Physiology Of Erection Research Articles

Physiology and pathophysiology of erection: consequences for present medical therapy of erectile dysfunction.

Smooth muscle relaxation of the corpus cavernosum is the key mechanism of erection. It depends on a cascade of consecutive regulatory systems starting in the central nervous system, and proceeding via peripheral neurotransmission to intracellular signal transmission within the cavernous smooth muscle cells. Knowledge of these interacting mechanisms of erection is fundamental for understanding of the mode of action of new and possibly selective pharmacological agents that are presently available or under evaluation for treatment of erectile dysfunction.

Erektile Dysfunktion: Indikator für Endorganschädigung beim kardiovaskulären Patienten

Prevalence of erectile dysfunction (ED) amounts to 20-30% in a general population and increases to 50-70% in cardiovascular high-risk patients. Association of ED with known cardiovascular risk factors is causal with endothelial function of penile vessels and corpora cavernosa playing a crucial role in physiology of erection. Moreover, severity of ED correlates with cardiovascular risk of patients and represents an early symptom of generalized atherosclerosis. Hence, cardiovascular risk factors and diseases are sooner diagnosed in patients with ED with the opportunity of risk-adjusted prevention. Furthermore, different trials suggest erectile function as a strong predictor of cardiovascular events like myocardial infarction or stroke.

Angiotensin II Signaling and Its Implication in Erectile Dysfunction

Angiotensin II (Ang II) is the primary effector of the renin-angiotensin system (RAS). Ang II exerts its diverse physiologic actions via angiotensin type 1 and type 2 receptors. Recent evidence shows that tissue RAS exists in the penis, therefore indicating a significant role for Ang II in erectile function. To summarize the recent findings on the importance of Ang II in normal erection physiology and the pathogenesis of erectile dysfunction (ED). This article reviews the literature that relates to the role of RAS in the regulation of erectile function. Evidence in the literature on the association between Ang II and the development of ED. Elevated Ang II levels contribute to the development of ED in humans and different animal models. Pharmacologic therapy interrupting RAS may be beneficial for patients with ED. Studies have demonstrated that RAS is crucial in erectile function. Better understanding of the signaling pathways mediating Ang II physiologic actions will provide important information for the treatment of ED.

Tadalafil in the treatment of erectile dysfunction

The treatment for erectile dysfunction (ED) was revolutionized with the development of phosphodiesterase type 5 (PDE5) inhibitors. Tadalafil (Cialis((R)); Eli Lilly and Company, Indianapolis, IN, USA) is the newest and most versatile PDE5 inhibitor in the clinical armamentarium for the treatment of ED. Its most unique characteristic is its long half-life of 17.5 hours, which lends itself to a longer therapeutic window with on-demand dosing and effective steady-state plasma concentrations with once-daily dosing. Clinical trials have proven its safety and efficacy with both dosing strategies for all severities and etiologies of ED, including difficult-to-treat ED. This thorough review will discuss ED, the physiology of penile erection and the role of PDE5, and all aspects of tadalafil, from its development, through its pharmacology, to its latest clinical studies and indications.

Erectile dysfunction: the role of penile Doppler ultrasound in diagnosis

Erectile dysfunction (ED) is a common and debilitating condition with physical, psychological, and pharmacological aetiologies. The physical causes can be divided into problems with arterial inflow, structural penile abnormalities, or problems with the venous occlusion mechanism. Penile Doppler sonography is a specialized technique requiring a thorough knowledge of the topic in order to aid diagnosis and direct subsequent treatment. This technique is indicated in those patients with erectile dysfunction who do not respond to oral pharmacological agents (e.g., PDE-5 inhibitors). This pictorial essay will visit the anatomy and physiology of penile erection, the technique for performing the procedure, and review the imaging features for specific causes of ED.

