Phosphodiesterases (PDEs) and PDE inhibitors for treatment of LUTS

Abstract

Lower urinary tract (LUT) smooth muscle can be relaxed by drugs that increase intracellular concentrations of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). Both of these substances are degraded by phosphodiesterases (PDEs), which play a central role in the regulation of smooth muscle tone. The distribution and functional significance of PDE enzymes vary in different tissues of the LUT. Targeting specific PDE isoenzymes should thus allow organ selectivity. PDE 4 and 5 appear to predominate in the prostate, PDE 1 and 4 are thought to influence detrusor smooth muscle function, and PDE 5 may be functionally important in the urethra and vasculature. Studies on the use of PDE inhibitors to treat various LUT symptoms (LUTS), have yielded favorable results. Thus, positive effects of the PDE 5 inhibitors sildenafil and tadalafil on symptoms and quality of life in men with LUTS, erectile dysfunction, and BPH have also been demonstrated. These effects may be due to effects on cGMP signaling and/or modification of afferent input from bladder, urethral, and prostate tissue. This review gives an update on the distribution of PDEs in structures relevant for LUT function, and discusses how inhibition of these enzymes can contribute to beneficial effects on LUTS. Information for the review was obtained from searches of the PubMed database, and from the authors' files.

Evaluation of Tadalafil effect on lower urinary tract symptoms of benign prostatic hyperplasia in patients treated with standard medication

“…Additional theories about PDE-5 inhibition of the lower urinary tract suggest that LUTS decrease via modification of afferent nerve signaling from the bladder and urethra (20).…”

Detrusor myocyte activity and afferent signaling

“…2,90 It is still unclear exactly how many functional classes of distension-sensitive afferents innervate the bladder. Several investigators have characterized bladder mechanoreceptors in terms of their adequate mechanical stimuli, chemosensitivity, location of their receptive field, and electrophysiologic parameters.…”

“…4 Use of PDE inhibitors to enhance the cAMP-and cGMPmediated relaxation of LUT smooth muscles (detrusor prostate, urethra) should then be a logical approach to treat OAB/ DO. 90 Studies with the PDE 1 inhibitor vinpocetin, which reduces the breakdown of cAMP, showed relaxant effects in vitro but poor clinical efficacy in OAB/DO patients. 132 PDE 4, which also preferably hydrolyses cAMP, has been implicated in the control of bladder smooth muscle tone.…”

Cyclic GMP signaling in rat urinary bladder, prostate, and epididymis: tissue-specific changes with aging and in response to Leydig cell depletion

“…Recent findings raised attention to cGMP-regulated functions and possible treatment options for PDE5 inhibitors in bladder, prostate, and epididymis (Andersson et al 2007, Dimitriadis et al 2009, Sandner et al 2009, Wang 2010. Local roles for cGMP signaling comprise the regulation of muscle contractions and micturition sensations in the bladder (Persson et al 2000, Andersson & Arner 2004, Sandner et al 2009, Caremel et al 2010, the relaxation of stromal smooth muscle and control of cell proliferation in the prostate (Gradini et al 1999, Sandner et al 2009, Fibbi et al 2010, Zenzmaier et al 2010, and regulation of peristalsis and secretory epithelial cell functions in the epididymis (Mewe et al 2006, Shum et al 2008.…”