Targeting of PDE5 for Preservation of Penile Health

[madman]

Molecular Pharmacotherapeutic Review Targeting of PDE5 for Preservation of Penile Health (2008)
ARTHUR L. BURNETT


ABSTRACT

The molecular science of erection physiology has established that phosphodiesterase 5 (PDE5) serves an important biological role in the penis. Current research in the field has revealed this molecular effector to be relevant for penile erection, controlling the erectile response by degrading the second messenger product of the erection mediatory nitric oxide (NO) signaling pathway, 3’, 5’- cyclic guanosine monophosphate. Accordingly, PDE5 has been targeted for sexual medicine purposes, and orally administered PDE5 inhibitors such as sildenafil, tadalafil, and vardenafil comprise a foremost intervention for erectile dysfunction (ED). A new investigation of PDE5 regulation in the penis has suggested alternative roles for the enzyme and new therapeutic opportunities involving its molecular interactions. In particular, PDE5 function is altered under derangements of androgen deficiency, decreased NO bioactivity, and oxidative stress-associated inflammatory changes, thus contributing to an assortment of erectile disorders including hypogonadism associated ED, recurrent ischemic priapism, penile vasculopathy, and penile fibrosis. This review provides a critical examination of the multifaceted role of the PDE5 regulatory system in the penis and its relevance for applying to existing and emerging therapeutic strategies for erectile disorders.




Phosphodiesterase type 5 (PDE5) is an important molecular player in the biology of penile erection. Acknowledged for its role in controlling the erectile response by degrading the second messenger product of the erection mediatory nitric oxide (NO) signaling pathway, 39,59-cyclic guanosine monophosphate (cGMP), the enzyme has been targeted for sexual medicine purposes. Presently available orally administered PDE5 inhibitors in the United States (ie, sildenafil, tadalafil, and vardenafil) comprise a foremost intervention for erectile dysfunction (ED), and they are now considered standard, first-line therapy for this indication (Montague et al, 2005). The advent of PDE5 inhibitor therapy has been momentous in advancing multiple clinical and scientific aspects surrounding this sexual dysfunction. Furthermore, the therapy can be credited with revolutionizing the entire field of sexual medicine, having brought increased awareness and legitimacy to all matters of sexual health across medical and public communities, and supporting sexual well-being as a foundation for general good health.

Such recent progress not only signifies increasing scientific rigor in the field of sexual medicine but also heralds the prospect of multiple new scientific directions that could lead to further therapeutic breakthroughs. This statement aptly applies to a range of disorders of penile erection, beyond the categorization of all erectile impairments generically as ED, classically defined as the inability to attain and maintain an erection satisfactorily for sexual performance (NIH Consensus Conference, 1993). Less well-recognized erectile disorders include hypogonadism-associated ED, recurrent ischemic priapism, penile vasculopathy, and penile fibrosis. Accordingly, the new science of erection physiology implies an expansion in concepts of the pathogeneses of all such disorders and the development of specific evidence-based rationales for their effective treatment. The ultimate goal of clinical management for any erectile disorder would be that of preserving erectile function as much as possible and preventing its loss.

In light of PDE5’s major involvement in the molecular mechanisms of penile erection, it is timely to conjecture how it may be further exploited beyond its direct pharmacologic inactivation for temporary erectogenesis. One may also surmise that the conventional practice of using PDE5 inhibitors for ED management as a short-term intervention is restrictive, and opportunities likely exist for applying these drugs in various novel ways to derive further penile health benefits. These ‘‘outside the box’’ thoughts are not at all illogical, and in fact, they are consistent with steady advances in the science of penile erection and in the molecular biology of PDE5.

