Influence of sildenafil on the purinergic components of nerve‐mediated and urothelial ATP release from the bladder of normal and spinal cord injured mice

Abstract

Background and purpose PDE inhibitors such as sildenafil alleviate lower urinary tract symptoms; however, a complete understanding of their action on the bladder remains unclear. We are investigating the effects of sildenafil, on post and preganglionic nerve‐mediated contractions of the mouse bladder, and neuronal and urothelial ATP release. Experimental approach Bladders were used from young (12 weeks), aged (24 months), and spinal cord transected (SCT), mice, for in vitro contractility experiments. An arterially perfused in situ whole mouse model was used to record bladder pressure. Nerve‐mediated contractions were generated by electrical field stimulation (EFS) of postganglionic nerve terminals or the pelvic nerve. ATP release during EFS in intact detrusor strips, and during stretch of isolated mucosa strips, was measured using a luciferin‐luciferase assay. Key results Sildenafil (20 μM) inhibited nerve‐mediated contractions in young mice, with an increase in f 1/2 values in force–frequency relationships, demonstrating a greater effect at low frequencies. Sildenafil reduced the atropine‐resistant, purinergic component of nerve‐mediated contractions, and suppressed neuronal ATP release upon EFS in vitro. Sildenafil reduced the preganglionic pelvic nerve stimulated bladder pressure recordings in situ; comparable to in vitro experiments. Sildenafil reduced stretch‐induced urothelial ATP release. Sildenafil also relaxed nerve‐mediated contractions in aged and SCT mice. Conclusion and implications Sildenafil has a greater effect on the low‐frequency, purinergic‐mediated contractions and suppresses neuronal ATP release. In addition, sildenafil reduces stretch‐induced urothelial ATP release. These results demonstrate a novel action of sildenafil to selectively inhibit ATP release from nerve terminals innervating detrusor smooth muscle and the urothelium.

Add‐on effects of tadalafil in tamsulosin‐treated patients with small benign prostatic enlargement: A randomized, placebo‐controlled, double‐blind, crossover study

“…As to individual IPSS items, we identified a significant improvement in the IPSS score for item 3 (intermittency). This improvement may have been attributable to the relaxing effect of nitric oxide on smooth muscles in the prostate: in vitro experiments have demonstrated synergism with α‐1 blockers in the corpus cavernosum . The enhanced relaxing effect of this combination has been also recognized in the treatment of lower ureteric stones .…”

“…Decreasing IPSS total scores without significant effects on Q max is a characteristic effect of PDE5is compared with α‐1 blockers. PDE5is have variable effects on LUT including reducing ATP release from urothelium, modulating afferent nerve sensitization, anti‐inflammation, antioxidative stress as well as relaxing smooth muscle and increasing blood supply . These effects may lead to the add‐on effects of tadalafil on tamsulosin.…”

Characterisation of nerve‐mediated ATP release from bladder detrusor muscle and its pathological implications

“…The ability to attenuate selectively nerve‐mediated release of ATP rather than that of ACh offers the possibility of an interesting therapeutic target, as atropine‐resistant contractions occur only in tissue from human‐DO bladders. Adenosine, acting via A 1 receptors, and the PDE5 inhibitor sildenafil both attenuate the consequences of nerve‐mediated ATP release (Chakrabarty et al, ; Pakzad et al, ; Searl et al, ). However, adenosine also reduces ACh release (Silva‐Ramos et al, ), and the role of sildenafil in this context requires evaluation.…”

“…Further insight into how ATP‐dependent contractions may be selectively manipulated comes from evidence that ATP and ACh may be released from postganglionic nerve terminals by different pathways. Indirect evidence suggests that ATP is released at lower stimulation rates, compared to those releasing ACh (Calvert et al, ; Chakrabarty et al, ; Pakzad et al, ). There is more direct evidence that the PDE‐5 inhibitor sildenafil abolishes nerve‐mediated ATP release (Chakrabarty et al, ); however, this should be set against the observation that ACh is also modulated by agents such as adenosine (Silva‐Ramos et al, ).…”

“…Indirect evidence suggests that ATP is released at lower stimulation rates, compared to those releasing ACh (Calvert et al, ; Chakrabarty et al, ; Pakzad et al, ). There is more direct evidence that the PDE‐5 inhibitor sildenafil abolishes nerve‐mediated ATP release (Chakrabarty et al, ); however, this should be set against the observation that ACh is also modulated by agents such as adenosine (Silva‐Ramos et al, ). The development of amperometric ATP‐selective electrodes potentially allows for the real‐time measurement of nerve‐mediated ATP release in detrusor muscle.…”