Received for publication June 12, 2006.
Revised August 8, 2006.
Accepted for publication August 9, 2006.

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

Abstract

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 (EFS) 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 to the impairment of nitrergic innervation and to increased responsiveness of capsaicin-sensitive relaxant nerves, possibly involving calcitonin gene-related peptide (CGRP). Melatonin treatment for four 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 (CCK) 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.

Key words: ageing, calcium homeostasis, gallbladder, melatonin, neuromuscular transmission, smooth muscle

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