The role of phosphodiesterases in bladder pathophysiology

Abstract

Nitric oxide and the cyclic nucleotide monophosphates cAMP and cGMP have a role in control of the micturition process and hence, are suggested to be involved in the pathophysiology of storage and voiding disorders. Phosphodiesterase enzymes (PDEs) hydrolyse cAMP and cGMP. Inhibition of PDEs increases cAMP and cGMP levels and relaxes urinary bladder smooth musculature. Although many preclinical studies have been conducted, to date, only PDE1 and PDE5 inhibitors have been tested clinically for the management of storage and voiding disorders. Treatment with PDE1 inhibitors might improve micturition frequency in patients with overactive bladder, whereas inhibition of PDE5 improves lower urinary tract symptoms in men, either with or without BPH and erectile dysfunction (ED). Furthermore, the combination of a PDE5 inhibitor and an α-adrenoceptor antagonist has superior efficacy to monotherapy with either agent. However, the role of PDE5 inhibitors in the treatment of women with detrusor overactivity remains unclear. The clinical application of agents that inhibit other PDEs, including PDE4, also certainly merits scientific attention. PDE inhibitors seem likely to become a valuable alternative treatment for patients with storage and voiding disorders in the future.

BK channel regulation by phosphodiesterase type 1: a novel signaling pathway controlling human detrusor smooth muscle function

“…6). The inhibition of PDE1 can be an effective alternative to suppress detrusor overactivity in OAB patients who do not respond to antimuscarinic treatment (20,25), and in patients with neurogenic detrusor overactivity (11). These investigations are an important step in validating PDE1 as a potential novel therapeutic target for OAB (20).…”

“…The current research aimed to investigate the regulatory mechanisms by which PDE1-mediated signaling pathways control human DSM excitability and contractility. The data obtained from human DSM in this study are the foundation for further investigations into the therapeutic potential of selective PDE inhibitors in the treatment of bladder dysfunction (20).…”

“…The inhibition of PDEs increases intracellular cAMP, activates protein kinase A (PKA), and thus stimulates BK channels to attenuate human DSM excitability and contractility (26,28). In addition, the mAChR signaling pathways are subjected to positive feedback regulation by PDEs, particularly the Ca 2ϩ -activated PDE type 1 isoform (PDE1) (5,6,20). PDE1, the only PDE isoform that is activated by Ca 2ϩ (5,6), is considered to be an important mediator of the cross talk between intracellular cAMP and Ca 2ϩ signaling pathways in the regulation of DSM excitability (23).…”

“…The selective inhibition of PDE1 elevates cellular cAMP levels and TBKC activity in DSM cells, while mAChR activation inhibits TBKCs (17,19,28). The mAChR-mediated and Ca 2ϩ -dependent PDE1 activation clearly suggests that PDE1 is a highly important regulatory element in human bladder physiology (15,20).…”

“…However, the physiological significance of PDE1 signaling in the regulation of human DSM function has not been fully investigated. As previous investigations have shown differential PDE expression in humans and guinea pigs, it is critically important to determine the functional role of PDE1 directly in human DSM as they are the target species of interest for therapeutic interventions (14,20). The current research aimed to investigate the regulatory mechanisms by which PDE1-mediated signaling pathways control human DSM excitability and contractility.…”