International Journal of Impotence Research (2007) 19, 533–543 & 2007 Nature Publishing Group All rights reserved 0955-9930/07 $30.00 www.nature.com/ijir REVIEW PDE5 inhibitors beyond erectile dysfunction P Sandner, J Hu¨ tter, H Tinel, K Ziegelbauer and E Bischoff Product-Related Research, Bayer HealthCare, Wuppertal, Germany The phosphodiesterase type-5 (PDE5) inhibitors sildenafil, vardenafil and tadalafil are widely used first-line therapy for erectile dysfunction (ED). Since the advent of sildenafil in 1998, more than 40 million men worldwide have been successfully treated with these compounds. The safety and high tolerability of PDE5 inhibitors make them an attractive tool to investigate further physiological functions of PDE5, for example the modulation of intracellular cyclic GMP (cGMP) pools. As cGMP is a key component of intracellular signaling this may provide novel therapeutic opportunities beyond ED even for indications in which chronic administration is necessary. The approval of sildenafil for the treatment of pulmonary hypertension in 2005 was a notable success in this area of research. A number of other potential new indications are currently in various phases of preclinical research and development. In recent years, extensive but very heterogeneous information has been published in this field. The aim of this review is to summarize existing preclinical and clinical knowledge and critically discuss the evidence to support potential future indications for PDE5 inhibitors. International Journal of Impotence Research (2007) 19, 533–543; doi:10.1038/sj.ijir.3901577; published online 12 July 2007 Keywords: lower urinary tract symptoms; benign prostate syndrome; premature ejaculation; Raynaud’s disease; Peyronie’s disease; heart failure Introduction cGMP-driven cascade of reactions. Ultimately, these pathways decrease intracellular calcium levels, It is well established that nitric oxide (NO) and thereby promoting relaxation of smooth muscle cells natriuretic peptides increase intracellular cGMP and a variety of other calcium-dependent pro- levels by stimulation of the soluble and membrane- cesses.3 Since inhibitors of PDE5 raise intracellular bound guanylate cyclase, respectively. This cGMP cGMP levels, the effects will be much more formation is the initial step of a ubiquitous bio- pronounced under conditions when cGMP forma- chemical pathway, regulating the cardiovascular, tion is already increased. Strong evidence to support central and peripheral nervous system.1 Phospho- this concept is the highly efficacious treatment of diesterases (PDEs) are intracellular enzymes that erectile dysfunction (ED) with PDE5 inhibitors.4 specifically catalyze the hydrolysis of the second Sexual stimulation induces a selective vasorelaxa- messengers cAMP and cGMP to the inactive meta- tion in penile tissue, which is predominantly bolites AMP and GMP. Among the 11 families of mediated by the release of NO in the cavernous PDEs a number are able to hydrolyze cGMP, but only nerve endings, the endothelium of penile arteries PDE5 exclusively catalyses the breakdown of and the corpora cavernosa. Relaxation is induced by cGMP.2 By counterbalancing cGMP production by the subsequent formation of cGMP. By preventing guanylate cyclases, PDE5 is able to decrease cGMP degradation of cGMP, PDE5 inhibitors reinforce this levels very effectively. Thus PDE5 inhibition in- physiological mechanism very efficaciously and creases intracellular cGMP levels and initiates a induce the appropriate vasorelaxation necessary to obtain an erection. It is the regulatory mechanism that forms the basis for the triumphal success of PDE5 inhibitors in the treatment of ED. Correspondence: Dr E Bischoff, Product-Related Research, Bayer HealthCare, Aprather Weg 18a, Wuppertal 42096, Three compounds are available worldwide, three Germany. others may enter into the market during the next E-mail: [email protected] years (Table 1). The wide, safe use of PDE5 Received 13 February 2007; revised 10 May 2007; inhibitors, together with an increasing understand- accepted 25 May 2007; published online 12 July 2007 ing of cGMP-regulated mechanisms, have triggered a PDE5 inhibitors beyond erectile dysfunction P Sandner et al 534 Table 1 Approved and emerging PDE5 inhibitors inhibitors. There is a large body of preclinical and clinical evidence showing that PDE5 inhibitors Compound Company Status reduce vascular resistance in the pulmonary circu- lation and pressure in the pulmonary arteries. The Sildenafil Pfizer Approved for ED and PAH rationale is based on the hypothesis that oxygena- Vardenafil Bayer AG Approved for ED Tadalafil Eli Lilly Approved for ED tion of the alveoli stimulates release of NO, which Udenafil5 Dong Pharmaceutical Approved for ED in