Physiology Of Erection Research Articles

EXPRESSION OF DIFFERENT PHOSPHODIESTERASE GENES IN HUMAN CAVERNOUS SMOOTH MUSCLE

Knowledge of intracellular signal propagation in smooth muscle tone regulation is of major importance in the understanding of the physiology of penile erection, and the development of new and selective pharmacological agents for the treatment of related disorders. Since phosphodiesterases (PDE) are key enzymes of the signaling pathway, we elucidate their presence and potential functional relevance in human cavernous tissue. To identify PDE messenger RNA in human cavernous tissue, we constructed primers for 14 published PDE isoforms. Expression of the genes was then analyzed by reverse transcriptase polymerase chain reaction under standard conditions and by subsequent sequencing. Messenger RNA was detected in human corpus cavernosum for the human phosphodiesterase isoenzymes and isoforms PDE1A, PDE1B, PDE1C, PDE2A, PDE3A, PDE4A, PDE4B, PDE4C, PDE4D, PDE5A, PDE7A, PDE8A and PDE9A. A total of 13 PDE genes were expressed in human cavernous tissue, indicating a role of these enzymes in penile erection regulation. The intracellular mechanisms of hydrolyzing cyclic adenosine monophosphate and cyclic guanosine monophosphate by PDEs are more complex than assumed previously. These findings open up new possibilities in the development of drugs for the treatment of erectile dysfunction.

Erectile Dysfunction: Diagnosis and Management with Newer Oral Agents

For centuries, men have been dealing with the issue of impotence. In this article, I review the physiology of erections and the new medications available to treat erectile dysfunction (ED). A number of new drugs are in phase I, II, and III trials. Most of them are similar to the drugs reviewed in this article in that they stimulate the corpus cavernosum or the central nervous system (CNS). In the 1990s and now the 21st century, ED has been defined as the consistent inability to attain and maintain penile erection sufficient to permit satisfactory intercourse. Based on data extrapolated from the Massachusetts Male Aging Study, ED affects some 20 million to 30 million American men today, most of them >50 years of age. The Massachusetts Male Aging Study is one of the best epidemiological studies ever done and it is ongoing, with some additional data from it published only recently (1). The original study looked at 1709 men in a suburban Boston community. Although the men studied were fairly homogeneous—mostly white and middle income—the Massachusetts Male Aging Study does provide insight into the incidence of ED among a community of noninstitutionalized men who are not under routine medical care. Overall, 52% of men aged 40 to 70 years had ED: 10% had complete ED; 25%, moderate; and 17%, minimal. The prevalence of ED increased with age (Figure 1). The percentages of ED were much higher—often double—in men who had risk factors such as taking cardiac, antihypertensive, or vasodilator drugs or using tobacco.

Tissue structure-specific distribution of glycosaminoglycans in the human penis

The aim of this work was to isolate and characterise the glycosaminoglycans present in the different tissue structures of the human penis in view of their potentially significant role in the physiology of erection. Penile tissue samples were obtained from patients who underwent penectomy and were subsequently dissected into individual tissue structures. Total glycosaminoglycans were isolated and purified from tunica albuginea, corpora cavernosa and corpus spongiosum, following tissue mincing, ultrasonication, lipid extraction, extensive digestion with pronase and DNase, treatment with alkali-borohydride and ethanol precipitation. Isolated glycosaminoglycans were separated by cellulose acetate electrophoresis and fractionated by anion exchange chromatography on DEAE Sephacel columns. Different glycosaminoglycan fractions were identified using glycosaminoglycan-degrading enzymes of known specificity. Gradient polyacrylamide gel electrophoresis was used to determine the average molecular mass of the glycosaminoglycans. The corpus cavernosum and the corpus spongiosum extracts contained almost twice the amount of glycosaminoglycan-associated uronic acids as compared to the tunical extracts (1.47±0.09, and 1.49±0.15 as opposed to 0.75±0.15 μg/mg dry defatted tissue, respectively; S.E.M., n=5). With the exception of hyaluronic acid, the relative amount of individual glycosaminoglycan types varied significantly among extracts of different origin. Heparan sulphate was more abundant in cavernosal, dermatan sulphate in tunical, and chondroitin-6-sulphate in corpus spongiosum extracts. No structure-specific differences were detected with respect to the molecular mass distribution of each glycosaminoglycan type. Our study shows that the different structures of the human penis produce distinct profiles of glycosaminoglycans, which are well suited to the individual functional characteristics of these structures.

