SCH 28080: A Potent Inhibitor of Gastric H⁺, K⁺–ATPase

Prod. No. S 4443

Parietal cells (gastric acid (HCl) secreting cells) are present in the stomach and ilium and regulate the secretion of highly concentrated HCl into the lumen. They also recruit and recycle the transport protein H⁺,K⁺-ATPase, the primary gastric proton pump. An overactive pump may lead to ulcers and other problems; therefore, inhibiting an overactive pump is a major target for researchers. Several compounds have been shown to effectively inhibit this pump, including omeprazole (Prod. No. O-104) and the histamine H2 receptor antagonists cimetidine (Prod. No. C4522), ranitidine (Prod. No. R-101), famotidine (Prod. No. F6889) and nizatidine (Prod. No. N7035). Omeprazole, however, binds irreversibly, thus blocking acid secretion, leading to anacidity, hyperplasia and hypergastremia¹.

Sigma-RBI now offers SCH 28080 (Prod. No. S4443), a potent, reversible inhibitor of gastric H⁺,K⁺-ATPase, which competitively binds to the luminal K⁺ high affinity site of H⁺,K⁺-ATPase. SCH-28080 does not inhibit Na⁺,K⁺-ATPase. In addition, SCH-28080 inhibits renal ouabain-insensitive H⁺,K⁺-ATPase, but not colonic ouabain-sensitive H⁺, K⁺-ATPase.² The inhibition of ATPase activity by ouabain (Prod. No. O3125) has been widely used as a marker of Na+ pump activity in vitro, while inhibition by SCH-28080 has been used as a marker of H⁺-K⁺-ATPase activity³, as the binding sites for these compounds have only been found on one or the other of the ATPases. The binding site of SCH 28080 is located in the gastric H⁺,K⁺-ATPase a-subunit, in the first extracellular loop between the M1 and M2 transmembrane segments², although further details are still being elucidated. ^4,5

SCH 28080 has been shown to possess both antisecretory and cytoprotective activities. The antisecretory ED₅₀ values obtained in the pylorus-ligated rat were 3.7 mg/kg p.o. and 2.8 mg/kg i.p., which were 7 and 10 times more potent than cimetidine (Prod. No. C4522), respectively. In rats, the compound's cytoprotective activity was demonstrated by inhibition of ethanol-induced gastric lesions in a dose-dependent manner (ED₅₀: 3.0 mg/kg p.o.)⁶. In addition, SCH 28080 (1-30 mg/kg p.o. in rats) inhibited gastric ulcers provoked by aspirin, aspirin plus acid, indomethacin and stress⁶.

Clearly, SCH 28080 will continue to be an indispensable tool for the study of gastric secretion and the X⁺,K⁺-ATPases.

References

1. Shamburek, R.D. and Schubert, M.L., Gastrenterol. Clin. North Am., 21, 527-550 (1992).
2. Asano, S., et al., J. Biol. Chem., 272, 17668-17674 (1997).
3. Codina, J., et al., Am. J. Physiol. Cell Physiol., 279, C1319-C1326 (2000).
4. Farley, R.A., et al., J. Biol. Chem., 276, 2608-2615 (2001).
5. Asano, S., et al., J. Biol. Chem., Published online ahead of printing Dec 29, 2003, www.jbc.org.
6. Long, J.F., et al., J. Pharmacol. Exp. Ther., 114-20 (1983).

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