Erectile Dysfunction and Lower Urinary Tract

Abstract

During the last decades it turned out that the NO/cGMP signaling cascade is one of the most prominent regulators of a variety of physiological and pathophysiological processes in a broad range of mammalian tissues. Thus cGMP is a key second messenger and targeting this pathway by increasing intracellular cGMP levels is a very successful approach in pharmacology as shown for nitrates, PDE5 inhibitors and more recently for stimulators of the guanylate cyclase. Besides the beneficial effects of cGMP elevation in cardiac, vascular, pulmonary, renal or liver disorders the launch of PDE5 inhibitors for the treatment of erectile dysfunction 10 years ago, has directed a lot of attention to the NO/cGMP signaling in the lower urinary tract. Triggered by the use of PDE5 inhibitors in ED it turned out that cGMP is a common regulatory mechanism for lower urinary tract function also beyond ED. In recent years intense research and development efforts were undertaken to elucidate the role of the NO/cGMP and to fully exploit the therapeutic implications of cGMP elevation in urological disorders in ED and beyond. Therefore we have summarized the effects of cGMP elevation for treatment of erectile dysfunction in males and in females. We have also reviewed the recent pre-clinical and clinical lines of evidence for treatment options of benign prostatic hyperplasia and lower urinary tract symptoms in male patients and overactive bladder and urinary incontinence in female patients. In addition we also touch more speculative concepts using cGMP elevating drugs for the treatment of premature ejaculation, peyornies disease and stone disease.

Mammalian Cyclic Nucleotide Phosphodiesterases: Molecular Mechanisms and Physiological Functions

“…Other possibilities for use of PDE5 inhibitors include treatment of Raynaud's disease (54,86,118), suppression of other autoimmune diseases (48, 343), and relief of symptoms associated with cystic fibrosis (67,222,223). Potential treatment of genitourinary tract dysfunctions (benign prostate syndrome, overactive bladder, and urge incontinence) has garnered a lot of attention (324,325,362,397,425), as has treatment of Peyronie's disease (128), premature ejaculation, and ureteral relaxation for passage of kidney stones (132,325). Some PDE5 inhibitors reportedly slow tumor cell growth (1,268,380).…”

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

“…Compared with lung, where high PDE5 provided a molecular basis for treatment of pulmonary hypertension (Corbin et al 2005), cytosolic PDE5 abundance is similar and membrane concentrations are even higher in the bladder. Immunohistochemical data localized PDE5 to the bladder smooth muscle (Fibbi et al 2010), and both NO donors and PDE5 inhibitors were found to reduce the muscle tonus in experiments with rat and human bladder tissues (Sandner et al 2009), although cAMPmediated pathways appear to play a predominant role for direct detrusor muscle relaxation (Andersson & Arner 2004). Tension release during the bladder filling phase is crucial and requires robust mechanisms to generate smooth muscle relaxation.…”

“…Although there is evidence for cGMP-mediated relaxing activity in prostate smooth muscle (Kedia et al 2008), recent findings focused the attention to local roles in the control of cellular proliferation and differentiation (Sandner et al 2009, Zenzmaier et al 2010. Pharmacological inhibition of PDE5 reduced the proliferation of primary prostate stromal cells and attenuated fibroblast-to-myofibroblast trans-differentiation, in common, suggesting therapeutic potential for prevention and treatment of benign prostatic hyperplasia (Zenzmaier et al 2010).…”

“…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.…”

“…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. Although certain factors implicated in cGMP pathways have been demonstrated by immunohistochemical, RT-PCR, and functional approaches, the cGMP signaling system in these organs is still poorly characterized.…”