Conservative treatment of erectile dysfunction. 3: Literature review.

This is the third of a three-part article addressing whether physiotherapy involving pelvic floor muscle exercises (PFMEs) is efficacious as a first-line treatment for erectile dysfunction (ED). The first part (Vol 9(11): 691-4) highlighted the prevalence of ED, associated risk factors, the anatomy of the penis and the physiology of erection. The second part (Vol 9(12): 755-62) concentrated on the published clinical trials investigating the treatment and prevention of ED. This part will critically analyse the literature. PFMEs using ischiocavernosus muscles (ICMs) and bulbocavernosus muscles (BCMs) seem to have merit as a treatment for ED due to mild or moderate venous leakage. Men suffering from ED due to other causes may also benefit. There is no strong evidence that electrical stimulation or electroacupuncture is effective or ineffective. No studies demonstrating preventive conservative treatments were found. There is evidence that the ICMs and BCMs increase penile rigidity in the tumescent penis, that pelvic floor muscle efficiency is higher in potent men than impotent men and that perineal muscle efficiency reduces with age in impotent men. There is limited evidence that pelvic floor exercises relieve ED due to venous leakage and are a realistic alternative to surgery. Randomized controlled trials are needed to explore the use of PFMEs as a first-line treatment for men with ED.

Conservative treatment of erectile dysfunction. 2: Clinical trials.

This is the second of a three-part paper addressing whether physiotherapy involving pelvic floor muscle exercises (PFMEs) is efficacious as a first-line treatment for erectile dysfunction (ED). The first part (Vol 9(11): 691-4) highlighted the prevalence of ED, associated risk factors, the anatomy of the penis and the physiology of erection. This part concentrates on the computer-aided and manual search for published clinical trials investigating the treatment and prevention of ED. The methodological quality of the trials was assessed using criteria based on generally accepted principles of interventional research. The literature search revealed 14 trials which met the broad inclusion criteria. Of these, eight trials used PFMEs with or without biofeedback or electrical stimulation.

Conservative treatment of erectile dysfunction. 1: Anatomy/physiology.

This is the first of a three-part article addressing whether physiotherapy involving pelvic floor muscle exercises is efficacious as a first-line treatment for erectile dysfunction (ED). In this, the first part of the article, the prevalence of ED and associated risk factors are considered after which the anatomy of the penis and the physiology of erection are outlined. This provides background for the second and third parts of the article which review the outcomes of published clinical trials investigating the treatment and prevention of ED, and assess the evidence for pelvic floor exercises relieving ED.

Nitric Oxide-Mediated Erectile Effects of Galantide but Not Galanin in Vivo

The purpose of this study was to investigate the in vivo effects of intracavernosal injections of galanin and galantide (a specific galanin receptor antagonist) on penile erection in the anesthetized cat. Erectile responses to galanin and galantide were compared with responses to a standard triple drug combination [1.65 mg papaverine, 25 μg phentolamine, and 0.5 μg prostaglandin E1 (PGE1)]. Intracavernosal injections of galanin (3–100 nmol) and galantide (0.1–3 nmol) induced penile erection in a dose-dependent manner. In terms of relative potency, galantide was approximately 100-fold more potent than galanin at increasing cavernosal pressure. The maximal increases in intracavernosal pressure in response to galanin and galantide were 83 and 95%, respectively, of the control triple drug combination. The total durations of erectile response caused by these peptides were significantly shorter (P < 0.05) than those by the triple drug combination. The nitric oxide synthase inhibitor L-NAME (20 mg) significantly decreased the erectile response in the cat to galantide but not to galanin, while the K+ATP channel antagonist U-37883A (3 mg) had no effect on the erectile response to galanin nor galantide. The results of the present study demonstrate that galantide, a putative antagonist for the galanin receptor, has more potent agonist activity than galanin in increasing intracavernosal pressure in the cat. Moreover, these data suggest that galantide, but not galanin, causes penile erection by an NO/cGMP-dependent mechanism. This is the first study to demonstrate that galanin may play a role in the physiology of penile erection.

