Can Phosphodiesterase Type 5 Inhibitors Cure Erectile Dysfunction?

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1 european urology 49 (2006) available at journal homepage: Review Sexual Medicine Can Phosphodiesterase Type 5 Inhibitors Cure Erectile Dysfunction? Francesco Montorsi a, *, Alberto Briganti a, Andrea Salonia a, Patrizio Rigatti a, Arthur L. Burnett b a Department of Urology, Università Vita-Salute San Raffaele, Milan, Italy b Department of Urology, Johns Hopkins Hospital, Baltimore, Maryland, USA Article info Article history: Accepted December 30, 2005 Published online ahead of print on January 13, 2006 Keywords: Erectile dysfunction Phosphodiesterase type 5 inhibitors Endothelial dysfunction Sildenafil Vardenafil Tadalafil Radical prostatectomy Abstract Introduction and objectives: To systematically analyze and review the available evidence about the potential role of chronic administration of phosphodiesterase type 5 (PDE-5) inhibitors for the cure of erectile dysfunction (ED) based on clinical and basic science data. Methods: Analysis of published full-length papers that were identified with Medline and Cancerlit from January 1993 to September Abstracts published in the journals European Urology, the Journal of Urology, the International Journal of Impotence Research, and the Journal of Sexual Medicine as official proceedings of internationally known scientific societies held in the same time period were also assessed. Results: Chronic administration of PDE-5 inhibitors have reportedly been associated with increased persistent vascular and endothelial function which represents a key factor in maintaining vascular tone and inducing vasodilation by increasing the level of endothelial cgmp generated by activation of endothelial nitric oxide. Clinical studies have revealed a potential protective role of these compounds on endothelial function in short- and long-term assessments. Several studies based on animal models have provided direct experimental support for the role of PDE- 5 inhibitors in improving the structure and function of the cavernosal tissue and have suggested potential molecular mechanisms involved. Conclusions: Although evidence increasingly supports the potential role of chronic administration of PDE-5 inhibitors for improving erectile function in patients affected by ED, long-term data are lacking. However, data available from animal models support the evidence of potential benefits induced on endothelial function by chronic exposure to PDE-5 inhibitors. # 2006 Elsevier B.V. All rights reserved. * Corresponding author. Department of Urology, Università Vita Salute San Raffaele, Via Olgettina 60, Milan, Italy. Tel ; Fax: address: montorsi.francesco@hsr.it (F. Montorsi) /$ see back matter # 2006 Elsevier B.V. All rights reserved. doi: /j.eururo

2 980 european urology 49 (2006) Introduction Erectile dysfunction (ED) is a common medical condition that affects millions of men. First-line oral therapy for ED includes phosphodiesterase type 5 (PDE-5) inhibitors such as sildenafil, vardenafil, and tadalafil, which inhibit hydrolysis of the second messenger cyclic guanosine monophosphate (cgmp), whose production is promoted by nitric oxide (NO) release within the penile smooth cells. Approaches to ED have often involved ondemand administration of PDE-5 inhibitors, although recent evidence suggests that chronic treatment with these compounds might influence penile and systemic vascular parameters [1,2]. Acute and chronic administration of a PDE-5 inhibitor can improve endothelial and vascular function [1,3 6] in patients with or without cardiovascular risk factors, by increasing the level of endothelial cgmp generated by activating endothelial NO, which modulates vascular tone at rest and facilitates vasodilation during stress. These vascular effects might be responsible for erectile improvement and a return to spontaneous erections in patients treated with PDE-5 inhibitors over the long term, and could represent a key factor in prophylactic administration of these compounds in selected patients, such as those who underwent radical prostatectomy. However, data about mechanisms involved in restoring erectile function (EF) in these patients categories are currently not available. The aim of this review was to evaluate the evidence from clinical and basic science studies about a potential cure for ED with long-term use of PDE-5 inhibitors. 