Physiology Of Penile Erection Research Articles

Physiology of Penile Erection-A Brief History of the Scientific Understanding up till the Eighties of the 20th Century.

IntroductionUnderstanding the physiology of penile erection is important for all who work in the field of sexual medicine.AimThe aim of this study was to highlight and analyze historical aspects of the scientific understanding of penile erection.Methods(i) Review of the chapters on the physiology of erection out of the author's collection of books dealing with male sexual functioning published in the German, French, Dutch, and English language in between 1780 and 1940. (ii) Review of the topic “physiology of penile erection” of relevant chapters of C lassical writings on erectile dysfunction. A n annotated collection of original texts from three millennia, including the study of all relevant references mentioned in these books.Main Outcome MeasureThe main outcome measure used for the study was the scientific understanding of the physiology of penile erection.ResultsIn Antiquity, Galen considered penile erection as the result the accumulation of air. His ideas so dominated medieval medicine that nearly everyone then alive was a Galenist. The beginning of the Renaissance shows meaningful examples of experimental scientific work on the penis. Da Vinci correctly concluded that erections were caused by blood, and in the 18th century, Von Haller from Switzerland was the first who explained that erections were under the control of the nervous system. In the 19th century, a mindset that emphasized on experimentation determined a new direction, namely experimental physiology. Animal studies clarified that stimulation of the nervi erigentes‐induced small muscle relaxation in the corpora cavernosa. Nearly all were published in the German language. That may be one of the reasons that the existence of the concept of smooth muscle relaxation remained controversial until the first World Congress on Impotence in 1984 in Paris.ConclusionsAs the Renaissance's innovative research defined neural and vascular physiologic phenomena responsible for penile erection. The concepts from animal experimentations in Europe in the 19th century significantly contributed to the current understanding of penile erection. van Driel MF. Physiology of penile erection—a brief history of the scientific understanding up till the eighties of the 20th century. Sex Med 2015;3:343–351.

Signs, symptoms and treatment of penile fracture.

Penile fracture is an uncommon injury and requires urgent treatment, therefore emergency nurses should be aware of the signs and symptoms and understand the importance of immediate surgical referral. This article describes the anatomy and physiology of penile erection and the ways in which penile fracture can occur. It also outlines the management of patients and includes a case study of a fracture caused by vigorous masturbation.

Role of Hydrogen Sulfide in the Physiology of Penile Erection

Hydrogen sulfide (H(2)S), which is a well-known toxic gas, has recently been recognized as a biological messenger that plays an important role in physiological and pathophysiological conditions. Relatively high levels of H(2)S have been discovered in mammalian tissues. It is mainly synthesized by 2 enzymes, including cystathionine β-synthase and cystathionine γ-lysase, which utilize L-cysteine as substrate to produce H(2)S. H(2)S has been demonstrated to exhibit potent vasodilator activity both in vitro and in vivo by relaxing vascular smooth muscle. Recently, H(2)S has been discovered in penile tissue with smooth muscle relaxant effects. Furthermore, other effects of H(2)S could play a role in the physiology of erection. Understanding H(2)S in the physiology of erection might provide alternative erectile dysfunction strategies for those patients with poor or no response to type 5 phosphodiesterase inhibitors. This review intends to present the H(2)S pathway in penile tissue and the potential role of H(2)S in the physiology of erections.

Role of androgens in modulating male and female sexual function.

Advancement in basic and clinical research has provided considerable evidence suggesting a key role of androgens in the physiology and pathophysiology of sexual function. Evidence from clinical studies in men and women with androgen deficiency support a role of androgens in maintaining sexual function in men and women and are integral in maintaining sexual health. Preclinical studies utilizing male animal models demonstrated a role of androgens in maintenance of: (i) penile tissue structural integrity, (ii) penile trabecular smooth muscle growth and function, (iii) integrity of penile nerve fiber network, (iv) signaling pathways in the corpora cavernosa, (v) myogenic and adipogenic differentiation in the corpora cavernosa, (vi) physiological penile response to stimuli, and (vii) facilitating corporeal hemodynamics. These findings strongly suggest a role for androgen in the physiology of penile erection. In addition, clinical studies in hypogonadal men with erectile dysfunction treated with testosterone provided invaluable information on restoring erectile function and improving ejaculatory function. Similarly, clinical studies in surgically or naturally postmenopausal women with androgen deficiency suggested that androgens are important for maintaining sexual desire and testosterone treatment was shown to improve sexual desire, arousal and orgasm. Furthermore, studies in female animal models demonstrated that androgens maintain the integrity of vaginal nerve fiber network, muscularis volume, and enhance genital blood flow and mucification. Based on the biochemical, physiological and clinical findings from human and animal studies, we suggest that androgens are integral for maintaining sexual function and play a critical role in maintaining sexual health in men and women.