Significance of the nitric oxide cascade in erectile function.

In recent years, a significant body of experimental evidence has accumulated implicating nitric oxide as the central component of a novel signal transduction system that functions in the penis to mediate penile erection. The involvement of nitric oxide in erection physiology appears to be quite complex, involving multiple regulatory interactions: this gaseous molecule has been found to trigger several biochemical events that elicit erectile tissue responses, while a host of modulatory factors have been identified that influence its release and action in erectile tissue. Ongoing investigations in nitric oxide biology in other organ systems also suggest mechanisms which, while yet to be fully established in the penis, may operate significantly to determine the role of nitric oxide in this organ. Further elucidation of cellular and molecular interactions involving nitric oxide effects in the penis can be expected to reveal diverse targets that may serve as a basis for novel pharmacotherapeutic strategies for the future management of erectile dysfunction.

Painful nocturnal erection.

Sleep related painful erection is a parasomnia occurring during rapid eye movement (REM) sleep. It is rarely dealt with in the literature, and is very often poorly understood. Because of repeated awakenings, it is interpreted as insomnia, and is attributed to anxiety. EEG recordings associated with nocturnal penile tumescence monitoring indicate the existence of disturbed sleep organization, with awakenings during REM sleep and frequent nocturnal erections, often unrelated to REM sleep. Though the pathophysiological mechanisms involved are not yet understood, an interpretation of sleep-related painful erections is proposed, based on the current understanding and physiology of diurnal and nocturnal erections.

THE EPIDEMIOLOGY AND PATHOPHYSIOLOGY OF ERECTILE DYSFUNCTION

Published studies on the epidemiology of erectile dysfunction and the physiology/ pathophysiology of erectile function are reviewed. A literature search of more than 400 studies of the epidemiology and pathophysiology of impotence and erectile dysfunction published during the last 3 decades was conducted and the most pertinent articles are discussed. It has been estimated that the prevalence of erectile dysfunction of all degrees is 52% in men 40 to 70 years old, with higher rates in those older than 70 years. Erectile dysfunction has a significant negative impact on quality of life. Risk factors for erectile dysfunction include aging, chronic illnesses, various medications and cigarette smoking. A nitric oxide/cyclic guanosine monophosphate mechanism has an important role in mediating the corporal smooth muscle relaxation necessary for erectile function. Other mechanisms involving neuropeptides, gap junctions and ion channels also may modulate corporal smooth muscle tone. Erectile dysfunction can be due to vasculogenic, neurogenic, hormonal and/or psychogenic factors as well as alterations in the nitric oxide/cyclic guanosine monophosphate pathway or other regulatory mechanisms, resulting in an imbalance in corporal smooth muscle contraction and relaxation. Erectile dysfunction is a common condition associated with aging, chronic illnesses and various modifiable risk factors. Normal penile erection is a hemodynamic process that is dependent on corporal smooth muscle relaxation mediated by parasympathetic neurotransmission, nitric oxide, and possibly other regulatory factors and electrophysiological events. As more knowledge is gained of the physiology and regulatory factors that mediate normal erectile function, the mechanisms involved in the pathophysiology of erectile dysfunction should be further elucidated.

RECOVERY OF SPONTANEOUS ERECTILE FUNCTION AFTER NERVE-SPARING RADICAL RETROPUBIC PROSTATECTOMY WITH AND WITHOUT EARLY INTRACAVERNOUS INJECTIONS OF ALPROSTADIL: RESULTS OF A PROSPECTIVE, RANDOMIZED TRIAL