2. Lessons learned from endothelial dysfunction: clinical studies Endothelial dysfunction can be defined as an abnormal endothelial response that reduces the bioavailability of NO and impairs vasodilation. It plays a major role in the development of atherosclerosis and acute coronary syndromes [7]. Endothelial NO is a key factor in modulating vascular tone at rest, facilitating vasodilation during stress, and inhibiting platelet aggregation by activating intracellular guanylate cyclase, which in turn generates cgmp. Endothelial dysfunction is usually associated with many cardiovascular risk factors (hypertension, dyslipidemia, diabetes mellitus, and smoking) that are often exhibited by patients with erectile difficulties [8]. Furthermore, endothelial injury with resulting dysfunction has been demonstrated as the initiating event in the atherosclerosis process and plays a crucial role in the ischemic manifestation of coronary disease [9]. Indeed, early endothelial dysfunction in patients who were subjected to cardiac transplantation has been shown to predict the development of coronary arteriosclerosis during the initial year after surgery [10].BecauseEDcan be considered a vascular phenomenon that requires an appropriate hormonal milieu, endothelium is important in the pathophysiology of ED in terms of vasodilation and smooth muscle proliferation. Given that the severity of endothelial dysfunction seems to correlate with systemic cardiovascular status [9], maintaining or restoring a correctly functioning penile endothelium might prevent or reverse ED in some cases. Many clinical trials point to potential endothelial benefits induced by acute and chronic PDE-5 administration in patients with or without cardiovascular risk factors. Halcox et al. [3] evaluated the effect of oral sildenafil on resting coronary vascular tone, endothelium-dependent and -independent function, and platelet activation in 24 patients with coronary artery disease (CAD) and ischemia during exercise. Patients and the 12 control subjects received 100 mg of sildenafil, 10 mg of isosorbide dinitrate (ISDN), or placebo during exercise on three separate days in a randomized, double-blind manner. Flow-mediated dilation (FMD) of the brachial artery was measured, and CAD patients underwent treadmill exercise testing. Sildenafil dilated epicardial coronary arteries (+6.9% 1.3%, p < ). Coronary epicardial and microvascular responses with acetylcholine and cold-pressor testing improved, with a greater enhancement in patients with CAD and endothelial dysfunction. Both resting and adenosine diphosphate-stimulated platelet IIb/ IIIa receptor activation was inhibited by sildenafil ( p < 0.05). Compared with placebo, ISDN improved myocardial ischemia during exercise ( p < 0.05), whereas the effect of sildenafil was intermediate between the two. Thus, sildenafil dilated epicardial coronary arteries, improved endothelial dysfunction, and had an intermediate effect on myocardial ischemia, compared with ISDN and placebo. Katz et al. [4] demonstrated an increase in FMD one, three, and five minutes after release of transient brachial artery occlusion in patients previously treated with oral sildenafil (12.5, 25, or 50 mg), compared with placebo, which suggests that sildenafil promotes epithelium-dependent, flowmediated vasodilation in patients with chronic heart failure. Different results were achieved in healthy men who participated in a double-blind randomized,

3 european urology 49 (2006) crossover study in which NO-mediated responses to acetylcholine (endothelium-dependent) and nitroglycerin (endothelium-independent) were measured in the dorsal hand vein after administration of sildenafil 50 mg or placebo, and FMD of the brachial artery was measured before and after administration of sildenafil 50 mg, ISDN 50 mg, or placebo [5]. Although sildenafil increased sensitivity to nitroglycerin, it did not have an independent effect on the hand vein or arterial vasculature, blood flow, or FMD. In a double-blind, randomized, placebo-controlled trial, 50 mg of oral sildenafil was administered to 10 healthy male volunteers two hours before 15 minutes of cuff-induced radial artery ischemia, followed by 15 minutes of reperfusion [6]. The drug produced a protective effect in terms of alleviating endothelial dysfunction. FMD impairment after the ischemia-reperfusion test was significantly reduced by sildenafil, compared with placebo. In the same study, 5 mg of glibenclamide, a nonselective adenosine triphosphate-sensitive potassium (KATP) channel antagonist, was randomly administered to a separate group of seven healthy volunteers one hour before administration of sildenafil. The protective effect of sildenafil was completely blocked by glibenclamide at a dose that had no effect on endothelial function in the absence of sildenafil. This is the first complete study in humans to suggest that sildenafil protects the endothelium from the deleterious effects of ischemia or reperfusion through activation of vascular KATP channels. Smoking has an acute unfavorable effect on endothelial cells and production and bioactivity of NO [11]. Short-term administration of sildenafil citrate 100 mg was also associated with improvement in forearm blood flow response to acetylcholine in long-term smokers (>10 years) and healthy men, to a similar degree, which suggests that PDE-5 has a similar effect on smokers and nonsmokers [12]. In another study, a single dose of sildenafil 50 mg abolished acute smoking-induced endothelial