Application of Evicel to Cavernous Nerves of the Rat Does Not Influence Erectile Function In Vivo

To evaluate the effect of the fibrin sealant, Evicel, on the neuroregulatory control of penile erections in an experimental rat model. Two groups of rats were used: sham-operated rats with exposure of the bilateral cavernous nerves (CNs) and application of saline vehicle (500 microL), and rats treated with direct application of Evicel (500 microL) bilaterally to the CNs. At 14 and 45 days after application of Evicel to the CNs, the CNs were stimulated to measure the in vivo erectile responses. Additionally, we evaluated the neuronal nitric oxide synthase immunoreactivity in the dorsal CNs of the penis and changes in the smooth muscle and collagen deposition in the penis using a trichrome stain. Evicel application to the CNs did not have any detrimental effect on the neurogenic erectile responses in vivo at 14 or 45 days after application. The neuronal nitric oxide synthase expression in the dorsal CNs of the penis was unchanged after Evicel application at all points studied, and we saw no change in the histomorphometric analysis findings of smooth muscle and collagen deposition in the penis. These data suggest that the hemostatic agent, Evicel, is safe in an experimental rat model of erection physiology, with no detrimental effects on neuroregulatory control of erection.

Stem and endothelial progenitor cells in erection biology

Erectile dysfunction (ED) is defined as the consistent inability to obtain or maintain an erection for satisfactory sexual relations. The past 20 years of basic science research on erection physiology has been devoted to investigating the pathogenesis of ED and has led to the conclusion that ED is predominately a disease of vascular origin with dramatic changes occurring in the endothelium. Research has also led to an understanding of the biochemical factors and intracellular mechanisms responsible for corporal smooth muscle contraction and relaxation and the influence of endothelium-derived relaxing factors. The development of methods to deliver both stem and endothelial cells to the penis has kindled a keen interest in treating ED with gene- and cell-based therapies. In this paper, erection physiology and stem cell biology is reviewed, and the potential application of novel cell-based therapies for the treatment of ED is discussed.

Molecular Pharmacotherapeutic Targeting of PDE5 for Preservation of Penile Health

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). 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 existing and emerging therapeutic strategies for erectile disorders.

Growth factors for therapeutic angiogenesis in hypercholesterolemic erectile dysfunction

The past decade has seen an explosion of new information on the physiology of penile erection, and pathophysiology of erectile dysfunction (ED). Hypercholesterolemia is a chronic condition that can lead to degeneration in the vasculature bed and can result in ED if the penile vasculature is involved. Angiogenesis is the growth of new blood vessels from preexisting vasculature. Therapeutic angiogenesis seeks to harness the mechanisms of vascular growth to treat disorders of inadequate tissue perfusion, such as coronary artery disease and ED. There have been tremendous changes in the field of therapeutic angiogenesis over the past decade, and there is much promise for the future. Initial preclinical work with cytokine growth factor delivery resulted in a great deal of enthusiasm for the treatment of ischemic heart and/or peripheral vascular disease, though clinical studies have not achieved similar success. With an increased understanding of the complex mechanisms involved in angiogenesis, novel therapies which target multiple different angiogenic pathways are also being developed and tested. The penis is a convenient tissue target for gene therapy because of its external location and accessibility, the ubiquity of endothelial lined spaces, and low level of blood flow, especially in the flaccid state. Therapeutic angiogenesis is an exciting field that continues to evolve. This review will focus on the development of growth factors for hypercholesterolemic ED, the use of various growth factors for ED therapy, their routes of delivery, and the results in animal studies.

Gene Therapy for Erectile Dysfunction

Erectile dysfunction is a disease that affects half of American men aged over 50 years. Many men respond to oral phosphodiesterase inhibitors but many do not. For this reason, many researchers are focusing their efforts on developing novel gene therapies for the treatment of erectile dysfunction. Aided by the meticulous characterization of the molecular cascades involved in the physiology of erection, several groups around the world are studying gene therapies in animal models, and one in a human clinical trial. Here we provide a review of the pathophysiology of erectile dysfunction and how it relates to the molecular targets of novel gene therapeutics. The field of gene therapy for the treatment of erectile dysfunction is continually growing, and this decade will likely see exciting results as the expansion from animal models to human clinical trials continues.