In this review, I examine the multifaceted role of the PDE5 regulatory system in the penis and its relevance for furthering therapeutics for a spectrum of penile health indications. We begin with an overview of the basic biology of PDE5 by highlighting the general properties and molecular interactions of this fascinating molecule. I also briefly describe its familiar characterization in the penis and summarize the conventional ‘‘on-demand’’ use of PDE5 inhibitors for the clinical management of ED. Then within the context of several specific erectile disorders, I explore the convergence of currently understood PDE5 molecular biologic principles and advancing knowledge of erectile mechanisms. Applying this framework, I discuss the potential pharmacotherapeutic advantages of PDE5 as a molecular target for interventions aimed toward preserving penile health and submit plausible strategies that employ PDE5 inhibitors for this endeavor.




*Molecular Biology of PDE5

*Role of PDE5 in Erectogenesis

*Clinical Applications
-Hypogonadism-Associated ED Treatment
-Management of Recurrent Priapism
-Penile Vascular Protection
-Penile Tissue Health Restoration




Summary

The significance of PDE5 in the penis is well understood in terms of its role in penile erection. There is ample evidence that this enzyme serves an important regulatory role for this biological function. However, increasing attention has been given recently to the regulatory basis of PDE5, which influences its operation in the penis. This concept implies that the regulatory determinants of PDE5 biology in this organ are as important for the mechanistic effects of PDE5 as its biologic activity alone. Regulators in this regard include both endogenous and exogenous factors. Endogenously, androgens and upstream components of the NO signaling cascade affect PDE5 expression and activity in the penis. Derangements in their actions account for pathologic consequences in the penis, and conversely, interventions such as exogenous androgen replacement or pharmacologic optimization of NO signaling in the penis using PDE5 inhibitors improve or restore penile physiology. The current understanding that PDE5 biology in the penis is not static but rather is modifiable and subject to various forms of modulation suggests that the enzyme is an opportune pharmacotherapeutic target for preserving penile health. Ongoing investigation in the field may suggest additional innovative strategies that may be specifically applied to advance this health objective.

 

[madman]

Figure 1. Schematic diagram of the nitric oxide (NO) signaling pathway in the penis in the context of normal erection physiology. The diagram shows the molecular determinants of a regulatory balance that governs alternative physiologic states of erectile tissue relaxation (erection) and erectile tissue contraction (flaccidity). NO, generated constitutively from L-arginine and released from nerves and endothelium, diffuses to local smooth muscle cells where it primarily activates guanylate cyclase to convert 59-guanosine triphosphate (GTP) to 39,59-cyclic guanosine monophosphate (cGMP). By way of cGMP-dependent downstream effector molecule actions, cGMP elicits penile erection. The catalytic function of phosphodiesterase type 5 accounts for the degradation of cGMP to its inactive form, 59-GMP, with the subsequent reformation of GTP.

 

[madman]

Figure 2. Schematic diagram of the nitric oxide (NO) signaling pathway in the penis in the context of hypogonadism-associated erectile dysfunction (ED). The diagram depicts a disturbed regulatory balance that predisposes reduced normal erections. The pathophysiology features low constitutive NO bioactivity and dysregulated phosphodiesterase type 5. Androgen deficiency affecting other erectile mechanisms also contributes to ED.

 

[madman]

Figure 3. Schematic diagram of the nitric oxide (NO) signaling pathway in the penis in the context of recurrent ischemic priapism. The diagram depicts a disturbed regulatory balance that predisposes to excessive penile erection. The pathophysiology features low constitutive NO bioactivity basally and dysregulated phosphodiesterase type 5. Upon periodic heightened NO generation and release, 39,59-cyclic guanosine monophosphate is not degraded and accumulates, causing an excessive erectile tissue vasorelaxant response.

 

[madman]

Figure 4. Schematic diagram of the nitric oxide (NO) signaling pathway in the penis in the context of penile vasculopathy and penile fibrosis. The diagram depicts a disturbed regulatory balance that predisposes reduced normal erections. The pathophysiology features low constitutive NO bioactivity. Pathologic conditions associated with these erectile disorders contribute to erectile dysfunction.

