Aging differentially modifies agonist-evoked mouse detrusor contraction and calcium signals

Although aging-induced changes in urinary bladder neurotransmission have been studied in some detail, information regarding alterations in detrusor muscle is scanty and addresses only partial aspects of the myogenic response of detrusor. Rodent bladder aging shows several features similar to those reported in humans. The aim of this study was to characterize in aged mouse the alterations of detrusor muscle contraction and the putative underlying changes in Ca2+ signals. We studied in vitro the myogenic contraction induced by agonists in detrusor strips from adult (3 months old) or aged (23-25 months old) mice. In addition, we determined the agonist-induced [Ca2+](i) signals by epifluorescence microscopy in fura-2 loaded isolated detrusor cells. Aging impaired the contractile response of bladder strips to cholinergic stimulation with bethanechol and to chemical depolarization with KCl-containing solutions. On the contrary, the response to purinergic stimulation (ATP) was enhanced. Aging also diminished the transient Ca2+ signal evoked by bethanechol and the Ca2+ influx induced by KCl in bladder strips. Treatments aimed to release calcium from intracellular stores (caffeine and a low level of ionomycin in Ca2+-free medium) showed that aging reduces the size of agonist-releasable stores. Similar to contraction, the mobilization of Ca2+ by ATP was increased in aged cells. Therefore, the differential effects of aging on detrusor contraction are associated to alterations of [Ca2+](i) signals: the cholinergic inhibition is due to inhibition of voltage-operated Ca2+ influx and reduction of the size of intracellular Ca2+ stores, while the age-induced ATP response is accompanied by an enhanced Ca2+ mobilization.