The pyridine-derived nucleotides cADPribose and NAADP are emerging as genuine Ca²⁺ mobilizing second messengers. These signalling nucleotides have been shown to modulate Ca²⁺ homeostasis in smooth muscle, but the impact of ageing on these novel messengers is completely unknown. The present study examines the effects of ageing on the contribution of NAADP-mediated pathway in detrusor contractility. Mice were grouped according to age in adult (2 months old) and aged (18 and 24 months old). Isometric tension changes in response to agonists were recorded from detrusor muscle strips and [Ca²⁺ ]_i was determined by epifluorescence microscopy in fura-2 loaded isolated detrusor cells.

In detrusor from adult mice, reactive red 120 (RR120, 200 mM), a tryazine dye that can bind NAADP receptors (Billington et al., Br. J. Pharmacol, 2004), reduced myogenic responses to cholinergic, purinergic and depolarization challenge, which correlated with reduced Ca²⁺ influx and decreased Ca²⁺ release through IP3 and ryanodine receptors in the presence of RR120. RR120 itself induced a transient [Ca²⁺ ]_i increase. These results suggest that NAADP-mediated signalling participates in detrusor Ca²⁺ homeostasis and contractility. Ageing reduced myogenic contractile responses to chemical agonists. The impaired contractility correlated with impaired calcium signalling. Ageing also reduced NAADP contribution, since RR120 resulted ineffective on calcium homeostasis and contractile assays. The study shows, for the first time, that ageing impairs detrusor contractility as consequence of alterations in both classical and novel Ca²⁺ homeostatic mechanisms. Supported by BFU2004-0637