Impact of Phosphodiesterase Type 5 Inhibitors on Endothelial Function

Treatment Update

RIU0323_03-14.qxd 3/15/08 2:59 AM Page 26 TREATMENT UPDATE Impact of Phosphodiesterase Type 5 Inhibitors on Endothelial Function Patrick E. Teloken, MS, John P. Mulhall, MD Department of Urology, Weill Medical College of Cornell University, New York, NY It is now known that endothelial health is essential for normal erectile function, and changes in endothelial integrity or function may lead to erectile dysfunction (ED). Because phosphodiesterase type 5 (PDE-5) inhibitors have been shown to improve endothelial function, many investigators have questioned whether PDE-5 inhibition will lead to improvement in erectile function. Data from the studies reviewed in this article show that therapy with PDE-5 inhibitors results in improvement in flow-mediated dilation, nocturnal penile tumescence and rigidity, and carotid artery intima-media thickness as well as higher scores on the Sexual Health Inventory for Men, International Index of Erectile Function, Erection Function Domain, and other instruments. Further research is needed to determine whether long-term PDE-5 inhibition can reverse ED and whether use of these agents will decrease cardiovascular morbidity in high-risk populations. [Rev Urol. 2008;10(1):26-30] © 2008 MedReviews, LLC Key words: Endothelial function • Erectile dysfunction • Phosphodiesterase type 5 inhibitors • Sildenafil • Tadalafil rectile dysfunction (ED) is a common disease with a significant negative impact on quality of life. As ED has been irrefutably linked to endothelial dysfunction, it has been questioned whether improvement in endothelial function can ameliorate ED. Phosphodiesterase type 5 (PDE-5) inhibitors have been implicated in improving endothelial function; therefore, their long-term use in the treatment of ED is currently under study. This article addresses 3 interrelated E 26 VOL. 10 NO. 1 2008 REVIEWS IN UROLOGY RIU0323_03-14.qxd 3/15/08 2:59 AM Page 27 PDE-5 Inhibitors and Endothelial Function Endothelial Function and Erectile Function Erectile tissue is composed of smooth muscle that lines lacunar spaces (sinusoids) that are lined by endothelium; thus, the 2 functional erectile tissues are muscle and endothelium. Normal penile erection requires the following physiologic processes: an increase in neurologically mediated penile arterial inflow, cavernosal smooth muscle relaxation, and restriction of penile venous outflow.1 These phenomena require neural integrity, patent cavernosal arteries, and healthy cavernosal tissue, including adequate endothelial function. The importance of adequate endothelial function was recognized after identification of similar risk factors for ED and coronary artery disease (CAD), such as obesity, dyslipidemias, sedentary lifestyle, smoking, diabetes mellitus, and hypertension. Erectile smooth muscle relaxes in response to nitric oxide (NO). This neurotransmitter leads to activation of guanylate cyclase, which leads to increased levels of the second messenger cyclic guanosine monophosphate (cGMP).2 This process results in calcium changes within the sarcoplasm, which eventuate in relaxation of the smooth muscle, which in turn causes arterial inflow of blood. Although a number of neurotransmitters are important for erectogenesis, NO is by far the most important. NO has 2 important sources. The cavernous nerves produce NO through the action of neuronal nitric oxide synthase (nNOS), which is responsible for the activation of the erectile cascade.3 Just as important is the endothelium-derived NO driven by endothelial nitric oxide synthase (eNOS) in response to shear stress, which is responsible for erection maintenance. Both of these negatively affect endothelial function, such as hypertension, dyslipidemia, diabetes, and the more recently recognized metabolic syndrome, have all been identified as key correlates of ED.2 In effect, ED may be caused by endothelial dysfunction. As a corollary, strategies that improve endothelial function may, in fact, have a positive impact on erectile function. enzymes are regulated predominantly at the posttranslational level. It is the endothelium-derived NO that results in erection maintenance. Thus, the