This study was aimed at assessing prospectively the effect of postoperative intracavernous injections of alprostadil on the recovery of spontaneous erectile function after nerve-sparing radical retropubic prostatectomy. A total of 30 potent patients with clinically localized prostate cancer (clinical stage B1 or B2, Gleason sum 7 or greater, prostatic specific antigen less than 20 ng./ml.) underwent nerve-sparing radical retropubic prostatectomy and was subsequently randomized to alprostadil injections 3 times per week for 12 weeks (group 1, 15 patients) or observation without any erectogenic treatment (group 2, 15 patients). Patients were assessed at the 6-month followup by sexual history, physical examination, color Doppler sonography of the cavernous arteries and polisomnographic recording of nocturnal erections. In group 1, 12 patients (80%) completed the entire treatment schedule and were evaluated at the long-term followup. Eight patients in this group (67%) reported the recovery of spontaneous erection sufficient for satisfactory sexual intercourse, compared with 3 patients (20%) in group 2. The difference between the 2 groups was statistically significant (p <0.01). In group 1, all but 1 patient reporting normal postoperative erections also showed normal erections at nocturnal testing, whereas color Doppler sonography demonstrated normal penile hemodynamics in all of them. In these patients, failures were the result of cavernous veno-occlusive dysfunction (2 cases, 17%) and cavernous nerve injury (2 cases, 17%). In group 2, patients with normal erections showed both normal nocturnal testing and penile hemodynamics, whereas failures were the result of cavernous veno-occlusive dysfunction (8 cases, 53%), cavernous arterial insufficiency (2 cases, 13%) or cavernous nerve injury (3 cases, 20%). Complications in patients treated with alprostadil injections accounted for 2 cases (13%) of a penile nodule and 1 further case (6%) of prolonged penile erection. Complications were not seen in group 2 patients. Early postoperative administration of alprostadil injections significantly increases the recovery rate of spontaneous erections after nerve-sparing radical retropubic prostatectomy. It is our belief that programmed vasoactive injections improve cavernous oxygenation, thereby limiting the development of hypoxia-induced tissue damage. The potential complications related to the use of intracavernous injections must be clearly explained to patients.

Contractility Changes of the Deep Dorsal Penile Vein Due to Serotonin

Purpose Penile erection is a complex neurovascular phenomenon that takes place with the active contribution of arterial and sinusoidal structures. However, some authors claim that larger veins including the deep dorsal veins that produce contractions, might be involved in the physiology of erection. This study was designed to clarify the contractile properties of deep dorsal penile veins (DDPV). Materials and Methods The effect of serotonin (5-HT), noradrenaline (NA), adenosine triphosphate (ATP) and acethylcholine (Ach) on the isolated DDPVs of 16 impotent men, 9 with veno-occlusive dysfunction and 7 without venous leakage, and 5 potent men (controls) who underwent radical prostatectomy, were examined in vitro. Results Although NA, ATP and Ach had no effect, 5-HT produced concentration-dependent contractions. E max and pEC 50 of 5-HT were 411 +/− 10 mg., 5.92 +/− 0.25; 1020 +/− 260 mg., 5.83 +/− 0.24 and 160 +/− 40 mg., 6.4 +/− 0.22 in controls and patients who had venous leakage and no venous leakage, respectively. Samples of controls were contracted only with 5-HT 2 agonist, DOI (pEC 50 = 5.63 +/− 0.02), and these contractions were antagonized with 5-HT 2 antagonist ketanserin. On the other hand, both DOI (pEC 50 = 6.30 +/− 0.77) and 5-HT 1 agonist, 5-CT (pEC 50 = 6.23 +/− 0.21) produced venoconstriction in patients with veno-occlusive dysfunction. Conclusions The present findings suggest that 5-HT receptor functions in the DDPVs are of 5-HT 2 subtype in potent men and the altered response to 5-HT in patients with veno-occlusive disease may play a role in the pathophysiology of impotence.

Signal transduction in cavernous smooth muscle.

Knowledge of intracellular signal propagation in smooth-muscle tone regulation is of major importance to the understanding of both the physiology of erection and the pathophysiology of erectile dysfunction and the development of new and selective pharmacological agents in the treatment of erectile dysfunction. Cavernous smooth-muscle tone depends heavily on the amount of intracellular free Ca2+. In the resting state the sarcoplasmic free Ca2+ amounts to about 120-270 nM, whereas in the extracellular fluid the Ca2+ level is in the range of 1.5-2 mM. Electromechanical and pharmacomechanical coupling induces an increase in the levels of free sarcoplasmic Ca2+ by a factor of 2-3 to 550-700 nM that triggers myosin phosphorylation and subsequent smooth muscle contraction. In this case, modulation of membrane-bound ion channels and regulation of the intracellular second-messenger system are attractive and feasible targets for pharmacological intervention. Besides the amount of free sarcoplasmic Ca2+, smooth-muscle tone is also modulated by the regulation of Ca2+ sensitivity ("Ca-sensitization") and Ca(2+)-independent contraction processes.

