Vol. 284, Issue 1, 37-42, 1998

Roles of Extracellular Ca⁺⁺ and Calmodulin in Roxatidine-Stimulated Secretion and Synthesis of Mucus by Cultured Rabbit Gastric Mucosal Cells¹

Satoru Takahashi and Susumu Okabe

Department of Applied Pharmacology, Kyoto Pharmaceutical University, Misasagi, Yamashina, Kyoto, Japan

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.