Abstract
We found that roxatidine stimulates mucus secretion and synthesis by cultured rabbit gastric mucosal cells. In this study, we examined the roles of the extracellular Ca++ and calmodulin in these effects of roxatidine. Reduction of the extracellular Ca++concentration decreased the roxatidine-induced increases in mucus secretion and synthesis by gastric mucosal cells. Roxatidine concentration-dependently promoted Ca++ influx and caused an increase in intracellular Ca++. After the addition of roxatidine, the increases in the secretion and synthesis reflected those in Ca++ influx and intracellular Ca++concentration and then disappeared as Ca++ influx and intracellular Ca++ concentration returned to the control level. The roxatidine-stimulated Ca++ influx and intracellular Ca++ mobilization were abolished by reduction of the extracellular Ca++ concentration. Nifedipine and diltiazem inhibited both the effects of roxatidine, but even at 10 μM, the inhibition was partial. Furthermore, W-7 (a calmodulin antagonist) completely abolished the effects of roxatidine on mucus secretion and synthesis without causing a reduction of the stimulated Ca++ influx. Taken together, these results suggest that roxatidine promotes Ca++ influx through both voltage-sensitive Ca++ channels and other Ca++entry gates and the subsequent intracellular Ca++mobilization, leading to potentiation of mucus secretion and synthesis by rabbit gastric mucosal cells. In addition, Ca++-activated calmodulin may play a pivotal role in these stimulatory effects of roxatidine.
Footnotes
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Send reprint requests to: Satoru Takahashi, Ph.D., Department of Applied Pharmacology, Kyoto Pharmaceutical University, Misasagi, Yamashina, Kyoto 607, Japan.
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↵1 This research was supported by a grant from the Ministry of Education, Science, Sports and Culture of Japan (Grant-in-Aid for Encouragement of Young Scientists #08772122).
- Abbreviations:
- PBS
- Dulbecco’s modified Ca++, Mg++-free phosphate-buffered saline
- MTT
- 3-(4, 5-dimethyl-2-thiazoyl)-2, 5-diphenyl-2H-tetrazolium bromide
- W-7
- N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide
- Received April 28, 1997.
- Accepted September 30, 1997.
- The American Society for Pharmacology and Experimental Therapeutics
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