Abstract
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.
JPET articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|