causes a local relaxation of pulmonary resistance Co Ltd Korea, Phase 3 in US vessels. Inhibition of cGMP cleavage results in 6 Avanafil Tanabe Seiyaku, Phase 2 amplification of this regulatory pathway, causing licensed by Vivus SLX-21017 Surface Logics Phase 1 increased vasodilation without inducing a ventila- tion–perfusion mismatch. Abbreviations: ED, erectile dysfunction; PAH, pulmonary hyper- In animal models, such as the monocrotaline- tension; PDE5, phosphodiesterase type-5. induced pulmonary hypertension (PAH) in rats, it has been demonstrated that the PDE5 inhibitor sildenafil reduces pulmonary arterial pressure and number of attempts to find new applications for right heart hypertrophy.19 Moreover, it has been these agents. It has been shown that besides corpus shown that inhibition of cGMP cleavage by sildena- cavernosum, PDE5 is also expressed in smooth fil reduces the hypoxia induced rise in pulmonary muscles of the systemic vasculature,8 prostate,9 pressure and partially reverses pulmonary artery bladder,10 cardiac tissues,11,12 brain and plate- muscularization.20 lets,13,14 which imply additional target tissues for In clinical studies sildenafil also has been shown PDE inhibitors. The aim of this paper was to to be a safe and effective drug for patients with PAH. critically review and discuss recent findings in this A small crossover study showed that sildenafil field, and highlight possible future therapeutic uses improved exercise time and cardiac output signifi- of PDE5 inhibitors beyond ED. cantly, whereas pulmonary arterial pressure was only slightly decreased.21 In the SUPER-1 (Sildena- fil Use in Pulmonary Hypertension) study (a large, PDE5 inhibitors to treat cardiovascular randomized, controlled, multinational trial) silde- nafil significantly improved exercise capacity, func- diseases and endothelial dysfunction tional class and hemodynamic parameters and was well-tolerated.22 On the basis of these data, sildena- PDE5 inhibitors may be optimally suited for the fil was approved in 2005 by the United States Food treatment of cardiovascular diseases, due to their and Drug Administration and the European Agency mechanism of action. Increases in intracellular for the Evaluation of Medicinal Products for the cGMP levels cause a relaxation of vascular smooth treatment of patients with PAH. muscles. This is not only a generalized vasodilation, since its extent depends on the physiological stimulus NO. In regions, where a relatively large NO production signals a high need for local Heart failure perfusion, the chosen PDE5 inhibitor should be Congestive heart failure (CHF) is a chronic debilitat- more efficacious than in areas with lower perfusion ing disease, which leads to infirmity and death demand. In contrast to unspecific vasodilators, within few years. Coronary artery disease, past PDE5 inhibitors trigger a demand-driven increase myocardial infarctions and hypertension are the in flow, which may offer the opportunity for a very major causes of heart failure. specific redistribution of blood flow into areas with There are numerous potential mechanisms by the highest perfusion needs. This may prevent which PDE5 inhibitors could exert positive effects luxury perfusion and steal phenomenon and a on the course and symptoms of this disease. The dramatic decrease in blood pressure. most prominent mechanism is a cGMP-mediated Other effects beyond vascular dilatation have relaxation of smooth muscle cells, which elicits a been described for PDE5 inhibitors, which may also direct vasodilation. Since this is observed primarily have a positive impact on cardiovascular diseases. in the pulmonary vasculature, it may particularly There are numerous reports that describe protective unload the right ventricle. In patients suffering from effects in ischemia/reperfusion in the heart.15 Other CHF, sildenafil decreased pulmonary resistance and authors have reported antihypertrophic,16 antiproli- improved peak oxygen uptake during exercise, ferative,17 and antifibrotic18 efficacy. whereas it did not influence these parameters in healthy volunteers.23 The positive effect of direct vascular dilation may be important in large blood Pulmonary hypertension vessels, since an improved compliance of the large The treatment of pulmonary arterial hypertension is arteries reduces peak ventricular pressure and the most established cardiovascular use of PDE5 improves peripheral perfusion during the diastole International Journal of Impotence Research PDE5 inhibitors beyond erectile dysfunction P Sandner et al 535 by lowering pulse pressure. Such an effect could be stress and smoking. Pharmacological treatments, demonstrated by Hirata et al.24 In patients with however, are often disappointing and inefficient. controlled