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Priapism is a true urological emergency that is typified by a persistent and painful erection. High-risk groups include patients with hematological or coagulative disorders; for example, those with sickle cell disease, leukemia or glucose-6-phosphate dehydrogenase deficiency. The diagnosis for priapism must be made urgently using patient history, physical examination and blood gas findings on corporal aspiration. Emergency treatment is needed to avoid erectile dysfunction. However, in high-risk groups, prophylaxis must be encouraged. A number of prophylactic measures are emerging based on progress in the understanding of the pathophysiology of priapism in these particular patients. In this Review, priapism as it relates to hematological disorders is discussed, focusing on treatment and prophylaxis.

Aging is associated with ED. Although age-related ED is attributed largely to increased oxidative stress and endothelial dysfunction in the penis, the molecular mechanisms underlying this effect are not fully defined. We evaluated whether endothelial nitric oxide synthase (eNOS) uncoupling in the aged rat penis is a contributing mechanism. Correlatively, we evaluated the effect of replacement with eNOS cofactor tetrahydrobiopterin (BH(4)) on erectile function in the aged rats. Male Fischer 344 'young' (4-month-old) and 'aged' (19-month-old) rats were treated with a BH(4) precursor sepiapterin (10 mg/kg intraperitoneally) or vehicle for 4 days. After 1-day washout, erectile function was assessed in response to electrical stimulation of the cavernous nerve. Endothelial dysfunction (eNOS uncoupling) and oxidative stress (thiobarbituric acid reactive substances, TBARS) were measured by conducting western blot in penes samples. Erectile response was significantly reduced in aged rats, whereas eNOS uncoupling and TBARS production were significantly increased in the aged rat penis compared with young rats. Sepiapterin significantly improved erectile response in aged rats and prevented increase in TBARS production, but did not affect eNOS uncoupling in the penis of aged rats. These findings suggest that aging induces eNOS uncoupling in the penis, resulting in increased oxidative stress and ED.

Glucose transporter 3 (GLUT3) is the main facilitative glucose transporter in neurons. Glucose provides neurons with a critical energy source for neuronal activity. However, the mechanism by which neuronal activity controls glucose influx via GLUT3 is unknown. We investigated the influence of synaptic stimulation on GLUT3 surface expression and glucose import in primary cultured cortical and hippocampal neurons. Synaptic activity increased surface expression of GLUT3 leading to an elevation of intracellular glucose. The effect was blocked by NMDA receptor (NMDAR) and neuronal nitric oxide synthase (nNOS) inhibition. The Akt inhibitor I (Akt-I) blocked NMDAR-induced GLUT3 surface expression while a nNOS-phosphomimetic mutant (S1412D) enhanced GLUT3 expression at cell surface. These results suggest that NMDAR/Akt-dependent nNOS phosphorylation is coupled to GLUT3 trafficking. We demonstrated that activation of cGMP-dependent protein kinase (cGK) increased the surface expression of GLUT3, which was repressed by Rp-8-pCPT-cGMPS, a potent cell-permeable inhibitor of cGKs. These studies characterize the molecular basis for activity-dependent increases in surface GLUT3 after stimulation of the NMDARs. NMDAR-induced increase in surface GLUT3 represents a novel pathway for control of energy supply during neuronal activity that is critical for maintaining glucose homeostasis during neuronal transmission.