Intracavernous pharmacotherapy.

Intracavernous application of vasoactive substances not only has enhanced our understanding of penile hemodynamics, the physiology of penile erection, and the pathophysiology of erectile dysfunction but also has revolutionized the diagnosis and treatment of erectile dysfunction in the last 15 years. Virag was the first to report on the erectile effect of papaverine in humans, and Brindley later reported the effect of intracavernous application of alpha-receptor-blocking agents on cavernous tissue. These reports led to numerous basic and clinical investigations and ultimately established a new treatment alternative for patients with erectile dysfunction that is now considered to be the treatment of choice for most patients. Changes in penile hemodynamics include the relaxation of cavernous smooth musculature and arteries, which leads to an increase in arterial blood flow and a restriction of venous outflow through a compression of subtunical veins. These hemodynamic changes are the prerequisite for the induction and maintenance of penile erection. With the intracavernous application of vasoactive substances it was possible to influence penile hemodynamics at a local level and to induce an erection despite alterations in the nervous system, penile arterial blood flow, cavernous musculature, or neurotransmitter status. In addition, the local application of pharmacologically active substances directly to the end organ enabled the achievement of high local drug concentrations without severe systemic side effects. The commonly used substances are papaverine the combination of papaverine and phentolamine, and prostaglandin E1 (alprostadil). In addition to these established substances, several other regimens, such as linsidomine (SIN-1), calcitonin gene-related peptide (CGRP), moxisylyte, and various triple- or quadruple-drug mixtures have been described. In addition, several other compounds as well as different routes of administration are on the horizon and may prove to be effective in the future diagnosis and treatment of erectile dysfunction.

Physiology of erection

The peripheral pharmacology of local mechanisms of penile erection is known today thanks to recent advance in the study of the regulation of erectile tissue smooth muscle tone. Smooth muscle fibers present in the corpus cavernosum and arteries destined to the penis relax in response to the release of non adrenergic non cholinergic neuromediators synthetized by postganglionic parasympathetic nerve fibers present in the cavernous nerves. Nitric oxide is the main proerectile neuromediator. Noradrenaline, released by sympathetic fibers, contracts penile smooth muscle fibers and is antierectile. Recent progress in the peripheral pharmacology of penile erection allows new perspectives in the treatment of erectile dysfunction. The spinal cord represents a major site for the neural regulation of penile erection. The latter occurs in response to stimuli from peripheral or supraspinal origin. Different neural structures in the brainstem (nucleus paragigantocellularis), pons and hypothalamus (nucleus paraventricularis) send projections to the thoracolumbar sympathetic and lumbosacral parasympathetic nuclei at the origin of proerectile peripheral pathways. Serotonin and oxytocin are candidates as neuromediators involved in the supraspinal control of penile erection. Studying the central command of penile erection allows an approach to the pathophysiology of psychogenic erectile dysfunction.

Accumulation of platelets as a key mechanism of human erection. A scintigraphic study in patients with erectile dysfunction receiving intracavernous injection of PGE1, papaverine/phentolamine.

