The gastric H,K-ATPase blocker lansoprazole is an inhibitor of chloride channels.
1. It was postulated that swelling dependent chloride channels are involved in the proton secretion of parietal cells. Since omeprazole, lansoprazole and its acid activated sulphenamide form AG2000 are structurally related to phenol derivatives known to block swelling dependent chloride channels, we set out to test, whether these substances--which are known to block the H,K-ATPase--could also lead to an inhibition of swelling-dependent chloride channels. Swelling-dependent chloride channels--characterized in many different cell types--show highly conserved biophysical and pharmacological features, therefore we investigated the effect of omeprazole, lansoprazole and its acid activated sulphenamide form AG2000 on swelling-dependent chloride channels elicited in fibroblasts, after the reduction of the extracellular osmolarity. 2. Omeprazole, lansoprazole and its acid activated sulphenamide form AG2000 are able to block swelling-dependent chloride channels (IClswell). 3. Lansoprazole and its protonated metabolite AG2000 act on at least two different sites of the IClswell protein: on an extracellular site which seems to be in a functional proximity to the nucleotide binding site, and on an intracellular site which allows the formation of disulfide-bridges. 4. The inhibition of the proton pump and the simultaneous blocking of chloride channels by omeprazole, lansoprazole and its acid activated sulphenamide form AG2000, as described here could be an effective mode to restrict proton secretion in parietal cells.
Schmarda
A
A
Department of Physiology, University of Innsbruck, Austria.
Dinkhauser
P
P
Gschwentner
M
M
Ritter
M
M
Fürst
J
J
Scandella
E
E
Wöll
E
E
Laich
A
A
Rossmann
H
H
Seidler
U
U
Lang
F
F
Paulmichl
M
M
D053799:2-Pyridinylmethylsulfinylbenzimidazoles; D016475:3T3 Cells; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology; D048429:Cell Size / Q000187:drug effects / Q000502:physiology; D018118:Chloride Channels / Q000037:antagonists & inhibitors*; D004229:Dithiothreitol / Q000494:pharmacology; D004594:Electrophysiology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005347:Fibroblasts; D064747:Lansoprazole; D051379:Mice; D009853:Omeprazole / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000494:pharmacology; D054328:Proton Pump Inhibitors; D011725:Pyridines / Q000494:pharmacology; D013270:Stomach / Q000187:drug effects / Q000201:enzymology*; D013439:Sulfhydryl Reagents / Q000494:pharmacology; D013942:Thymine Nucleotides / Q000494:pharmacology
D053799:2-Pyridinylmethylsulfinylbenzimidazoles; D001562:Benzimidazoles; D018118:Chloride Channels; D004791:Enzyme Inhibitors; D054328:Proton Pump Inhibitors; D011725:Pyridines; D013439:Sulfhydryl Reagents; D013942:Thymine Nucleotides; D064747:Lansoprazole; C058689:AG 2000; C027923:thymidine 5'-diphosphate; D009853:Omeprazole; D004229:Dithiothreitol