Introduction: Sickle cell disease (SCD)-associated priapism is characterized by endothelial nitric oxide synthase (eNOS) dysfunction in the penis. However, the mechanism of decreased eNOS function/activation in the penis in association with SCD is not known., Aims: Our hypothesis in the present study was that eNOS is functionally inactivated in the SCD penis in association with impairments in eNOS post-translational phosphorylation and the enzyme's interactions with its regulatory proteins., Methods: Sickle cell transgenic (sickle) mice were used as an animal model of SCD. Wild-type (WT) mice served as controls. Penes were excised at baseline for molecular studies. eNOS phosphorylation on Ser-1177 (positive regulatory site) and Thr-495 (negative regulatory site), total eNOS, and phosphorylated AKT (upstream mediator of eNOS phosphorylation on Ser-1177) expressions, and eNOS interactions with heat-shock protein 90 (HSP90) and caveolin-1 were measured by Western blot. Constitutive NOS catalytic activity was measured by conversion of L-[14C]arginine-to-L-[14C]citrulline in the presence of calcium., Main Outcome Measures: Molecular mechanisms of eNOS dysfunction in the sickle mouse penis., Results: eNOS phosphorylated on Ser-1177, an active portion of eNOS, was decreased in the sickle mouse penis compared with WT penis. eNOS interaction with its positive protein regulator HSP90, but not with its negative protein regulator caveolin-1, and phosphorylated AKT expression, as well as constitutive NOS activity, were also decreased in the sickle mouse penis compared with WT penis. eNOS phosphorylated on Thr-495, total eNOS, HSP90, and caveolin-1 protein expressions in the penis were not affected by SCD., Conclusions: These findings provide a molecular basis for chronically reduced eNOS function in the penis by SCD, which involves decreased eNOS phosphorylation on Ser-1177 and decreased eNOS-HSP90 interaction., (© 2010 International Society for Sexual Medicine.)

Prostate cancer is the most common cancer among men, representing approximately 25% of all new cancer diagnoses in the USA. For clinically localized prostate cancer, the gold standard for therapy remains radical prostatectomy. One of the main adverse effects of this procedure is erectile dysfunction, which can have a significant impact on the patient's quality of life. There are several mechanisms of erectile dysfunction postprostatectomy, including arteriogenic, venogenic and neurogenic types, as well as the potentially heightened risk of postprostatectomy patients to develop Peyronie's disease. The purpose of this review is to explain the various treatment options available, including phosphodiesterase type 5 inhibitors, intracavernosal injections, intraurethral alprostadil suppositories, vacuum erection devices, and penile prostheses. The role of these therapies in an erectile-dysfunction-treatment function, as well as in penile rehabilitation, will be discussed. Finally, a review of research on novel therapies will also be presented. A comprehensive literature review was performed using the PubMed database. Articles were chosen based on topical relevance and assessed for methodology and major findings. There are data to support the use of each of the therapeutic options in both treatment and rehabilitative roles. More study is needed, however, specifically in regard to penile rehabilitation, to confirm its benefits, as well as to determine optimal rehabilitation protocols.

Introduction: Although anxiety and depression have long been implicated as factors in the development and maintenance of sexual dysfunction, other emotional states, more typical and within the range of normality, have received little attention. Aim.  To investigate key differences in self-reported affective responses between sexually functional and dysfunctional males in the context of a sexual episode with their partner., Methods: Participants were men seeking treatment at a urology clinic for either a sexual problem (N=79) or another urological disorder (N=16). Individuals rated their affective state across 28 descriptors in response to a partnered sexual experience., Main Outcome Measure: The 28-item Psychoaffective Response Form consisted of items assessing positive and negative affect. Principle components analysis was used to identify major underlying positive and negative factors., Results: Significant differences were found on nearly all 28 measures of affective response as well as five major underlying factors constructed from those measures. Dysfunctional men more strongly endorsed negative affects and functional men more strongly endorsed positive affects, even though all suffered from a significant urological health issue. No differences existed in sexual desire or the value ascribed to sexual intimacy, suggesting that negative feelings were specifically associated with inadequate sexual performance and not general health concerns., Conclusion: These findings reiterate the importance of addressing patients' emotional issues as part of any overall treatment strategy., (© 2010 International Society for Sexual Medicine.)