Anatomy, Physiology, and Pathophysiology of Erectile Dysfunction

Significant scientific advances during the past 3 decades have deepened our understanding of the physiology and pathophysiology of penile erection. A critical evaluation of the current state of knowledge is essential to provide perspective for future research and development of new therapies. To develop an evidence-based, state-of-the-art consensus report on the anatomy, physiology, and pathophysiology of erectile dysfunction (ED). Consensus process over a period of 16 months, representing the opinions of 12 experts from seven countries. Expert opinion was based on the grading of scientific and evidence-based medical literature, internal committee discussion, public presentation, and debate. ED occurs from multifaceted, complex mechanisms that can involve disruptions in neural, vascular, and hormonal signaling. Research on central neural regulation of penile erection is progressing rapidly with the identification of key neurotransmitters and the association of neural structures with both spinal and supraspinal pathways that regulate sexual function. In parallel to advances in cardiovascular physiology, the most extensive efforts in the physiology of penile erection have focused on elucidating mechanisms that regulate the functions of the endothelium and vascular smooth muscle of the corpus cavernosum. Major health concerns such as atherosclerosis, hyperlipidemia, hypertension, diabetes, and metabolic syndrome (MetS) have become well integrated into the investigation of ED. Despite the efficacy of current therapies, they remain insufficient to address growing patient populations, such as those with diabetes and MetS. In addition, increasing awareness of the adverse side effects of commonly prescribed medications on sexual function provides a rationale for developing new treatment strategies that minimize the likelihood of causing sexual dysfunction. Many basic questions with regard to erectile function remain unanswered and further laboratory and clinical studies are necessary.

Role and Management of Coagulopathies in Vascular Erectile Dysfunction

Erectile dysfunction (ED) is frequently a symptom of underlying vascular disease. Vascular risk factors are the most common cause of erectile dysfunction. Endothelium of the penile vasculature plays an important role in the physiology of penile erection. Most patients presenting with vascular erectile dysfunction have a combination of trivascular disease, that being diabetes, hypertension and dyslipidemia, which may result in endothelial dysfunction. Other co-morbidities for vascular erectile dysfunction include smoking, sedentary life style, obstructive sleep apnea syndrome and obesity. When common vascular risk factors are absent, the critical role of a hypercoagulable state as contributing risk factor should be suspected. The inherited hypercoagulable syndromes primarily have an effect on veins, and only occasionally result in arterial thrombosis. The acquired hypercoagulable states which may cause endothelial dependent erectile dysfunction include antiphospholipid antibody syndrome, protein s, protein c and antithrombin III deficiencies, factor V Leiden and prothrombin gene mutation, hyperhomocysteinemia, dysfibrogenenmia and plasminogen deficiency. This paper reviews common hypercoagulable states that may result in endothelial dysfunction, and be an unsuspected cause 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.

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.

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.

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.

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.

Gene therapy for erectile dysfunction

The past decade has seen an explosion of new information on the physiology of penile erection, pathophysiology of erectile dysfunction (ED), and development of new oral agents (e.g., three PDE5 inhibitors) to manage ED. Although all three selective PDE5 inhibitors are effective in the majority of ED cases, these oral medications have failed in certain disease states, such as diabetic ED, postprostatectomy ED, and severe veno-occlusive dysfunction. Only about 50% to 60% of these cases benefit from PDE5 inhibitor therapy, prompting the development of new approaches, including gene-based therapies for the treatment of ED. 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. Initially, gene therapy has been reserved for the treatment of life-threatening disorders including cancer, hereditary and acquired diseases. However, gene therapy is an attractive therapeutic possibility for the treatment of ED. Evolution of nitric oxide (NO), a small gaseous, lipophilic signaling molecule that is produced by nitric oxide synthase (NOS) activates guanylate cyclase (GC), resulting in increased cyclic guanosine monophosphate (cGMP) production, plays a significant role in our understanding of cavernosal smooth muscle physiology. Many gene therapy strategies have focused on the NO/GS/cGMP pathway. All three NOS isoforms, endothelial NOS (eNOS), neuronal NOS (nNOS), and iNOS have been used for gene therapy in order to modulate erectile response. Various viral and nonviral vectors have been used to date for the transfer of genetic material to the target cell or tissues with various degrees of success. Recently, second generation or "gutless" (helper-dependent) adenovirus vectors have been developed in order to reduce cellular toxicity and immune response, while increasing efficient gene therapy. Varieties of other gene therapy trials have also been undertaken for the treatment of ED and are the focus of this review.