endothelium, which lines the lacunar spaces within the erectile tissue, is a key regulator of erection that functions in a fashion similar to the brachial artery endothelium, which plays a role in the production of postartery compression vasodilatation (flow-mediated dilation [FMD]). Endothelial dysfunction is commonly defined as an altered endothelial response that diminishes NO bioavailability, impairing vasodilatation. Given that most healthy men have regular nocturnal erections even in the absence of stimulation, it has been hypothesized that oxygen tension, which increases during erection, either stimulated or nocturnal, has an important role in maintaining cavernosal tissue integrity.4 Conditions that PDE-5 Inhibitors and Endothelial Function PDE-5 is an enzyme that belongs to a superclass of enzymes containing 11 families and 21 subfamilies.5 It catalyzes the degradation of cGMP, reducing its relaxant effect. Thus, inhibition of PDE-5 results in accumulation of the proerectile cGMP. One of the first indications that PDE-5 inhibition may have a positive impact on endothelial health is the fact that the incidence of myocardial Figure 1. Effects of sildenafil on brachial artery flow-mediated dilatation (FMD) in type 2 diabetes. Desouza and colleagues6 assessed the acute and prolonged effects of a low dose of sildenafil on FMD in patients with type 2 diabetes and impaired nitric oxide–dependent endothelial function. The mean  SD brachial artery diameter (BAD) increased 8% after inducing FMD. One hour after oral administration of sildenafil 25 mg, FMD increased the BAD significantly by 15%, whereas it did not change with placebo. After treatment with sildenafil 25 mg daily for 2 weeks and testing 24 hours after the last dose, the mean BAD was 14% greater compared with 9% for placebo. * P  .01 versus preocclusion. NS, not significant versus preocclusion. 18 15* 15 Percent Increase subjects: ED, endothelial dysfunction, and PDE-5 inhibitor utilization. 14* 12 9 9 (NS) 8 (NS) 8 6 3 0 1 Hour After Administration 24 Hours After Last Dose of 14-Day Treatment 4.28 ⫾ 0.6 4.34 ⫾ 0.5 4.61 ⫾ 0.6 4.99 ⫾ 0.5 4.32 ⫾ 0.5 4.31 ⫾ 0.6 4.72 ⫾ 0.5 4.91 ⫾ 0.5 At First Visit Brachial Artery Diameter Preocclusion (mm) Postocclusion (mm) 4.33 ⫾ 0.6 4.66 ⫾ 0.5 Baseline Placebo VOL. 10 NO. 1 2008 Sildenafil REVIEWS IN UROLOGY 27 RIU0323_03-14.qxd 3/15/08 2:59 AM Page 28 PDE-5 Inhibitors and Endothelial Function continued infarction was lower in the sildenafil arms of phase II, III, and IV studies compared with the placebo arms (0.56/100 patient-years vs 0.84/100 patient-years; data on file, Pfizer Inc). In 2002, Desouza and colleagues6 published data that demonstrated the positive effect of long-term sildenafil dosing on endothelial function. In 14 patients with ED and type 2 diabetes, the acute and chronic effect of sildenafil on brachial artery FMD was investigated. All patients received both sildenafil and placebo in a staggered fashion. FMD was measured at baseline and 1 hour after administration of placebo or 25 mg of sildenafil. Significant improvement in brachial artery diameter was demonstrated in the sildenafil arm (15% vs 8% for placebo; pretreatment after inducing FMD was 8%). This finding had been previously shown by Katz and associates7 in patients with chronic heart failure. In the chronic phase, patients received either sildenafil 25 mg or placebo daily for 14 nights (all patients received both agents); 24 hours after the last dose, the patients’ FMD was measured again. Once again, sildenafil resulted in significant changes in FMD (14% vs 9%; pretreatment was 8%). Thus, sildenafil seems to have a significant effect on endothelium, even at a time point beyond its duration of action (half-life of 4 hours; presence in serum for 4 to 5 half-lives). This finding has been confirmed experimentally by demonstrating that sildenafil activates the PI3/AKT/eNOS pathway.8 Halcox and coworkers9 found that acute sildenafil dosing caused not only basal epicardial dilation but also an increased response to acetylcholine (endothelial-dependent vasodilatation) independent of baseline sildenafil vasodilator effect, as as- These findings suggest that the impact of phosphodiesterase type 5 inhibitors on