Purpose: RhoA and rho kinase serve as key regulators of penile vascular homeostasis. The role of RhoA/rho kinase signaling in the penis after cavernous nerve injury has not been fully investigated. We characterized the molecular expression profiles of RhoA/rho kinase signaling that occur in the penis after cavernous nerve injury. We hypothesized that erectile dysfunction after bilateral cavernous nerve injury is accompanied by up-regulation of RhoA/rho kinase activity in the rat penis., Material and Methods: We used 2 groups, including sham operation and bilateral cavernous nerve injury. At 14 days after nerve injury each group underwent cavernous nerve stimulation to determine erectile function at baseline and after intracavernous injection of the rho kinase inhibitor Y-27632 (Tocris Bioscience, Ellisville, Missouri). Penes were assessed at baseline for protein expression of neuronal nitric oxide synthase, RhoA, and rho kinase 1 and 2 by Western blot, immunoreactivity of neuronal nitric oxide synthase, rho kinase 1 and 2, RhoA-guanosine triphosphatase and rho kinase activity., Results: Erectile function was decreased in nerve injured rats. Neuronal nitric oxide synthase protein was significantly decreased while RhoA and rho kinase 2 protein levels were significantly increased in rat penes with nerve injury. Rho kinase 1 protein expression was equivalent. Rho kinase immunoreactivity was qualitatively increased in the corporeal smooth muscle of nerve injured rats. RhoA-guanosine triphosphatase and rho kinase activity was significantly increased in injured rat penes compared to that in sham operated penes. Intracavernous injection of Y-27632 caused a significantly greater increase in intracavernous pressure in nerve injured rats compared to that in sham operated rats, suggesting increased rho kinase activity., Conclusions: Data suggest that RhoA/rho kinase up-regulation in response to cavernous nerve injury contributes to penile vasculature dysfunction after cavernous nerve injury. Thus, the RhoA/rho kinase pathway may be a suitable target for treating post-radical prostatectomy erectile dysfunction., (Copyright © 2010 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Introduction: Sexual function in men and women incorporates physiologic processes and regulation of the central and peripheral nervous systems, the vascular system, and the endocrine system. There is need for state-of-the-art information as there is an evolving research understanding of the underlying molecular biological factors and mechanisms governing sexual physiologic functions., Aim: To develop an evidence-based, state-of-the-art consensus report on the current knowledge of the major cellular and molecular targets of biologic systems responsible for sexual physiologic function., Methods: State-of-the-art knowledge representing the opinions of seven experts from four countries was developed in a consensus process over a 2-year period., Main Outcome Measures: Expert opinion was based on the grading of evidence-based medical literature, widespread internal committee discussion, public presentation, and debate., Results: Scientific investigation in this field is needed to increase knowledge and foster development of the future line of treatments for all forms of biological-based sexual dysfunction. This article addresses the current knowledge of the major cellular and molecular targets of biological systems responsible for sexual physiologic function. Future treatment targets include growth factor therapy, gene therapy, stem and cell-based therapies, and regenerative medicine., Conclusions: Scientific discovery is critically important for developing new and increasingly effective treatments in sexual medicine. Broad physiologic directions should be vigorously explored and considered for future management of sexual disorders., (© 2010 International Society for Sexual Medicine.)

Introduction: Hypercholesterolemia induces erectile dysfunction (ED) mostly by increasing oxidative stress and impairing endothelial function in the penis, but the mechanisms regulating reactive oxygen species (ROS) production in the penis are not understood., Aims: We evaluated whether hypercholesterolemia activates nicotinamide adenine dinucleotide phosphate (NAD[P]H) oxidase in the penis, providing an initial source of ROS to induce endothelial nitric oxide synthase (eNOS) uncoupling and endothelial dysfunction resulting in ED., Methods: Low-density-lipoprotein receptor (LDLR)-null mice were fed Western diet for 4 weeks to induce early-stage hyperlipidemia. Wild type (WT) mice fed regular chow served as controls. Mice received NAD(P)H oxidase inhibitor apocynin (10 mM in drinking water) or vehicle. Erectile function was assessed in response to cavernous nerve electrical stimulation. Markers of endothelial function (phospho [P]-vasodilator-stimulated-protein [VASP]-Ser-239), oxidative stress (4-hydroxy-2-nonenal [HNE]), sources of ROS (eNOS uncoupling and NAD[P]H oxidase subunits p67(phox) , p47(phox) , and gp91(phox) ), P-eNOS-Ser-1177, and eNOS were measured by Western blot in penes., Main Outcome Measures: The main outcome measures are the molecular mechanisms of ROS generation and endothelial dysfunction in hypercholesterolemia-induced ED., Results: Erectile response was significantly (P<0.05) reduced in hypercholesterolemic LDLR-null mice compared with WT mice. Relative to WT mice, hypercholesterolemia increased (P<0.05) protein expressions of NAD(P)H oxidase subunits p67(phox) , p47(phox) and gp91(phox) , eNOS uncoupling, and 4-HNE-modified proteins, and reduced (P<0.05) P-VASP-Ser-239 expression in the penis. Apocynin treatment of LDLR-null mice preserved (P<0.05) maximal intracavernosal pressure, and reversed (P<0.05) the abnormalities in protein expressions of gp67(phox) and gp47(phox) , 4-HNE, P-VASP-Ser-239, and eNOS uncoupling in the penis. Apocynin treatment of WT mice did not affect any of these parameters. Protein expressions of P-eNOS-Ser-1177 and total eNOS were unaffected by hypercholesterolemia., Conclusion: Activated NAD(P)H oxidase in the penis is an initial source of oxidative stress resulting in eNOS uncoupling, thus providing a mechanism of eNOS uncoupling and endothelial dysfunction in hypercholesterolemia-induced ED., (© 2010 International Society for Sexual Medicine.)