Pharmacotherapy for Erectile Dysfunction

Advances in understanding of the biochemistry and physiology of penile erection have led to breakthroughs in pharmacotherapy of erectile dysfunction. To provide recommendations/guidelines concerning state-of-the-art knowledge for the putative molecular and cellular mechanisms of action of centrally and peripherally acting drugs currently utilized in pharmacotherapy of erectile dysfunction. An international consultation in collaboration with the major urology and sexual medicine associations assembled over 200 multidisciplinary experts from 60 countries into 17 committees. Committee members established specific objectives and scopes for various male and female sexual medicine topics. The recommendations concerning state-of-the-art knowledge in the respective sexual medicine topic represent the opinion of experts from five continents developed in a process over a two-year period. Concerning the Pharmacotherapy for Erectile Dysfunction Committee there were 25 experts from 10 countries. Expert opinion was based on grading of evidence-based medical literature, widespread internal committee discussion, public presentation and debate. Selective and potent oral PDE5 inhibitors have significantly more affinity than cGMP and form broader molecular interactions with multiple amino acids, thereby blocking access to cGMP in the catalytic sites of the PDE5 enzyme. PDE5 inhibitors, which vary as to biochemical potency, selectivity and pharmacokinetics, lead to cGMP elevation and relaxation facilitation of penile corpus cavernosum smooth muscle cells following sexual stimulation. Various centrally acting drugs influence sexual behaviour. In particular, the dopaminergic substance apomorphine is a central enhancer that acts in the paraventricular nucleus of the hypothalamus as a dopamine (D2) receptor agonist, induces and increases penile erection responses via disinhibition, following sexual stimulation. There is a need for more research in the pharmacotherapeutic development of central and peripheral agents for safe and effective erectile dysfunction treatment.

WHAT NONRESPONSE TO INTRACAVERNOUS INJECTION REALLY INDICATES: A DETERMINATION BY QUANTITATIVE ANALYSIS

In addition to its usefulness as a therapeutic modality, intracavernous injection may also be done in a diagnostic capacity. While a good response to an intracavernous injection test rules out venous leakage, a failed erectile response to the test in the office setting may not be completely representative of the patient erectile state. We determined by quantitative analysis the likely significance of failure to respond to intracavernous injection testing. Patients evaluated with the standard erectile dysfunction assessment at our andrology clinic between 1996 and 1999 were included in analysis. All 122 patients who did not meet study exclusion criteria underwent a test dose of intracavernous injection with papaverine, phentolamine and prostaglandin E1. Regardless of the response or lack of response to the test the men then underwent nocturnal penile tumescence testing, penile blood flow study and re-dose pharmacocavernosography. Results of these adjunctive tests were compared to the outcome of a papaverine, phentolamine and prostaglandin E1 intracavernous injection test by quantitative analysis. A total of 87 patients failed to respond to the test dose. Average age of the nonresponders versus responders was 46.8 versus 33.8 years. The duration of erectile dysfunction in nonresponders versus responders was 31.0 versus 13.7 months. Poor intracavernous injection responders required an average of 1.9-fold greater induction flow and 6-fold greater maintenance flow than good responders. Receiver operator characteristics (ROC) curve analysis revealed that the best predictors of the intracavernous injection test response were erectile dysfunction duration (ROC 0.99), patient age (ROC 0.87), maintenance flow (ROC 0.86), pressure loss (ROC 0.83) and resistive index (ROC 0.82). The ROC area for peak systolic velocity was 0.69. Our results indicate that age and erectile dysfunction duration alone are the most important variables affecting the results of an intracavernous injection test. However, in patients older than 40 years with a greater than 2-year history of erectile dysfunction failure to respond to intracavernous injection testing is most closely associated with venous insufficiency, as evidenced by the high ROC values for variables indicative of venous insufficiency, namely maintenance flow, pressure loss and the resistive index. Therefore, nonresponse to an office intracavernous injection test in an older patient with erectile dysfunction of long duration is most likely due to venous leakage. If only 1 confirmatory test is possible, cavernosometry provides the most information.

THE ORAL EFFICACY OF VARDENAFIL HYDROCHLORIDE FOR INDUCING PENILE ERECTION IN A CONSCIOUS RABBIT MODEL

Inhibiting cyclic guanosine monophosphate metabolism may induce penile erection during concomitant nitric oxide production. Vardenafil hydrochloride is a new, highly selective, potent cyclic guanosine monophosphate phosphodiesterase 5 inhibitor. We determined the oral effectiveness of vardenafil in a simple and quantitative conscious rabbit model. Vardenafil was given orally to conscious rabbits. Erection was assessed in a time dependent manner by measuring the length of the uncovered penile mucosa. Erection was evaluated in the absence and presence of intravenous sodium nitroprusside, a nitric oxide donor. Vardenafil induced dose dependent penile erection in conscious rabbits after the oral administration of 1 to 30 mg./kg. The efficacy of vardenafil was potentiated and effective doses were significantly reduced by the simultaneous administration of sodium nitroprusside. The effect of vardenafil on penile erection after oral administration was clearly demonstrated in the conscious rabbit model. The time course and early onset of activity indicate that it may be useful for treating erectile dysfunction. Potentiation of the effect by the nitric oxide donor sodium nitroprusside implies that it would have enhanced activity during sexual arousal, when nitric oxide is produced endogenously. The clinical development of this product for erectile dysfunction is proceeding.

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.

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.

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 penile erection.

Physiology of penile erection.