endothelium at the cellular level may be self-sustaining long after drug has been metabolized. sessed by the acetylcholine/verapamil ratio before and after sildenafil administration. This effect was more pronounced in patients with altered coronary angiography. On the other hand, a significant increase in FMD was seen only in healthy controls and not in patients with CAD. Table 1 Chronic Treatment With Tadalafil Improves Endothelial Function in Men With Increased Cardiovascular Risk Baseline 4 Weeks Brachial Artery Flow-Mediated Dilation Tadalafil 4.2%  3.2% 9.3%  3.7%, P  .01 Placebo 4.1%  2.8% 4.0%  .4%, P  NS 6 Weeks 9.1%  3.9% No change Nitrite/Nitrate Levels Tadalafil 38.2%  12.3% 52.6%  11.7% 51.1%  3.1%, P  .05 Endothelin-1 Levels Tadalafil 3.3%  0.9% 2.9%  0.7% 2.9%  0.9%, P  .05 10 Rosano and colleagues randomized 32 patients with increased cardiovascular risk to receive either tadalafil 20 mg on alternate days or placebo for 4 weeks. Patients underwent evaluation of brachial artery flow-mediated dilation, nitrite/nitrate, and endothelin-1 plasma levels at baseline, at the end of treatment period, and after 2 weeks follow-up. 28 VOL. 10 NO. 1 2008 More recently, Rosano and colleagues10 evaluated 32 men using FMD who had an increased cardiovascular risk (ie, ED with more than 2 risk factors for CAD, resulting in a 10-year cardiovascular risk  20%). The patients were randomly assigned to receive either tadalafil (20 mg) every other day or placebo. At 4 weeks, tadalafil significantly improved FMD from 4.2% to 9.3% (change between pre- and postocclusion brachial artery diameters). Note that in the Desouza sildenafil study, the baseline change was 8% and increased to 15% at 1 hour and 24 hours after a 25-mg dose (a quarter of the maximum approved REVIEWS IN UROLOGY dose). The improvements with tadalafil were sustained at 6 weeks, that is, 2 weeks after cessation of the medication. These data mirror those from the sildenafil study in that significant improvements were seen in endothelial function (approximately a doubling of the degree of vasodilatation), even beyond the survival of the drug within the body. These findings suggest that the impact of PDE-5 inhibitors on endothelium at the cellular level may be self-sustaining long after drug has been metabolized. Long-Term PDE-5 Inhibition and Erectile Function Given the accumulation of evidence suggesting that PDE-5 inhibitors positively affect endothelial function, it has been hypothesized that its chronic use may be beneficial for ED patients. To investigate this issue, Caretta and associates11 administered tadalafil (20 mg) on alternate days for 3 months to 60 subjects aged 60 to 70 years with a history of ED for 6 to 12 months without cardiovascular disease or risk RIU0323_03-14.qxd 3/15/08 2:59 AM Page 29 PDE-5 Inhibitors and Endothelial Function factors and to 30 men younger than 40 years with presumably psychogenic ED. At baseline, all patients were evaluated with nocturnal penile tumescence and rigidity (NPTR), penile Doppler ultrasound, and carotid artery intima-media thickness (IMT) studies. One month after the end of treatment, the patients repeated the NPTR and penile Doppler ultrasound studies and completed the Sexual Health Inventory for Men (SHIM). Elderly men with an IMT less than 1.3 mm showed improvement in all NPTR parameters; those with an IMT of 0.9 to 1.3 mm also had improved peak systolic velocity on penile Doppler ultrasound. Normalization of SHIM score occurred in 60% of elderly men with an IMT less than 1.3 mm, 16% of those with an IMT greater than 1.3 mm, and 66% of controls. Although interesting, this study suffers from important methodologic limitations, particularly the lack of a preoperative SHIM score report. The SURE (Scheduled Use vs Ondemand Regimen Evaluation) study, a randomized, crossover, open-label study, compared on-demand with thrice-weekly tadalafil (20 mg) in patients with ED of any severity or etiology.12 After a 3- to 4-week runin, treatment-free period, patients followed either treatment regimen for a period of 5 to 6 weeks followed by a 1-week wash-out period, then crossed over to the other group for 5 to 6 weeks. The primary outcome was treatment preference; secondary outcomes