dysfunction by reversing the decrease in FMD induced by smoking [13]. This result was significantly different from that achieved with placebo. No significant interaction was observed between sildenafil and smoking with regard to systolic blood pressure. The effect of short-term and prolonged sildenafil administration on endothelial function was also assessed in a population of men with both ED and type 2 diabetes, which is associated with abnormal NO production and action [14]. In thisdouble-blind, placebo-controlled, crossover trial, short-term administration of low-dose sildenafil (25 mg) was associated with a significant increase in brachial artery diameter induced by FMD. This effect was not seen with placebo. These significant changes in FMD parameters were maintained 24 hours after the last treatment with sildenafil (25 mg/day for two weeks), which suggests that sildenafil-induced vascular changes might persist well beyond the time of the last dose. Short-term administration of tadalafil has also been associated with improvement in endothelial function in patients with ED and several cardiovascular risk factors [1]. Thirty-two patients with a broad spectrum of ED severity were randomized to either tadalafil 20 mg on alternate days or placebo for four weeks. Endothelial function was assessed by determining brachial artery FMD, nitrite/nitrate and endothelin-1 plasma levels, at baseline, at the end of the treatment period, and at two-week follow-up. Tadalafil was associated with improved FMD values, increased nitrite/nitrate levels, and decreased endothelin-1 levels compared with placebo, which suggested improved endothelial function induced by the drug. Moreover, all these beneficial effects were maintained more than two weeks after treatment ended. The sustained beneficial effect of tadalafil on endothelial function reported in this study could be related to induction of NO production, given that nitrite/nitrate levels were still elevated two weeks after treatment. 3. Curing ED with PDE-5 inhibitors: IS there clinical evidence? PDE-5 inhibitors represent the first-line oral therapy for ED. Three PDE-5 inhibitors are currently available worldwide. Sildenafil is the most widely prescribed oral agent for ED and has a satisfactory efficacysafety profile in all patient categories. Tadalafil and vardenafil were introduced to the European Union and the United States in 2003 and 2004, respectively. Although the three PDE-5 inhibitors share many pharmacological and clinical characteristics, each has unique features. Long-term administration of PDE-5 inhibitors has been demonstrated to increase endothelial function [1,14], a consistent factor in the pathophysiology of ED, as patients with this condition often share several cardiovascular risk factors, which in turn affect endothelial and vascular properties [15]. Trials in which PDE-5 inhibitors were used to treat ED have mostly involved use of the drug in an on-demand schedule of administration, with different timings of drug intake related to different pharmacokinetic profiles for the three compounds. Because sildenafil has a terminal

4 982 european urology 49 (2006) half-life of three to five hours, with a time of maximal plasma concentration (T max ) after oral absorption in the fasting state of minutes (median, 60 minutes) [16], it can be safely administered every day. Sildenafil taken at bedtime was associated with significant improvement in nocturnal penile tumescence [17]. Only sporadic randomized, comparative trials are available that administer PDE-5 inhibitors daily as a potential cure for ED. A prospective, randomized, controlled trial was aimed to determine whether one year of daily sildenafil administration was superior to the ondemand administration schedule in terms of recovery of sexual function, preference, and safety profile [2]. Seventy-six patients (mean age 47.1) were randomly assigned to 50 mg of sildenafil every night at bedtime (group 1), mg of sildenafil on demand (group 2), or follow-up without any medical therapy (group 3) for one year. Each treatment group underwent a washout phase (one and six months in groups 1 and 2, respectively). Treatment efficacy was assessed after 12 and 13 months by means of International Index of Erectile Function (IIEF) administration and determination of peak systolic velocity (PSV) during dynamic penile colour Doppler ultrasound. After the one-month washout phase, a significantly higher percentage of patients in group 1 had restored normal EF (IIEF domain score 26) compared with group 2 (60% vs. 10%). Significant improvement in PSV was reported after one year of treatment in group 1, whereas a not statistically significant, average improvement and a slight decrease in PSV were seen in groups 2 and 3, respectively. The differences in restoring EF and improving PSV among groups were maintained even after the washout phase; six months after protocol termination, 95% of patients in group 1 who had