Neurophysiological basis of penile erection

Penile erection involves a complex interaction between the central nervous system and local factors. It is a neurovascular event modulated by psychological and hormonal factors. The discovery of nitric oxide (NO) as an intercellular messenger or neurotransmitter paved the way for identifying important mechanisms underlying physiological and pathophysiological events in the penis, in addition to providing the knowledge for the development of new therapeutics based on a novel concept of molecule and cell interaction. Despite the fact that sinusoidal endothelial cells also produce and release NO in response to chemical and possibly physical stimuli, roles of neurogenic NO in penile erection appear to be more attractive and convincing, since the pharmacological neuromodulation represents an essential step to attaining penile erection. Erectile dysfunction (ED) is caused by a variety of pathogenic factors, particularly impaired formation and action of NO. Hence, a thorough knowledge of the physiology of erection is essential for future pharmacological innovations in the field of male ED, particularly targeting NO or intracellular cyclic GMP, which represent the most promising therapeutic approach to treat patients with ED.

Dossier Thématique / Thematic file

Although extensive literature is available concern- ing the physiology of erection, the physiological events associated with ejaculation, and their peripheral and central regulations are poorly addressed by the scientific community. This is in contrast with a high prevalence of ejaculatory disorders in men as well as very few clinical studies on drugs that act on premature ejaculation. Recent data from basic experiments on rats suggest that a group of spinal neurons may act as a central generator to coordinate the different physiological events during ejaculation. The evidence of such a spinal generator in men is also supported by the possibility of inducing a reflex ejaculation in spinal cord injured patients by mechanical stimulation of the dorsal penile nerve afferences.

Endothelium Dependent Relaxation in Rabbit Genital Resistance Arteries is Predominantly Mediated by Endothelial-Derived Hyperpolarizing Factor in Females and Nitric Oxide in Males

In nongenital arteries a sex difference has been postulated in the dominant endothelium-derived relaxant factor(s), eg nitric oxide, prostacyclin or endothelial-derived hyperpolarizing factor. Knowledge of endothelium-derived relaxant factor mechanisms in genital tissues could influence the development of novel treatments for sexual dysfunction. We compared nitric oxide and endothelial-derived hyperpolarizing factor contributions to acetylcholine induced relaxation in the genital arteries of the 2 sexes. Male dorsal and cavernous penile arteries, and female extravaginal and intravaginal arteries from New Zealand White rabbits were studied. Acetylcholine concentration-vasodilator response curves were constructed in the presence of the nitric oxide synthase inhibitor Nomega-nitro-L-arginine methyl ester, K(+) channel blockers (apamin and charybdotoxin) or a combination. Indomethacin was present throughout to exclude prostacyclins. Extravaginal artery relaxation was predominantly endothelial-derived hyperpolarizing factor induced. Apamin plus charybdotoxin decreased maximal relaxations from a mean +/- SEM of 77% +/- 4% to 23% +/- 3% in 6 preparations (p <0.01). However, nitric oxide and endothelial-derived hyperpolarizing factor contributed to overall function. Dorsal artery relaxation was largely nitric oxide induced. Nomega-nitro-L-arginine methyl ester decreased maximal relaxations from 90% +/- 3% to 41% +/- 9% (p <0.001) with no endothelial-derived hyperpolarizing factor involvement (p >0.05). In cavernous and intravaginal arteries nitric oxide and endothelial-derived hyperpolarizing factor contributed to acetylcholine induced relaxation, while nitric oxide predominated. Blocking nitric oxide synthase or K(+) channels indicated that myogenic tone and constitutive activity of endothelium-derived relaxant factors were present. Vasodilator nerve mediated responses were influenced by each with the former more effective. Vaginal inflow arteries showed a dominance of endothelial-derived hyperpolarizing factor, contrasting with nitric oxide in penile arteries. Penile arteries followed the trend that endothelial-derived hyperpolarizing factor involvement increased with decreasing vessel caliber, while the reverse was demonstrated in female arteries.