included International Index of Erectile Function (IIEF) and sexual encounter profile (SEP) data. Of the 3861 subjects who answered the treatment preference question (TPQ), 57.8% chose the on-demand treatment (P  .001). Both regimens were similar with regard to IIEF score change, IIEF score normalization, and per patient rate on all 5 SEP questions. Side effects of both regimens also were similar. A randomized, crossover, openlabel study comparing on-demand tadalafil (20 mg) to daily tadalafil (10 mg) was carried out by McMahon.13 After a 4-week run-in period, 145 men older than 18 years who reported having ED for more than 6 months were randomized. After 12 weeks of treatment, the subjects underwent a 2-week wash-out and crossed to the other regimen for another 12 weeks. Outcome measures were IIEF, SEP, global assessment question (GAQ), and TPQ. After 12 weeks of treatment, the daily tadalafil group showed better results on Erectile Function (EF) Domain score, return to normal EF Domain score, penetration success (SEP2), intercourse completion (SEP3), and GAQ when compared with the on-demand group (all P  .05). At the end of the trial, 72% of patients preferred the daily regimen. Side effects were similar in both groups, with the exception of headache, which was less common in Main Points • As erectile dysfunction (ED) has been irrefutably linked to endothelial dysfunction, it has been questioned whether improvement in endothelial function can ameliorate ED. Phosphodiesterase type 5 (PDE-5) inhibitors have been implicated in improving endothelial function; therefore, their long-term use in the treatment of ED is currently under study. • Although a number of neurotransmitters are important for erectogenesis, nitric oxide is by far the most important. • In several studies looking at the effect of PDE-5 inhibitors on endothelial health, significant improvements were seen in endothelial function (approximately a doubling of the degree of vasodilatation), even beyond the survival of the drug within the body. These findings suggest that the impact of PDE-5 inhibitors on endothelium at the cellular level may be self-sustaining long after drug has been metabolized. • In a study by Caretta and associates on long-term administration of tadalafil (20 mg every other day for 3 months), elderly men with a carotid artery intima-media thickness (IMT) less than 1.3 showed improvement in all nocturnal penile tumescence and rigidity parameters; those with an IMT of 0.9 to 1.3 also had improved peak systolic velocity on penile Doppler ultrasound. • SURE (Scheduled Use vs On-demand Regimen Evaluation) compared on-demand with thrice-weekly tadalafil in patients with ED. Although both regimens were similar with regard to International Index of Erectile Function (IIEF) score change, IIEF score normalization, per patient rate on all 5 sexual encounter profile (SEP) questions, and side effects, 57.8% of the patients chose the on-demand treatment. • In a study by McMahon comparing on-demand tadalafil (20 mg) to daily tadalafil (10 mg), the daily tadalafil group showed better results on Erectile Function (EF) Domain score, return to normal EF Domain score, penetration success (SEP2), intercourse completion (SEP3), and global assessment question when compared with the on-demand group. At the end of the trial, 72% of patients preferred the daily regimen. VOL. 10 NO. 1 2008 REVIEWS IN UROLOGY 29 RIU0323_03-14.qxd 3/15/08 2:59 AM Page 30 PDE-5 Inhibitors and Endothelial Function continued the daily group (P  .001), probably because of lower plasma peaks and the steady plasma level achieved. Of note, it is recognized that daily dosing of tadalafil for 5 days in a row results in serum levels 1.6 times that of a single dose (data on file, Lilly-ICOS). Although similar, these 2 trials have methodologic differences that may have accounted for the discrepant results. Each treatment period in the SURE study was half as long as those in the McMahon study. Also, long-term treatment regimens were different and exclusion criteria more comprehensive in the McMahon study, perhaps enriching the study population somewhat. In investigating the possibility of tachyphylaxis effect, Musicki and coworkers14 administered