 

[madman]

Penile Vascular Protection

The medical literature widely supports vascular health objectives as a means toward achieving long-term health maintenance and longevity. Several thought leaders in sexual medicine have further pointed to penile vascular health as a critical gauge of this outcome (Kloner et al, 2003; Solomon et al, 2003). The pathogenesis of vascular disease both systemically and locally in the penis is linked with NO imbalance via endothelial defects and/or oxidative stress, which subsequently diminishes the physiologic actions of NO and its effectors (Cooke and Dzau, 1997; Bonetti et al, 2003) (Figure 4). To address this pathophysiology, suggested preventative practices have been advocated to include increasing physical fitness, improving healthful dietary habits, and reducing obesity (Esposito et al, 2004; Esposito et al, 2006). Additional consideration has been given to medical therapies such as regularly used PDE5 inhibitors under the premise that this treatment may afford long-term vascular healthful benefits for the penis (Montorsi et al, 2000; Burnett, 2005a).

Basic scientific evidence supports a penile vasculoprotective premise associated with long-term PDE5 inhibitor use. Several scientific studies have shown the utility of chronically applied PDE5 inhibitors in improving the structure and function of the cavernosal tissue and provided plausible mechanisms for these beneficial effects. In experimental paradigms involving rats that were chemically diabetogenic (De Young et al, 2003; Ahn et al, 2005), intact (Behr-Roussel et al, 2005), or aged (Musicki et al, 2005b; Ferrini et al, 2007) or had cavernous nerve injuries (Vignozzi et al, 2006; Ferrini et al, 2006a; Lagoda et al, 2007), continuous systemic PDE5 inhibitor treatment ranging from several days to 3 months preserved erectile tissue morphology and erection physiology to a better extent than did control treatments. Improved erectile responses were found to be sustained after confirmed drug clearance or withdrawal of the active drug in vivo (Musicki et al, 2005a; Lagoda et al, 2007) and in vitro (Behr-Roussel et al, 2005) protocols, respectively. Foremost possible biologic mechanisms by which PDE5 inhibitors afford penile vascular protection include antioxidation (De Young et al, 2003; Lagoda et al, 2007), antiapoptosis (Ahn et al, 2005; Musicki et al, 2005b), and activation of blood flow-associated vasodilatory effectors (BehrRoussel et al, 2005; Musicki et al, 2005b; Ferrini et al, 2006a; Vignozzi et al, 2006; Ferrini et al, 2007).

A growing body of clinical literature also suggests that chronically used PDE5 inhibitors exert sustained healthful effects on the penile vasculature. Efficacy and tolerability have been demonstrated for sildenafil and tadalafil using once-daily or alternate day dosing regimens in men with ED enrolled in uncontrolled, open-label design studies (McMahon, 2004; Caretta et al, 2005; McMahon, 2005; Mirone et al, 2005; Sommer and Schulze, 2005; Buvat et al, 2006). In clinical trials with the rigor of randomization and placebo control design, efficacy and safety endpoints have also been shown for tadalafil (Porst et al, 2006; Rajfer et al, 2007). A substantial groundswell of interest has been generated to apply this mode of therapy to the postradical prostatectomy population according to a conceptual ‘‘penile rehabilitation’’ strategy. This population experiences at least some temporary degree of ED as a consequence of the surgery, even when cavernous nerve-sparing techniques are applied (Burnett, 2005b). Much attention was paid to the placebo-controlled study involving postoperative nightly administration of sildenafil, which found a 27% return of spontaneous, normal erectile activity rate compared with the 4% rate found in the placebo arm at 1 year after surgery (Padma-Nathan et al, 2004b). In other reports involving open-label study designs, investigators attempted to define an optimal therapeutic regimen in terms of such variables as dosing schedule, duration of administration, and timing of application while also describing improvements in spontaneous erectile function resulting from chronic PDE5 inhibitor use (Gontero et al, 2005; Mulhall et al, 2005)