Treating Erectile Dysfunction in Renal Transplant Recipients

Erectile dysfunction is common in male kidney transplant recipients. Interference with the physiology of erections can be attributed to recipient co-morbidities, the renal transplant operation, medication adverse effects, relationship problems and changes in mental health. A treatment-oriented evaluation of erectile dysfunction allows the development of treatment plans that are patient-specific. Hypo-gonadal men whose hormone parameters do not improve after renal transplantation may respond to testosterone replacement therapy. Use of recommended doses of the phosphodiesterase-5 inhibitor sildenafil does not significantly modify trough concentrations of the calcineurin inhibitors ciclosporin and tacrolimus or result in impaired renal allograft function. Tacrolimus has been shown to increase the peak concentration and prolong the elimination half-life of sildenafil in kidney transplant recipients. Daily administration of sildenafil has resulted in decreased blood pressure in kidney transplant recipients with treated hypertension and tacrolimus immunosuppression. Intracavernosal injections of alprostadil, with or without papaverine and phentolamine, are effective treatments for erectile dysfunction after renal transplantation and have not resulted in alterations of ciclosporin concentrations or in deterioration of renal function. Penile prostheses can be successfully implanted after pelvic organ transplantation without significant risk of infection.

PRESENTATIONS AND REPORTS: Nitric Oxide in the Penis—Science and Therapeutic Implications from Erectile Dysfunction to Priapism

Perhaps as much as any other subspecialty of urology, sexual medicine has undergone a wondrous evolution in the past 10–20 years. Great advances have been made generating from the study and discovery of molecular mechanisms governing diverse sexual functions. This observation is particularly relevant to the field of erection physiology. Our patients with erectile dysfunction have benefited accordingly as recipients of improved therapies along with optimized management strategies, from which they have gained increasingly healthful and high‐quality lives.

ENOS Function and Dysfunction in the Penis

Endothelial nitric oxide (NO) synthase (eNOS) has an indispensable role in the erectile response. In the penis, eNOS activity and endothelial NO bioavailability are regulated by multiple post-translational molecular mechanisms, such as eNOS phosphorylation, eNOS interaction with regulatory proteins and contractile pathways, and actions of reactive oxygen species (ROS). These mechanisms regulate eNOS-mediated responses under physiologic circumstances and provide various mechanisms whereby endothelial NO availability may be altered in states of vasculogenic erectile dysfunction (ED). In view of the recent advances in the field of eNOS function in the penis and its role in penile erection, the emphasis in this review is placed on the mechanisms regulating eNOS activity and its interaction with the RhoA/Rho-kinase pathway in the physiology of penile erection and the pathophysiology of ED.

The Nitric Oxide Signaling Pathway in the Penis

It is widely accepted that nitric oxide plays an important role in the biology of the penis, serving most familiarly as the agent responsible for penile erection. Early investigation in the field led to the identification of the signaling function of the molecule in the penis which yields corporal smooth muscle relaxation fundamental for the erectile response. Ongoing study of this molecule and its signaling pathway in erectile tissue has served to revise and clarify its importance. Current information conveys the prerequisite of the nitric oxide signaling pathway for penile erection, the regulatory basis for the generation and actions of nitric oxide in the penis, the diverse roles of its synthetic enzyme isoforms in penile biology, and the interaction between nitric oxide and other molecular pathways operative in the broad context of erection physiology. Insight into these subject areas has therapeutic relevance for pathologic conditions of the penis. The purpose of this review is to highlight the latest areas of investigation related to the science of nitric oxide in the penis, as a gateway for considering novel therapeutic strategies for erectile disorders now and in the future.

Testosterone and Sleep‐Related Erections: An Overview*

Sleep-related erections have been reported to occur from the intrauterine life to senescence. It has been speculated that the main function of nocturnal erections is to provide adequate engorgement of the corpora cavernosa, which then leads to increased tissue oxygenation. This is in turn to prevent cavernous fibrosis, the histopathological basis for corporeal venoocclusive dysfunction, which probably is the most common cause of organic erectile dysfunction. It has been suggested that sleep-related erections are triggered by the release of nitric oxide by the nitrergic nerve fibers within the cavernous nerves. Androgens regulate this mechanism as well as some other non-nitrergic processes within the corpora cavernosa and within the central nervous system. By contrast, the erectile response to tactile or visual erotic stimuli in wakefulness predominantly involves an androgen-independent system, although it may, at least to a certain degree, also be influenced by androgen-sensitive mechanisms. No doubt, androgens are key players in the physiology of nocturnal erections, and the availability of new, user-friendly testosterone preparations such as transdermal gel and intramuscularly administered testosterone undecanoate stimulates further investigations on this field. The prospect that the quality of sleep may also be improved by an androgen therapy administered to improve sleep-related erections in hypogonadal men needs further basic research and appropriate clinical studies.

