of the gastric H+/K+-ATPase activity depressed by omeprazole was completely blocked by an inhibitor of protein synthesis, cycloheximide, whereas that by T-330 was not prevented. This indicates that restoration of the enzyme activity after inhibition in vivo by T-330 does not require de novo synthesis of the enzyme in contrast to inhibition by omeprazole. beta-Mercaptoethanol (1 mM) fully restored the H+/K+-ATPase activity inhibited in vivo by T-330 but not by omeprazole. These observations indicate that T-330 reversibly inhibits gastric H+/K+-ATPase, resulting in a short-lasting antisecretory effect, and that the sulfhydryl groups of the enzyme are involved in the action of T-330.
Kinoshita
M
M
Department of Pharmacology, Pharmaceutical Development Research Laboratory, Tanabe Seiyaku Co., Ltd., Saitama, Japan.
Saito
N
N
Noto
T
T
Tamaki
H
H
D000818:Animals; D003513:Cycloheximide / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005744:Gastric Acid / Q000378:metabolism; D005753:Gastric Mucosa / Q000187:drug effects* / Q000201:enzymology; D007093:Imidazoles / Q000494:pharmacology*; D008297:Male; D008623:Mercaptoethanol / Q000494:pharmacology; D009853:Omeprazole / Q000494:pharmacology; D054328:Proton Pump Inhibitors; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
D004791:Enzyme Inhibitors; D007093:Imidazoles; D054328:Proton Pump Inhibitors; D011725:Pyridines; C099138:T 330; D008623:Mercaptoethanol; D003513:Cycloheximide; D009853:Omeprazole