Several caveats should be addressed in considering the utility of long-term PDE5 inhibitor treatment for this clinical application. One early identified controversy was whether the therapeutic strategy could cause pharmacologically induced ‘‘tachyphylaxis,’’ as suggested by a report that described a 20% dose elevation rate and 17% discontinuation rate due to loss of efficacy in patients with ED using sildenafil ‘‘on-demand’’ over a 2-year interval (El-Galley et al, 2001). However, likely explanations for declines in treatment effect over the long term are underlying disease state progression, inadequate dosing, application of the therapy, relationship difficulties, and psychogenic factors (Steers, 2002). Furthermore, findings of consistent efficacy and tolerability of treatment following both long-term, ‘‘on-demand’’ schedules reported previously (Carson, 2003) and long-term, continuous dosing reported more recently (Porst et al, 2006; Rajfer et al, 2007) argue against the development of treatment tolerance. It is acknowledged that PDE5 expression levels apparently increase with continuous treatment in basic science experimental paradigms (Lin et al, 2003; Musicki et al, 2005a), but the consequence of increasing PDE5 expression above normative levels in the penis was not demonstrated to negatively impact physiologic erectile responses (Musicki et al, 2005a; Behr-Roussel et al, 2005).

Another matter for consideration is whether prophylactic PDE5 inhibitor therapy should be given only to patients with certain underlying medical conditions. Much interest exists to apply the therapy to patients with severe forms of ED or conditions that would predict the likely development of ED. In this vein, the therapy would apply to those individuals with such risk factors as diabetes, cardiovascular disease, prior pelvic surgery, and aging. In their rat model study of chronic sildenafil dosing, Musicki et al (2005b) found that erections improved only in erection-impaired, aged rats but not in erection-intact, young rats. Compensatory homeostatic mechanisms were found to develop in young rats, suggesting to the investigators that such mechanisms are operable in the penis of the ‘‘healthy’’ individual in response to long-term PDE5 inhibitor treatment which limits supernormal erectogenic effects and concurrently prevents potentially harmful excessive erections.

Continued study is needed to confirm clinical impressions of a penile vascular protection benefit, which at this stage should be considered preliminary. Additionally, further investigation is needed to clarify molecular mechanisms associated with the presumed therapeutic benefit. Investigative work done in the cardiovascular field has shown the preconditioning effects of PDE5 inhibition against ischemic/reperfusion injury in the intact heart (Das et al, 2002; Kukreja, 2007). Cardioprotective effects have been related to activation of protein kinase C/extracellular signal-regulated kinase signaling, the opening of mitochondrial adenosine triphosphate-sensitive potassium channels, and attenuation of cell death resulting from necrosis and apoptosis (Kukreja, 2007). Further investigation may reveal whether or not such cellular or subcellular effects actually occur in the penis following long-term PDE5 inhibitor treatment. It is recognized that advancing the knowledge base in this area may occur most readily at the experimental animal model level, in which penile tissues are more easily obtained for molecular studies and objective erection testing is also more feasible. However, important inferences may still result from continued active research efforts expended at the clinical level. Recent work in men by Foresta et al (2007) showing that vardenafil increases circulating progenitor cells, which are involved in the process of neovascularization and continuous repair of the endothelium, via bone marrow stimulation has contributed to defining the endothelial protective role of PDE5 inhibitors.

 

[madman]

Physiology of Erection and Erectile Dysfunction

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New Concepts in Cavernous Nerve Localization and Functional Recovery after Radical Prostatectomy

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ED - Evidence Based Causes and Treatments

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[TLawyer]

Penile Vascular Protection

The medical literature widely supports vascular health objectives as a means toward achieving long-term health maintenance and longevity. Several thought leaders in sexual medicine have further pointed to penile vascular health as a critical gauge of this outcome (Kloner et al, 2003; Solomon et al, 2003). The pathogenesis of vascular disease both systemically and locally in the penis is linked with NO imbalance via endothelial defects and/or oxidative stress, which subsequently diminishes the physiologic actions of NO and its effectors (Cooke and Dzau, 1997; Bonetti et al, 2003) (Figure 4). To address this pathophysiology, suggested preventative practices have been advocated to include increasing physical fitness, improving healthful dietary habits, and reducing obesity (Esposito et al, 2004; Esposito et al, 2006). Additional consideration has been given to medical therapies such as regularly used PDE5 inhibitors under the premise that this treatment may afford long-term vascular healthful benefits for the penis (Montorsi et al, 2000; Burnett, 2005a).

