inositol-1-4-5-trisphosphate and Esophagitis

We previously showed that lower esophageal spincter (LES) tone depends on spontaneous production of inositol 1,4,5-trisphosphate (IP3) and release of intracellular Ca2+ and that acute experimental esophagitis reduces LES tone and IP3 production, suggesting damage to mechanisms responsible for release of Ca2+ from intracellular stores. In the present investigation, we examined the possibility that mechanisms responsible for Ca2+ storage or uptake may also be damaged. LES circular muscle cells were isolated by enzymatic digestion. Contraction was measured in response to IP3 and thapsigargin, which enhances release of Ca2+ from intracellular stores, and in response to calmodulin and to diacylglycerol. In addition, normal cells were incubated in thapsigargin to assess the effect of depletion of intracellular Ca2+ stores on contractile response. Contraction in response to IP3 and thapsigargin was reduced in experimental esophagitis, but contraction in response to calmodulin or diacylglycerol was not. Acetylcholine (ACh)-induced contraction of normal cells was inhibited by the calmodulin antagonist CGS-9343B but not by 1-(5-isoquinolinesulfonyl)-2-methyl-piperazine dihydrochloride (H-7). In contrast, in cells from animals with esophagitis or in thapsigargin-treated cells from normal animals, ACh-induced contraction was inhibited by H-7 and not by CGS-9343B. We conclude that experimental esophagitis may damage intracellular Ca2+ stores in the LES and change the intracellular contractile pathways activated by ACh from calmodulin dependent in normal cells to protein kinase C dependent in esophagitis.

Topics: 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; Acetylcholine; Analysis of Variance; Animals; Benzimidazoles; Calcium; Calmodulin; Cats; Diglycerides; Esophagitis; Esophagogastric Junction; Female; In Vitro Techniques; Inositol 1,4,5-Trisphosphate; Kinetics; Male; Muscle Contraction; Muscle, Smooth; Thapsigargin; Time Factors