Optical nerve stimulation using infrared laser radiation has recently been developed as a potential alternative to electrical nerve stimulation. However, recent studies have focused primarily on pulsed delivery of the laser radiation and at relatively low pulse rates. The objective of this study is to demonstrate faster optical stimulation of the prostate cavernous nerves using continuous-wave (cw) infrared laser radiation for potential diagnostic applications. A thulium fiber laser (λ=1870 nm) is used for noncontact optical stimulation of the rat prostate cavernous nerves in vivo. Optical nerve stimulation, as measured by an intracavernous pressure (ICP) response in the penis, is achieved with the laser operating in either cw mode, or with a 5-ms pulse duration at 10, 20, 30, 40, 50, and 100 Hz. Successful optical stimulation is observed to be primarily dependent on a threshold nerve temperature (42 to 45 °C), rather than an incident fluence, as previously reported. cw optical nerve stimulation provides a significantly faster ICP response time using a lower power (and also less expensive) laser than pulsed stimulation. cw optical nerve stimulation may therefore represent an alternative mode of stimulation for intraoperative diagnostic applications where a rapid response is critical, such as identification of the cavernous nerves during prostate cancer surgery.

Three studies were conducted to examine the curative activity of azoxystrobin, trifloxystrobin, and pyraclostrobin + boscalid against Monilinia fructicola, causal agent of brown rot on peach. In the first study, 'Autumnglo' peach trees were treated with each of the three fungicides both before and after fruit inoculation. In the second study, the effects of fungicide active ingredient, rate/volume, and inoculation timing were examined on inoculated 'Suncrest' peach fruit. Results of these studies showed that sporulating area, on average across all treatments, was reduced by 15.9, 42.4, and 0.4% for azoxystrobin, trifloxystrobin, and pyraclostrobin + boscalid, respectively. In any single treatment, trifloxystrobin provided the greatest benefit with two consecutive sprays, reducing sporulating area by 53 to 60%. In contrast to sporulation activity, the three fungicides exhibited less of an inhibitory effect on fruit colonization. When applied at maximum labeled rates in the various treatments, azoxystrobin, trifloxystrobin, and pyraclostrobin + boscalid reduced colony growth, on average, by 12.3, 7.5, and 7.4%, respectively. Because the pathogen was inoculated into the mesocarp, this low level of activity against colonization may be due to a lack of deeper systemic movement of the fungicides into fruit tissue. In the final study, the three fungicides were examined for their antisporulant activity on blossom blight twig cankers. Unlike results observed on fruit, significant reductions in spore production on cankers were observed for all three fungicides. Azoxystrobin, trifloxystrobin, and pyraclostrobin + boscalid provided 56, 71, and 53% reductions, respectively, in the number of conidia produced per unit canker length. Overall results of these studies indicated that quinone outside inhibitor fungicides, in addition to their known protectant activity, also possess varying levels of curative activity against M. fructicola. In particular, trifloxystrobin demonstrated good antisporulant activity on both fruit infections and cankers.