Basic scientific evidence supports a penile vasculoprotective premise associated with long-term PDE5 inhibitor use. Several scientific studies have shown the utility of chronically applied PDE5 inhibitors in improving the structure and function of the cavernosal tissue and provided plausible mechanisms for these beneficial effects. In experimental paradigms involving rats that were chemically diabetogenic (De Young et al, 2003; Ahn et al, 2005), intact (Behr-Roussel et al, 2005), or aged (Musicki et al, 2005b; Ferrini et al, 2007) or had cavernous nerve injuries (Vignozzi et al, 2006; Ferrini et al, 2006a; Lagoda et al, 2007), continuous systemic PDE5 inhibitor treatment ranging from several days to 3 months preserved erectile tissue morphology and erection physiology to a better extent than did control treatments. Improved erectile responses were found to be sustained after confirmed drug clearance or withdrawal of the active drug in vivo (Musicki et al, 2005a; Lagoda et al, 2007) and in vitro (Behr-Roussel et al, 2005) protocols, respectively. Foremost possible biologic mechanisms by which PDE5 inhibitors afford penile vascular protection include antioxidation (De Young et al, 2003; Lagoda et al, 2007), antiapoptosis (Ahn et al, 2005; Musicki et al, 2005b), and activation of blood flow-associated vasodilatory effectors (BehrRoussel et al, 2005; Musicki et al, 2005b; Ferrini et al, 2006a; Vignozzi et al, 2006; Ferrini et al, 2007).

A growing body of clinical literature also suggests that chronically used PDE5 inhibitors exert sustained healthful effects on the penile vasculature. Efficacy and tolerability have been demonstrated for sildenafil and tadalafil using once-daily or alternate day dosing regimens in men with ED enrolled in uncontrolled, open-label design studies (McMahon, 2004; Caretta et al, 2005; McMahon, 2005; Mirone et al, 2005; Sommer and Schulze, 2005; Buvat et al, 2006). In clinical trials with the rigor of randomization and placebo control design, efficacy and safety endpoints have also been shown for tadalafil (Porst et al, 2006; Rajfer et al, 2007). A substantial groundswell of interest has been generated to apply this mode of therapy to the postradical prostatectomy population according to a conceptual ‘‘penile rehabilitation’’ strategy. This population experiences at least some temporary degree of ED as a consequence of the surgery, even when cavernous nerve-sparing techniques are applied (Burnett, 2005b). Much attention was paid to the placebo-controlled study involving postoperative nightly administration of sildenafil, which found a 27% return of spontaneous, normal erectile activity rate compared with the 4% rate found in the placebo arm at 1 year after surgery (Padma-Nathan et al, 2004b). In other reports involving open-label study designs, investigators attempted to define an optimal therapeutic regimen in terms of such variables as dosing schedule, duration of administration, and timing of application while also describing improvements in spontaneous erectile function resulting from chronic PDE5 inhibitor use (Gontero et al, 2005; Mulhall et al, 2005)

