Melatonin treatment reverts age-related changes in guinea pig gallbladder neuromuscular transmission and contractility

The incidence of gallbladder illness increases with age, but the altered mechanisms leading to gallbladder dysfunction are poorly understood. Here we determine the age-related alterations in gallbladder contractility and the impact of melatonin treatment. Isometric tension changes in response to electrical field stimulation and to agonists were recorded from guinea pig gallbladder muscle strips. [Ca2+](i) was determined by epifluorescence microscopy in fura-2 loaded isolated gallbladder smooth muscle cells, and F-actin content was quantified by confocal microscopy. Aging reduced neurogenic contractions, which was associated with the impairment of nitrergic innervation and with increased responsiveness of capsaicin-sensitive relaxant nerves, possibly involving calcitonin gene-related peptide. Melatonin treatment for 4 weeks restored neurogenic responses to normal values, with an associated recovery of nitrergic function and the disappearance of the capsaicin-sensitive component. Aging also reduced the contractile responses to cholecystokinin and Ca2+ influx. The impaired contractility only correlated with diminished Ca2+ mobilization in response to activation of Ca2+ influx. Melatonin improved contractility and increased smooth muscle F-actin content without changing Ca2+ homeostasis. In conclusion, aging impairs gallbladder function as the result of changes in the inhibitory neuromodulation of smooth muscle contractility and the reduction in the myogenic response to contractile agonists. Impaired contractility seems to be related to decreased Ca2+ influx and damage of contractile proteins. Melatonin significantly ameliorated these age-related changes.