Objectives: The Ras homolog gene family, member A (RhoA) and its main downstream effector, Rho-kinase (ROCK) are important in maintaining the penis in the flaccid state. The pathophysiology of sickle cell disease-associated priapism is not well defined. We hypothesized that the RhoA/ROCK vasoconstrictive pathways might be involved in the development of priapism. Therefore, the objective of the present study was to evaluate the molecular changes in RhoA and ROCK in an established transgenic sickle cell mouse model of priapism., Methods: Two groups of mice were used: wild type (WT; C57BL/6) mice and transgenic sickle cell mice. We evaluated RhoA guanosine triphosphatase and total ROCK activities, as well as ROCK1 and ROCK2 protein expression, in WT and sickle mice penises. We also evaluated the in vivo erectile responses to cavernous nerve stimulation and the frequency and duration of spontaneous erections before and after cavernous nerve stimulation., Results: Sickle mice demonstrated significantly (P <.05) enhanced erectile responses to cavernous nerve stimulation and frequency of spontaneous erections both before and after cavernous nerve stimulation compared with the WT mice. The sickle mice penises had a significant decline in RhoA guanosine triphosphatase (P <.01) and total ROCK activities (P <.05) compared with the WT mice. A significant (P <.05) reduction in ROCK2 protein expression in sickle mice penises compared with WT mice protein expression. No change in ROCK1 protein expression was observed in either cohort of mice penises., Conclusions: These data suggest that sickle cell disease associated-priapism might be contributed by a lack of RhoA/ROCK-mediated vasoconstriction and highlight a novel molecular mechanism in the pathophysiology of priapism., (Copyright 2010 Elsevier Inc. All rights reserved.)

Introduction: Estrogens control vaginal blood flow during female sexual arousal mostly through nitric oxide (NO). Although vascular effects of estrogens are attributed to an increase in endothelial NO production, the mechanisms of endothelial NO synthase (eNOS) regulation by estrogens in the vagina are largely unknown., Aims: Our hypothesis was that estrogens regulate eNOS post-translationally in the vagina, providing a mechanism to affect NO bioavailability without changes in eNOS protein expression., Methods: We measured eNOS phosphorylation and eNOS interaction with caveolin-1 and heat shock protein 90 (HSP90) in the distal and proximal vagina of female rats at diestrus, 7 days after ovariectomy and 2 days after replacement of ovariectomized rats with estradiol-17beta (15 microg)., Main Outcome Measures: Molecular mechanisms of eNOS regulation by estrogen in the rat vagina., Results: We localized phospho-eNOS (Ser-1177) immunohistochemically to the endothelium lining blood vessels and vaginal sinusoids. Estrogen withdrawal decreased phosphorylation of eNOS on its positive regulatory site (Ser-1177) and increased eNOS binding to its negative regulator caveolin-1 (without affecting eNOS/HSP90 interaction), and they were both normalized by estradiol replacement. Protein expressions of phosphorylated Akt (protein kinase B) and extracellular signal-regulated protein kinase 1/2 (ERK1/2) were not affected by estrogen status, suggesting that the effect of estrogens on eNOS (Ser-1177) phosphorylation was not mediated by activated AKT or ERK1/2. eNOS phosphorylation on its negative regulatory site (Ser-114) was increased in the vagina by estrogen withdrawal and normalized by estradiol replacement, implying that the maintenance of low phosphorylation of eNOS on this site by estradiol may limit eNOS interaction with caveolin-1 and preserve the enzyme's activity. Total eNOS, inducible NOS, caveolin-1, and HSP90 protein expressions were not affected by ovariectomy or estradiol replacement in the distal or proximal vagina., Conclusions: These results define novel estrogen signaling mechanisms in the vagina which involve eNOS phosphorylation and eNOS-caveolin-1 interaction.

