title: Bismuth subsalicylate increases intracellular Ca2+, MAP-kinase activity, and cell proliferation in normal human gastric mucous epithelial cells.
abstract: Clinical and laboratory studies have shown that bismuth subsalicylate (BSS) is helpful in the healing of gastric ulcers because of the bactericidal effects of bismuth (Bi3+) on H. pylori. Bismuth or BSS has also been reported to possess other nonbactericidal or "gastroprotective" effects in the stomach. It is known in other cell types that the effects of extracellular divalent or trivalent cations (e.g., Ca2+) can activate a plasma membrane-bound calcium-sensing receptor (CaSR). In a previous study, we found the existence of a CaSR which was activated by extracellular Ca2+ and found to increase intracellular Ca2+ [Ca2+]i, MAP-kinase activity, and gastric epithelial cell proliferation. In the present study, we were interested in determining whether the effects of the trivalent cation Bi3+ (in the form of BSS) on [Ca2+]i, MAP-kinase activity, and proliferation of gastric cells. We found that BSS dose dependently increased [Ca2+]i, p44/p42 and p38 MAP-kinase activites, and gastric mucous epithelial cell growth. The addition of BAPTA to chelate intracellular Ca2+ blocked BSS-induced p44/p42 MAP-kinase activities but not p38 MAP-kinase activity. The p44/p42 MAP-kinase inhibitor PD98059 and the p38 MAP-kinase inhibitor SB203580 dose dependently decreased gastric mucous cell growth over a 24 hr. All of the BSS-induced changes in [Ca2+]i, MAP-kinase activity, and gastric cell proliferation could be reproduced with the CaSR-agonist gadolinium (Gd3+). Our data suggest that BSS may possess additional novel effects by increasing gastric mucous epithelial cell growth through a Ca2+/MAP-kinase-dependent pathway.
authors.affiliation: Department of Surgery, Oregon Health and Science University, Portland, Oregon 97201, USA.
authors.forename: Jason
authors.initials: J
authors.lastname: Gilster
authors.forename: Kathy
authors.initials: K
authors.lastname: Bacon
authors.forename: Katie
authors.initials: K
authors.lastname: Marlink
authors.forename: Brett
authors.initials: B
authors.lastname: Sheppard
authors.forename: Clifford
authors.initials: C
authors.lastname: Deveney
authors.forename: Michael
authors.initials: M
authors.lastname: Rutten
mesh_terms: D000085:Acetates / Q000494:pharmacology; D001729:Bismuth / Q000494:pharmacology*; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism / Q000502:physiology*; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000502:physiology; D002455:Cell Division / Q000502:physiology; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004847:Epithelial Cells / Q000502:physiology; D005419:Flavonoids / Q000494:pharmacology; D005753:Gastric Mucosa / Q000166:cytology / Q000187:drug effects*; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009942:Organometallic Compounds / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology; D044169:Receptors, Calcium-Sensing / Q000037:antagonists & inhibitors / Q000502:physiology; D012459:Salicylates / Q000494:pharmacology*; D015398:Signal Transduction / Q000502:physiology; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: D000085:Acetates; D004791:Enzyme Inhibitors; D005419:Flavonoids; D007093:Imidazoles; D009942:Organometallic Compounds; D011725:Pyridines; D044169:Receptors, Calcium-Sensing; D012459:Salicylates; C060927:gadolinium (+3) acetate; C015715:bismuth subsalicylate; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one; D002118:Calcium; D001729:Bismuth