restored EF after treatment maintained potency, according to long-term IIEF EF domain score analysis. Thus, these results seem to suggest a sustained significant regression of ED after one year of daily treatment with sildenafil, even after drug therapy termination. This finding was not noted among patients treated with an on-demand schedule; their EF declined rapidly after the end of treatment. No information regarding pretreatment ED severity and patients comorbidities has been reported; indeed, this high restoring rate of EF after treatment might be reported by patients with lower ED severity and fewer cardiovascular risk factors. Tadalafil is a potent selective inhibitor of PDE-5 whose pharmacokinetic peculiarities deserve attention. After oral administration of a 20-mg dose, tadalafil is readily absorbed, with a median T max of two hours (range, hours). The mean terminal half-life is 17.5 hours [18]. The advantage of this long half-life is that a patient may engage in sexual activity more than once after a single administration of tadalafil and the drug can be administered over the long term, with different dosing regimens. Of particular interest is a study in which three weeks of daily doses of 10, 25, 50, and 100 mg of tadalafil were compared with placebo; more than 80% of patients treated with tadalafil consistently reported improvements in erections [19]. Patients included in these studies reported headache, dyspepsia, and back pain as the most frequent adverse effects. These effects tended to decrease significantly after several doses of the drug. Thrice-weekly dosing of tadalafil was also compared with on-demand dosing (N = 2239) in a recent European, multicenter, crossover, open-label study [20]. Men with ED were randomized to tadalafil 20 mg either on demand (maximum of one dose per day, before sexual activity; group 1) or three times per week for five to six weeks (group 2). ED severity at baseline was equally distributed among mild (39.2%), moderate (27.9%), and severe (32.9%), and 85% of patients had a history of ED for more than one year. Primary endpoint analysis included a treatment preference question plus IIEF EF domain score, and secondary endpoint analysis included Sexual Encounter Profile (SEP) questions. In this crossover study, tadalafil conferred clinically significant equivalent changes from baseline in IIEF EF domain scores ( ) and responses to SEP question 3 (SEP-Q3) (72% 74%) with either dose regimen. Percentages of patients who attained normal IIEF EF domain scores (26 30) were also similar (60% 62%). No significant difference in terms of overall sexual satisfaction was evident between the two groups. A substantial number of patients (42%) preferred, when asked, the thrice-per-week regimen, although the remaining 58% chose the on-demand schedule of administration. No data are available in the report about the reasons for treatment preference. Treatment-emergent adverse effect profiles were similar in both groups, and included headache, dyspepsia, and back pain. Different results were reported in a recent openlabel, parallel-arm, crossover, randomized clinical trial aimed at assessing clinical differences between two tadalafil regimens: on-demand tadalafil 20 mg (group 1) and daily tadalafil 10 mg (group 2) for 26 weeks [21]. Each treatment phase was separated by a two-week, treatment-free washout period. Sixtyone percent of patients enrolled had moderate or severe ED at baseline. Although both treatment regimens were associated with a significant mean improvement in IIEF EF domain score, the mean

5 european urology 49 (2006) change from baseline was significantly higher for daily-dose tadalafil than for on-demand tadalafil (23.3 vs in groups 1 and 2, respectively; p < 0.05). Furthermore, although both types of tadalafil administration significantly improved the mean successful penetration rate (SEP-Q2) and the mean intercourse completion rate (SEP- Q3), the daily dose regimen was significantly superior to the on-demand one in terms of global efficacy reported, ability to initiate and complete vaginal intercourse, and the percentage of men who returned to normal EF ( p < 0.05 for each). Thus, overall, 72% of patients preferred daily tadalafil 10 mg and 28% of patients reported more benefits with the on-demand regimen; the predominant reasons for this preference included superior sexual spontaneity (55%) and superior efficacy (30%). No significant differences in terms of prevalence and severity of adverse effects were reported between the two groups, except for headache, which was less common with daily tadalafil 10 mg. No current studies are available about daily use of vardenafil in the treatment of ED. Finally, major investments should be made either by institutional funding or pharmaceutical companies to address in a long-term randomized fashion whether chronic PDE-5 inhibitor administration can be definitely considered as a therapy to restore normal EF in patients affected