Recent advances in the functional anatomy, neurophysiology and pharmacology of penile erection have fostered a dramatic improvement in the understanding of the physiology of erection and the approaches to correct impotence. However, the complex mechanism of human erection still remains incompletely explained. In vivo animal studies in the Chacma baboon (Dormehl et al., 1984) suggested that an enhanced platelet activity exits in the penis during erection. In this study we evaluate whether a similar accumulation of platelets during erection also occurs in humans.KeywordsSingle Photon Emission Computerize TomographyErectile DysfunctionCorpus CavernosumPenile ErectionAutologous PlateletThese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

PRIAPISM

Priapism in adult patients with sickle cell disease is a devastating complication for which there is no consensus regarding management. Innumerable attempts at pharmacologic and surgical intervention have been employed. Distinction between infarctive low-flow priapism with hypoxia and acidosis and normal-flow priapism without acidosis can be obtained using currently available imaging techniques. Cavernosonography and radionuclide scanning to assess penile hemodynamics are useful in determining whether priapism is of the low-flow type. Advances in our understanding of the physiology of erection have prompted a more physiologic approach to the assessment and management of priapism. Based on this technology, it would be possible to develop a prospective multiinstitutional study, thereby providing sufficient numbers of patients to better evaluate therapy. After the episode of priapism has abated and detumescence has occurred, we recommend that the patient be given the option of beginning a trial of hydroxyurea or another antisickling agent.

SLEEP-RELATED ERECTILE ACTIVITY

Sleep-related erections occur in all healthy, potent men in close temporal association with REM sleep. These erections are naturally occurring and can be assessed quantitatively. The nocturnal tumescence cycle seems unaffected by behavioral factors. Furthermore, sleep-related erections are present across the life span with only a slight decline in older healthy people. Analogous phenomena are present in women. The function of sleep-related erections is not known; however, they clearly involve vascular, neurologic, and hormonal mechanisms. Sleep-related erection testing provides a physiologic, objective, diagnostically useful technique for evaluating erectile capacity. Laboratory-based studies with comprehensive polysomnography offer the most complete diagnostic picture of erectile function available. Nonlaboratory procedures require further validation. The sleep-related tumescence pattern contains a wealth of information about the physiology and pathophysiology of erection. The coordination between REM sleep and erection, the differential expansion at the penile base and upper shaft, and the rate of circumference increase and decrease are meaningful indicators for determining if erectile dysfunction exists. Sleep-related erection testing indexes the magnitude and nature of organic involvement and takes the differential diagnosis of impotence beyond a simplistic psychogenic-organic dichotomy.

Erectile dysfunction: The medicalization of male sexuality

Erectile dysfunction (ED) is a highly prevalent disorder in males that increases markedly with aging. Diagnostic and treatment approaches for the disorder have proliferated in the past decade, along with increased understanding of the underlying physiology of male erection. Two specific themes have emerged in the recent literature on the topic: 1. (a) erectile dysfunction is a socially legitimate, medically treatable problem 2. (b) medical treatments are more reliable and effective than psychological interventions. This article reviews the efficacy and outcome data available for each of the major treatment approaches for ED, in addition to the risks and benefits associated with each approach. A variety of methodological issues are identified, including the lack of prospective study designs, inadequate assessment of sexual function, absence of long-term follow-up, and lack of attention to interactive effects of medical and psychological treatments. Although less widely publicized, cognitive-behavioral and interpersonal treatment approaches have been shown to be effective in a number of studies. Overall, there is a strong need for integration of medical and psychological approaches, in addition to increased outcome research in this area.

Corpus spongiosum penis pressure and perineal muscle activity during reflexive erections in the rat.

This experiment represents the first simultaneous analysis of corpus spongiosum of the penis (CSP) pressure and perineal muscle activity during reflex-induced penile erections in the awake rat and provides new data on the coordination of muscular and vascular events in erection physiology. Nine male Sprague-Dawley rats were implanted with pressure transducers under pentobarbital anesthesia (60 mg/kg) for use in a new technique of chronic erection recording involving simultaneous CSP pressure monitoring and electromyography (EMG) of the ischiocavernosus (IC) and bulbospongiosus (BS) muscles. The association of these physiological measurements with visually scored ex copula erectile events was investigated. Reflexive erectile events were systematically associated with an increase in baseline CSP pressure. Glans erections were associated with dramatic suprasystolic CSP pressure peaks concurrent with BS muscle bursts. Indeed, measures of CSP pressure and BS EMG activity were found to vary significantly with the intensity of glans erection. Flips of the penile body, however, involved small CSP pressure increases and IC bursts. These data demonstrate for the first time that both CSP pressures and perineal muscle activity vary significantly with the intensity of penile erection.