Several caveats should be addressed in considering the utility of long-term PDE5 inhibitor treatment for this clinical application. One early identified controversy was whether the therapeutic strategy could cause pharmacologically induced ‘‘tachyphylaxis,’’ as suggested by a report that described a 20% dose elevation rate and 17% discontinuation rate due to loss of efficacy in patients with ED using sildenafil ‘‘on-demand’’ over a 2-year interval (El-Galley et al, 2001). However, likely explanations for declines in treatment effect over the long term are underlying disease state progression, inadequate dosing, application of the therapy, relationship difficulties, and psychogenic factors (Steers, 2002). Furthermore, findings of consistent efficacy and tolerability of treatment following both long-term, ‘‘on-demand’’ schedules reported previously (Carson, 2003) and long-term, continuous dosing reported more recently (Porst et al, 2006; Rajfer et al, 2007) argue against the development of treatment tolerance. It is acknowledged that PDE5 expression levels apparently increase with continuous treatment in basic science experimental paradigms (Lin et al, 2003; Musicki et al, 2005a), but the consequence of increasing PDE5 expression above normative levels in the penis was not demonstrated to negatively impact physiologic erectile responses (Musicki et al, 2005a; Behr-Roussel et al, 2005).

Another matter for consideration is whether prophylactic PDE5 inhibitor therapy should be given only to patients with certain underlying medical conditions. Much interest exists to apply the therapy to patients with severe forms of ED or conditions that would predict the likely development of ED. In this vein, the therapy would apply to those individuals with such risk factors as diabetes, cardiovascular disease, prior pelvic surgery, and aging. In their rat model study of chronic sildenafil dosing, Musicki et al (2005b) found that erections improved only in erection-impaired, aged rats but not in erection-intact, young rats. Compensatory homeostatic mechanisms were found to develop in young rats, suggesting to the investigators that such mechanisms are operable in the penis of the ‘‘healthy’’ individual in response to long-term PDE5 inhibitor treatment which limits supernormal erectogenic effects and concurrently prevents potentially harmful excessive erections.

Continued study is needed to confirm clinical impressions of a penile vascular protection benefit, which at this stage should be considered preliminary. Additionally, further investigation is needed to clarify molecular mechanisms associated with the presumed therapeutic benefit. Investigative work done in the cardiovascular field has shown the preconditioning effects of PDE5 inhibition against ischemic/reperfusion injury in the intact heart (Das et al, 2002; Kukreja, 2007). Cardioprotective effects have been related to activation of protein kinase C/extracellular signal-regulated kinase signaling, the opening of mitochondrial adenosine triphosphate-sensitive potassium channels, and attenuation of cell death resulting from necrosis and apoptosis (Kukreja, 2007). Further investigation may reveal whether or not such cellular or subcellular effects actually occur in the penis following long-term PDE5 inhibitor treatment. It is recognized that advancing the knowledge base in this area may occur most readily at the experimental animal model level, in which penile tissues are more easily obtained for molecular studies and objective erection testing is also more feasible. However, important inferences may still result from continued active research efforts expended at the clinical level. Recent work in men by Foresta et al (2007) showing that vardenafil increases circulating progenitor cells, which are involved in the process of neovascularization and continuous repair of the endothelium, via bone marrow stimulation has contributed to defining the endothelial protective role of PDE5 inhibitors.

Madman - would you advocate for daily Tadalafil as a preventative measure even in the absence of any current ED issues?

 

[madman]

Madman - would you advocate for daily Tadalafil as a preventative measure even in the absence of any current ED issues?

If you were young and physically healthy no unless you were suffering from psychogenic ED then on-demand or short-term daily use of a PDE5i can do wonders.

To anyone taking Cialis daily — did you develop a dependence on it?

Anyone been on Cialis for extended periods of time to comment on whether they became dependent on it? Granted if you had ED before taking it and it fixed it for you then I can see that being some form of dependence, but I’m mainly interested in people or anecdotes of others that have taken it...

www.excelmale.com

My reply from a previous thread:

Looking at the bigger picture there is a good chance that you will suffer from some degree of ED eventually.

Aging let alone underlying vascular health will play a significant role.

If anything low dose tadalafil (daily) would have a beneficial effect on the overall health of penile tissue.


*Preliminary data suggest that products that upregulate this NO producing pathway and/or pharmacologically release NO, and/or protect its product, cGMP, show promise in halting or reversing the cellular changes associated with this aging process.