Gomez-Pinilla Pedro J, Camello-Almaraz Cristina, Moreno Rosario, Camello Pedro J, Pozo María J
Department of Physiology, Nursing School, Avda Universidad s/n, 10071 Cáceres, Spain.
J Pharmacol Exp Ther. 2006 Nov;319(2):847-56. doi: 10.1124/jpet.106.109256. Epub 2006 Aug 11.
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. Ca(2+) 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 Ca(2+) influx. The impaired contractility only correlated with diminished Ca(2+) mobilization in response to activation of Ca(2+) influx. Melatonin improved contractility and increased smooth muscle F-actin content without changing Ca(2+) 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 Ca(2+) influx and damage of contractile proteins. Melatonin significantly ameliorated these age-related changes.
胆囊疾病的发病率随年龄增长而增加，但导致胆囊功能障碍的机制变化尚不清楚。在此，我们确定了与年龄相关的胆囊收缩性变化以及褪黑素治疗的影响。记录了豚鼠胆囊肌条对电场刺激和激动剂的等长张力变化。通过对负载fura-2的分离胆囊平滑肌细胞进行落射荧光显微镜检查来测定[Ca(2+)]i，并通过共聚焦显微镜对F-肌动蛋白含量进行定量。衰老降低了神经源性收缩，这与一氧化氮能神经支配的受损以及辣椒素敏感的舒张神经反应性增加有关，可能涉及降钙素基因相关肽。褪黑素治疗4周后，神经源性反应恢复到正常值，一氧化氮能功能也随之恢复，辣椒素敏感成分消失。衰老还降低了对胆囊收缩素和Ca(2+)内流的收缩反应。收缩功能受损仅与Ca(2+)内流激活后Ca(2+)动员减少相关。褪黑素改善了收缩功能并增加了平滑肌F-肌动蛋白含量，而未改变Ca(2+)稳态。总之，衰老损害胆囊功能是平滑肌收缩性抑制性神经调节变化和对收缩激动剂肌源性反应降低的结果。收缩功能受损似乎与Ca(2+)内流减少和收缩蛋白损伤有关。褪黑素显著改善了这些与年龄相关的变化。