by ED. 4. Postprostatectomy prophylaxis of ED with PDE-5 inhibitors The clinical setting of ED after radical prostatectomy is an ideal situation to consider implementation of PDE-5 inhibitors as curative therapy. An urgency to restore and preserve EF in this setting is evident, since so many men are potent before surgery and many lose their potency or endure a substantial period of erection recovery afterward before resuming satisfactory sexual activity. This occurs even when nerve-sparing radical prostatectomy is performed [22]. Exploring strategies in clinical management after radical prostatectomy that may facilitate the return of natural EF seems entirely logical and purposeful. As an indication that vasoactive pharmacotherapy could fill this role, Montorsi et al. first demonstrated the improved erection rate in a series of men who used intracavernous injection therapy as an early postoperative intervention [23]. Inherently more attractive because of their noninvasiveness, simpli-city, and tolerability, PDE-5 inhibitors have most recently been proposed for erection rehabilitation or prophylaxis of ED. In a pioneering study that received significant attention, Padma-Nathan et al. found an apparently curative benefit of sildenafil in a placebo-controlled clinical trial that involved preoperatively potent men treated with the PDE-5 inhibitor nightly starting four weeks after nerve-sparing radical prostatectomy and continuing for approximately nine months [24]. Eight weeks after discontinuation of therapy (one year after surgery), 14 (27%) of 51 men who used sildenafil, in contrast to one (4%) of 25 men in the control group, reported recovery of spontaneous EF. The investigators applied subjective reporting criteria (a fully rigid erection suitable for intercourse) for this analysis, which explains the apparently low reported rates of functional recovery in this report. In a corresponding objective evaluation at the one-year interval that involved 54 men from this same study, 10 (29%) of 35 sildenafil-treated patients and one (5%) of 19 placebo-treated patients met criteria for erection recovery by nocturnal penile tumescence and rigidity evaluation [25]. Despite the enthusiasm associated with this initial study, the precise role of PDE-5 inhibitors as curative therapy after radical prostatectomy remains unclear. Additional controlled clinical trials are needed to establish this benefit. In the meantime, clinical investigators have begun to explore the feasibility of this pharmacotherapeutic strategy and define therapeutic regimens that may be considered [26,27]. Further investigation may also reveal the mechanism by which such therapy exerts beneficial effects. In line with the evidence-based description of its mechanism of action, PDE-5 inhibitor therapy in this setting quite likely reduces to some extent the intracorporal vascular compromise that occurs in association with the neuropathic effects of the surgery [28,29]. It may also serve some sort of neuroprotective role, but that possibility is currently not well supported. 5. Basic science evidence Basic science evidence that PDE-5 inhibitors exert sustained healthful effects on the penile vascular system lends substantial support to the notion that such agents fulfill a curative role for ED. Although the premise that such therapy produces or maintains normal erectile ability seems feasible and has drawn major interest, the scientific grounds for such an application should be questioned before its curative benefit is established. In this regard, several scientific studies have provided direct experimental support for the role of PDE-5 inhibitors in improving the structure and

6 984 Erectile dysfunction is a highly prevalent medical condition that is often associated with cardiovaseuropean urology 49 (2006) function of the cavernosal tissue and have suggested plausible molecular mechanisms for these effects. In rats chemically induced with streptozotocin to become diabetic, oral sildenafil (5 mg/kg) administered daily for three weeks better preserved penile tissue morphology, cavernosal tissue expression of the erection factor neuronal NO synthase, and erection physiology than vehicle control treatment, and the beneficial effects were intensified in combination with free oxygen radical scavengers [30]. A similar preservation of erectile tissue morphology after PDE-5 inhibitor treatment was described in an investigation at the human level. In this study, preoperatively potent men were randomized to sildenafil 50 mg or 100 mg every day for six months after nerve-sparing radical prostatectomy. Men who took the 100-mg dose had better preserved intracorporal smooth muscle content than those who took the medication at the lower dosage [31]. This protective effect was further demonstrated in a study that used the PDE-5 inhibitor DA-8159 (5, 10, and 20 mg/kg; Dong-A Pharmaceutical Co., Youngin, Korea), orally administered once a day for eight weeks to