Bismuth subsalicylate increases intracellular Ca²⁺, MAP-kinase activity, and cell proliferation in normal human gastric mucous epithelial cells

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⁺ [Ca ²⁺]_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 [Ca ²⁺]_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.