The significant overlap in sexual dysfunction and LUTS has led to the proposal that a common pathophysiology may account for the symptoms. Subsequently, it has been proposed that if there is a shared underlying process, then a single common agent may be a feasible treatment for both. Hence, there has been a surge in research of phosphodiesterase type-5 inhibitors (PDE5-I) for the cotreatment of LUTS and ED. Pathophysiology and Pharmacology There is substantial evidence that the pathogenic mechanisms underlying LUTS and ED share many common pathways. The nitric oxidecyclic guanosine monophosphate (NO-cGMP)

pathway has been proposed as the main shared mechanism of LUTS and ED.6 It is thought that LUTS Inhibitors,research,lifescience,medical result from check details increased smooth

muscle tension mediated by NO.7–10 NO is released by neuronal NO synthase (nNOS) and endothelial NO synthase (eNOS) found within the urothelium, smooth muscle, prostatic stroma and glandular Inhibitors,research,lifescience,medical epithelium, blood vessels, bladder nerves, and outlet. NO activates the enzyme guanylate cyclase that generates cGMP, causing a downstream decrease in intracellular calcium levels and ultimately smooth muscle relaxation.6,11 Decreases in the NO-cGMP pathway with age would result in decreased levels of intracellular cGMP and calcium, leading to less smooth muscle relaxation of the Inhibitors,research,lifescience,medical bladder and prostate, thus worsening LUTS. Erections are mediated in a similar fashion. Following stimulation of the penile erectile nerves, nNOS and eNOS produce NO, which is released into the vascular smooth Inhibitors,research,lifescience,medical muscle lining, the corpora cavernosa, and its vessels. This results in increased blood flow and vascular dilatation. On a cellular level, NO diffuses into the vascular smooth muscle cell where it binds to a heme moiety on the NO-guanylyl cyclase (GC). It activates the GC enzyme resulting in increased conversion of guanosine triphosphate (GTP) to cGMP. Cyclic GMP binds to protein kinase

Gs and activates the phosphotransferase activity to cause phosphorylation of several cellular proteins, resulting in reduced intracellular Inhibitors,research,lifescience,medical calcium and desensitization to calcium signaling. This results in the vasodilatation, smooth muscle relaxation, and increased blood flow for an erection. An increase in the Cell Metabolism Rho-Rhoassociated protein kinase (ROCK) calcium sensitizing pathway may also contribute to impaired smooth muscle relaxation and bothersome LUTS and ED. Increased Rho-ROCK signaling has been demonstrated in penile and bladder pathology, such as ED and overactive bladder in men with diabetes.12,13 Autonomic hyperactivity resulting in increased sympathetic activity has also been shown as a causative agent in LUTS and ED.14 The corpus cavernosum, prostate (subtype α1A), and detrusor muscle (subtype α1D) demonstrate high concentrations of α1-adrenergic receptors. Derangements in their autonomic activity have led to ED and bladder overactivity, as demonstrated in rat models.