rats with streptozotocin-induced diabetes [32]. The treatment resulted in reduced ED and preserved cavernosal tissue smooth muscle and endothelial components, compared with findings in untreated diabetic control rats. In addition, the beneficial effects were dose dependent and correlated with reduced expression levels of the profibrotic cytokine TGF-b1 (transforming growth factor b1) in penile tissue. A daily, eight-week treatment with sildenafil (60 mg/kg) administered subcutaneously to intact rats was recently shown to produce an enhanced relaxation response in isolated cavernosal tissue strips under an organ bath experimental protocol in response to acetylcholine but not to the calcium ionophore A23187 or sodium nitroprusside [33]. The investigators also showed that this treatment improved intact animal erection physiological responses, although they conceded that this result was likely confounded by persistent drug in the animals systems because of an insufficient washout period. Nonetheless, the findings suggested that the endothelium-dependent response is promoted with long-term PDE-5 inhibitor treatment and that the therapy does not confer an adverse effect on cavernosal tissue responsiveness involved in physiological erection. Another group of investigators also examined the possible physiological benefit of long-term sildenafil treatment in a rat model to define a molecular basis for any beneficial effect. The study involved old rats that represented an age-associated ED model, and young rats with normal EF [34]. The rats were treated with sildenafil (20 mg/kg) subcutaneously every eight hours for three weeks in combination with assays of free plasma levels of the drug. After confirmed clinically relevant dosing and then washout of sildenafil, old rats displayed an improvement in erection ability by erection physiological testing, along with measured significant increases in the activated form of endothelial NO synthase, which has been associated with blood flow-stimulated proerectile effects and cavernosal tissue health [35,36]. Although young rats also showed increases in this molecular factor and its signalling pathway after sildenafil treatment, the increase over baseline was minimal and the biological effect was apparently countered by increased cavernosal tissue expression levels of PDE-5 and phosphomyosin phosphatase target subunit 1, a marker of Rho-kinase activity, which both oppose erectile ability. The investigators concluded that long-term sildenafil treatment may have long-lasting, physiologically significant erectile tissue benefits. They also determined that such treatment is effective under conditions of erectile impairment, rather than when EF is intact, and mechanisms are operable in the penis of the healthy individual in response to long-term PDE- 5 inhibitor treatment to prevent potentially harmful excessive erections. In all, these reports suggest that PDE-5 inhibitor therapy exerts healthful effects on erectile tissue, with sustained benefits that can be demonstrated after a continuous, extended course of therapy. Current science suggests that the effect involves molecular mechanisms that operate at the level of the penile vascular endothelium, with particular benefit under conditions of erectile impairment. This targeted therapy would seem to be particularly advantageous for ED states associated with endothelial dysfunction such as diabetes, hypertension, heart disease, hypercholesterolemia, and other vascular disorders. PDE-5 inhibitors may exert functional effects beyond the vascular supply of the penis and operate according to molecular mechanisms separate from vascular biological actions. For instance, the action of PDE-5 inhibitors as a form of neuroprotective therapy has been put forward as a hypothesis, particularly in considering its apparent benefit after radical prostatectomy. Such possibilities may be established with further investigation. 6. Conclusions

7 european urology 49 (2006) cular risk factors and endothelial dysfunction. Although recent clinical studies have shown that chronic use of PDE-5 inhibitors is effective and safe, data about potential mechanisms induced by longterm PDE-5 administration in men who are affected by ED are lacking. Animal studies indicate that chronic exposure to PDE-5 inhibitors could have a beneficial effect on endothelial dysfunction. Further well-designed, prospective randomized trials are urgently needed to assess whether chronic administration of PDE-5 inhibitors may help restore EF in patients affected by ED. References [1] Rosano GM, Aversa A, Vitale C, Fabbri A, Fini M, Spera G. Chronic treatment with tadalafil improves endothelial function in men with increased cardiovascular risk factors. Eur Urol 2005;47: [2] Sommer F, Engelmann U. Curing erectile dysfunction: long term effects of taking PDE-5 inhibitors on a daily basis. Eur Urol 2004;2(Suppl.):32, (abstract 118). 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