Experimental esophagitis affects intracellular calcium stores in the cat lower esophageal sphincter.
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.
Rich
H
H
Department of Medicine, Veterans Administration Medical Center, Providence, Rhode Island, USA.
Sohn
U D
UD
Behar
J
J
Kim
N
N
Biancani
P
P
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000494:pharmacology; D000109:Acetylcholine / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D002147:Calmodulin / Q000037:antagonists & inhibitors / Q000494:pharmacology; D002415:Cats; D004075:Diglycerides / Q000494:pharmacology; D004941:Esophagitis / Q000503:physiopathology*; D004943:Esophagogastric Junction / Q000187:drug effects / Q000502:physiology / Q000503:physiopathology*; D005260:Female; D066298:In Vitro Techniques; D015544:Inositol 1,4,5-Trisphosphate / Q000494:pharmacology; D007700:Kinetics; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology / Q000503:physiopathology*; D019284:Thapsigargin / Q000494:pharmacology; D013997:Time Factors
D001562:Benzimidazoles; D002147:Calmodulin; D004075:Diglycerides; C044295:1,2-dioctanoylglycerol; C052087:CGS 9343B; D019284:Thapsigargin; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D015544:Inositol 1,4,5-Trisphosphate; D000109:Acetylcholine; D002118:Calcium