Protective effect of melatonin on Ca2+ homeostasis and contractility in acute cholecystitis.
Impaired Ca2+ homeostasis and smooth muscle contractility co-exist in acute cholecystitis (AC) leading to gallbladder dysfunction. There is no pharmacological treatment for this pathological condition. Our aim was to evaluate the effects of melatonin treatment on Ca2+ signaling pathways and contractility altered by cholecystitis. [Ca2+]i was determined by epifluorescence microscopy in fura-2 loaded isolated gallbladder smooth muscle cells, and isometric tension was recorded from gallbladder muscle strips. Malondialdehyde (MDA) and reduced glutathione (GSH) contents were determined by spectrophotometry and cycloxygenase-2 (COX-2) expression was quantified by western blot. Melatonin was tested in two experimental groups, one of which underwent common bile duct ligation for 2 days and another that was later de-ligated for 2 days. Inflammation-induced impairment of Ca2+ responses to cholecystokinin and caffeine were recovered by melatonin treatment (30 mg/kg). This treatment also ameliorated the detrimental effects of AC on Ca2+ influx through both L-type and capacitative Ca2+ channels, and it was effective in preserving the pharmacological phenotype of these channels. Despite its effects on Ca2+ homeostasis, melatonin did not improve contractility. After de-ligation, Ca2+ influx and contractility were still impaired, but both were recovered by melatonin. These effects of melatonin were associated to a reduction of MDA levels, an increase in GSH content and a decrease in COX-2 expression. These findings indicate that melatonin restores Ca2+ homeostasis during AC and resolves inflammation. In addition, this indoleamine helps in the subsequent recovery of functionality.
Gomez-Pinilla
Pedro J
PJ
Department of Physiology, Nursing School, University of Extremadura, Caceres, Spain.
Camello
Pedro J
PJ
Pozo
María J
MJ
D042101:Acalculous Cholecystitis / Q000188:drug therapy* / Q000503:physiopathology*; D000818:Animals; D002110:Caffeine / Q000494:pharmacology; D002118:Calcium / Q000502:physiology*; D041881:Cholecystitis, Acute / Q000188:drug therapy* / Q000503:physiopathology; D003135:Common Bile Duct; D004195:Disease Models, Animal; D005704:Gallbladder / Q000187:drug effects / Q000502:physiology; D006168:Guinea Pigs; D006706:Homeostasis / Q000187:drug effects*; D008026:Ligation; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D008550:Melatonin / Q000627:therapeutic use*; D009119:Muscle Contraction / Q000187:drug effects; D009568:Nitrendipine / Q000494:pharmacology; D020110:Pinacidil / Q000494:pharmacology; D019284:Thapsigargin / Q000494:pharmacology
D002110:Caffeine; D019284:Thapsigargin; D020110:Pinacidil; D009568:Nitrendipine; D008550:Melatonin; D002118:Calcium