ERYTHROPOIETIN PROMOTES THE RECOVERY OF ERECTILE FUNCTION FOLLOWING CAVERNOUS NERVE INJURY

We investigated the effects of recombinant human (rh) erythropoietin (EPO) on erectile function recovery in a rat model of cavernous nerve (CN) injury. Male rats underwent unilateral CN transection and excision of a 5 mm segment of the contralateral CN. One group received rhEPO (5,000 U/kg) subcutaneously daily for 14 days, while another received rhEPO 1 day and 1 hour prior to nerve injury. An additional group of animals was pretreated with 1 dose of darbepoetin (25 microg/kg). At 14 days following CN injury rats underwent erection physiology studies. Axonal regeneration was evaluated by electron microscopy. EPO receptor expression in the penis and major pelvic ganglion was evaluated immunohistochemically and by real-time polymerase chain reaction. Daily rhEPO effectively recovered erections after CN injury compared with saline treatment. Maximal intracavernous pressure area under the curve normalized to mean arterial pressure was significantly greater in EPO treated vs saline treated animals (p < 0.05). rhEPO and darbepoetin pretreatment was as effective as continuous 14-day therapy. EPO receptor expression was localized to neuronal cell bodies of the major pelvic ganglion, penile nerves and endothelial cells in the penis. Electron microscopy revealed significant improvement in axonal regeneration in rhEPO treated animals 14 days following injury compared to controls. EPO receptors are expressed in local neuronal and vascular tissues. Exogenous administration of rhEPO or darbepoetin in the setting of CN injury promotes erectile function recovery. This occurs through axonal regeneration of the injured nerve and possible penile protection.

Phosphodiesterase inhibitors in female sexual dysfunction

Based on the increasing knowledge on both the physiology of penile erection and the pathophysiology of erectile dysfunction, selective phosphodiesterase (PDE) inhibitors have been successfully introduced in the oral treatment of male erectile dysfunction. Because of their central role in smooth muscle tone regulation, PDEs remain an attractive target for drug development in urology. Since the distribution and functional significance of PDE isoenzymes vary in different tissues, selective inhibitors of the isoenzymes have the potential to exert at least partially specific effects on the target tissue. Currently, PDE inhibitors are under investigation with potential uses in urinary stone disease, overactive bladder and the so-called benign prostatic syndrome. The convincing clinical data on the use of the orally active PDE5 inhibitors sildenafil (VIAGRA), vardenafil (LEVITRA) and tadalafil (CIALIS) in the treatment of erectile dysfunction are accompanied by boosting research activities on intracellular signal transduction and PDE characterisation in female genital tissues with the aid of immunohistochemistry and immunocytochemistry and molecular biology. The expression of various PDE isoforms in the human clitoris, vagina and labia minora was shown by means of immunohistochemistry and RT-PCR analyses and it was concluded from functional studies that an increase in cGMP or cAMP might be involved in the regulation of female genital blood flow and the control of genital non-vascular smooth muscle. As a consequence, the efficacy and safety of the PDE5 inhibitor sildenafil in the treatment of symptoms of female sexual dysfunction (FSD), including female sexual arousal disorders (FSAD), have been evaluated. Although the experiences from these early clinical studies have so far not been conclusive, they suggest that, after appropriate evaluation of patients, inhibition of PDE5 might be of benefit for selected individuals with FSAD. Such research efforts will possibly allow the identification of efficacious and diagnostic tools for erectile dysfunction and of even more selective drugs in its therapy.