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

Abstract

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 Ca(2+) 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 [Ca(2+)](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 Ca(2+) signal evoked by bethanechol and the Ca(2+) influx induced by KCl in bladder strips. Treatments aimed to release calcium from intracellular stores (caffeine and a low level of ionomycin in Ca(2+)-free medium) showed that aging reduces the size of agonist-releasable stores. Similar to contraction, the mobilization of Ca(2+) by ATP was increased in aged cells. Therefore, the differential effects of aging on detrusor contraction are associated to alterations of [Ca(2+)](i) signals: the cholinergic inhibition is due to inhibition of voltage-operated Ca(2+) influx and reduction of the size of intracellular Ca(2+) stores, while the age-induced ATP response is accompanied by an enhanced Ca(2+) mobilization.

Aging impairs Ca2+ sensitization pathways in gallbladder smooth muscle

“…It is well established that aging evokes tissuespecific changes in Ca 2+ homeostasis in nerves and in skeletal, cardiac and smooth muscles (Gomez-Pinilla et al 2007;Gomez-Pinilla et al 2011;PuzianowskaKuznicka and Kuznicki 2009). In the guinea pig gallbladder, aging reduced calcium influx but not calcium mobilization from internal stores even if contractile impairment is present for both maneuvers (Gomez-Pinilla et al 2006).…”

Chondrosenescence: Definition, hallmarks and potential role in the pathogenesis of osteoarthritis

“…For example, in senescent detrusor as well as cerebral arterial smooth muscle cells, calcium signals with decreased amplitudes but with increased durations were observed, reflecting on disturbances in both Ca 2+ influx (e.g. inhibition of voltage-operated calcium influx, increased calcium mobilization by ATP) and elimination pathways [77,78]. This suggests that alterations in Ca 2+ signalling can also be expected in ageing chondrocytes.…”

Pathophysiology and Animal Modeling of Underactive Bladder

“…Decreased detrusor contractility in UAB can result from a lack of contractile stimulus (acetylcholine and ATP) [77] and/or a lack of tissue responsiveness due to irreversible changes in the bladder wall described as sarcopenia (loss of muscle tissue, increased collagen deposition) [26,78]. Several factors may contribute to altered excitationcontraction coupling mechanisms including changes in the properties and density of calcium [79] and potassium channels, gap junctions and receptors in detrusor smooth muscles of aged and UAB patients.…”