sildenafil mesylate (20 mg/kg) or saline subcutaneously every 8 hours for 3 weeks to young and aged rats. Responses were compared with those from acute sildenafil administration. Chronic sildenafil treatment increased the detumescence phase, particularly in aged animals. PDE-5 activity inhibition was similar with acute and chronic sildenafil administration. These results suggest that tachyphylaxis does not occur with sildenafil. The clinical effects of long-term PDE-5 inhibitor use are yet to be determined. The number of circulating endothelial progenitor cells, which are impor- 30 VOL. 10 NO. 1 2008 tant for neovascularization and endothelial repair and are reduced in patients with cardiovascular risk factors, increases after vardenafil administration.15,16 6. Summary 7. Endothelial health is essential for normal erectile function, and changes in endothelial integrity or function may lead to ED. The PDE-5 inhibitors sildenafil and tadalafil have been shown to improve endothelial function; besides the obvious inhibition of PDE-5, their erectogenic effects may partly be mediated through endothelial effects. The questions that remain to be answered are whether long-term use of these agents can reverse—that is, essentially cure—ED and whether the use of these drugs results in lowering of cardiovascular morbidity in high-risk populations, such as those with diabetes. 8. 9. 10. 11. 12. References 1. 2. 3. 4. 5. REVIEWS IN UROLOGY Giuliano F, Rampin O, Bernabe J, et al. Neural control of penile erection in the rat. J Auton Nerv Syst. 1995;55:36-44. Lue TF. Erectile dysfunction. N Engl J Med. 2000;342:1802-1813. Burnett AL, Calvin DC, Silver RI, et al. Immunohistochemical description of nitric oxide synthase isoforms in human clitoris. J Urol. 1997;158:75-78. Moreland RB. Is there a role of hypoxemia in penile fibrosis: a viewpoint presented to the Society for the Study of Impotence. Int J Impot Res. 1998;10:113-120. Wallis RM, Corbin JD, Francis SH, et al. Tissue distribution of phosphodiesterase families and the effects of sildenafil on tissue cyclic nu- 13. 14. 15. 16. cleotides, platelet function, and the contractile responses of trabeculae carneae and aortic rings in vitro. Am J Cardiol. 1999;83:3C-12C. Desouza C, Parulkar A, Lumpkin D, et al. Acute and prolonged effects of sildenafil on brachial artery flow-mediated dilatation in type 2 diabetes. Diabetes Care. 2002;25:13361339. Katz SD, Balidemaj K, Homma S, et al. Acute type 5 phosphodiesterase inhibition with sildenafil enhances flow-mediated vasodilation in patients with chronic heart failure. J Am Coll Cardiol. 2000;36:845-851. Musicki B, Kramer MF, Becker RE, Burnett AL. Inactivation of phosphorylated endothelial nitric oxide synthase (Ser-1177) by O-GlcNAc in diabetes-associated erectile dysfunction. Proc Natl Acad Sci U S A. 2005;102:11870-11875. Halcox JP, Nour KR, Zalos G, et al. The effect of sildenafil on human vascular function, platelet activation, and myocardial ischemia. J Am Coll Cardiol. 2002;40:1232-1240. Rosano GM, Aversa A, Vitale C, et al. Chronic treatment with tadalafil improves endothelial function in men with increased cardiovascular risk. Eur Urol. 2005;47:214-220. Caretta N, Palego P, Ferlin A, et al. Resumption of spontaneous erections in selected patients affected by erectile dysfunction and various degrees of carotid wall alteration: role of tadalafil. Eur Urol. 2005;48:326-331. Mirone V, Costa P, Damber JE, et al. An evaluation of an alternative dosing regimen with tadalafil, 3 times/week, for men with erectile dysfunction: SURE study in 14 European countries. Eur Urol. 2005;47:846-854. McMahon C. Comparison of efficacy, safety, and tolerability of on-demand tadalafil and daily dosed tadalafil for the treatment of erectile dysfunction. J Sex Med. 2005;2:415-425. Musicki B, Champion HC, Becker RE, et al. In vivo analysis of chronic phosphodiesterase-5 inhibition with sildenafil in penile erectile tissues: no tachyphylaxis effect. J Urol. 2005;174:14931496. Garmy-Susini B, Varner JA. Circulating endothelial progenitor cells. Br J Cancer. 2005;93: 855-858. Foresta C, Caretta N, Lana A, et al. Circulating endothelial progenitor cells in subjects with erectile dysfunction. Int J Impot Res. 2005;17:288-290.