Context: Detailed knowledge of the anatomy of the prostate and adjacent tissues is mandatory during radical prostatectomy to ensure reliable oncologic and functional outcomes., Objective: To review critically and to summarize the available literature on surgical anatomy of the prostate and adjacent structures involved in cancer control, erectile function, and urinary continence., Evidence Acquisition: A search of the PubMed database was performed using the keywords radical prostatectomy, anatomy, neurovascular bundle, fascia, pelvis, and sphincter. Relevant articles and textbook chapters were reviewed, analyzed, and summarized., Evidence Synthesis: Anatomy of the prostate and the adjacent tissues varies substantially. The fascia surrounding the prostate is multilayered, sometimes either fused with the prostate capsule or clearly separated from the capsule as a reflection of interindividual variations. The neurovascular bundle (NVB) is situated between the fascial layers covering the prostate. The NVB is composed of numerous nerve fibers superimposed on a scaffold of veins, arteries, and variable amounts of adipose tissue surrounding almost the entire lateral and posterior surfaces of the prostate. The NVB is also in close, cage-like contact to the seminal vesicles. The external urethral sphincter is a complex structure in close anatomic and functional relationship to the pelvic floor, and its fragile innervation is in close association to the prostate apex. Finally, the shape and size of the prostate can significantly modify the anatomy of the NVB, the urethral sphincter, the dorsal vascular complex, and the pubovesical/puboprostatic ligaments., Conclusions: The surgical anatomy of the prostate and adjacent tissues involved in radical prostatectomy is complex. Precise knowledge of all relevant anatomic structures facilitates surgical orientation and dissection during radical prostatectomy and ideally translates into both superior rates of cancer control and improved functional outcomes postoperatively., (Copyright 2009 European Association of Urology. All rights reserved.)

Introduction: Priapism is a poorly understood disease process with little information on the etiology and pathophysiology of this erectile disorder. One group of patients with a high prevalence of priapism is men with sickle-cell disease., Aim: Establish an in vivo transgenic sickle-cell mouse model to study the pathophysiology of sickle-cell disease-associated priapism., Methods: Transgenic sickle-cell disease mice, expressing human sickle hemoglobin, were utilized. Three groups of mice were used: (i) wild type (WT), (ii) sickle-cell heterozygotes (Hemi), and (ii) sickle-cell homozygotes (Sickle). Two age groups of each cohort of mice were utilized: young adult (4-6 months) and aged (18-22 months)., Main Outcome Measures: Histological (trichrome stain to measure ratio of collagen to smooth muscle), penile hydroxyproline content (collagen content), and transmission electron microscopic analysis of WT, Hemi, and Sickle mice penes, as well as in vivo erectile responses [change in intracavernous pressure (ICP)] to cavernous nerve stimulation (CNS), were determined. The frequency of erectile responses (erections/hour) pre- and poststimulation was also measured in each of the experimental groups., Results: Sickle mice had increased (P < 0.05) collagen to smooth muscle ratio and hydroxyproline content in the penis when compared with WT and Hemi mice penes. Transmission electron microscopy demonstrated thickened smooth muscle cell bundles, disruption of the endothelial lining of the corporal sinusoids, and increased (P < 0.05) caveolae number. Sickle mice had significantly (P < 0.05) higher ICP to CNS and increased (P < 0.05) frequency of erections pre- and post-CNS when compared with WT and Hemi mice erectile responses. Sickle mice did develop ED (change in ICP in response to CNS) with increasing age., Conclusion: The morphometric changes of the penis and exaggerated in vivo erectile responses support the use of this transgenic sickle-cell disease animal model to study the pathophysiological mechanisms involved in sickle-cell disease-associated priapism.

Introduction: Oral phosphodiesterase type 5 inhibitors (PDE5i) have improved treatment options for erectile dysfunction (ED). In case of unresponsiveness to PDE5i, alternative therapies are considered., Aim: To evaluate whether combination of vacuum erection device (VED) and PDE5i is effective as salvage therapy in subjects with ED in whom PDE5i alone failed., Methods: From September 2007 to May 2008, we evaluated 69 men (aged 36-82 years) in whom PDE5i treatment at the highest recommended dose, with at least 4-6 attempts at intercourse during a 3 months period, had failed. The clinical efficacy of combination therapy was evaluated using the International Index of Erectile Function-5 (IIEF-5) questionnaire, Sexual Encounter Profile (SEP)-2, SEP-3, and Global Patient Assessment Scale (GPAS)., Main Outcome Measures: Scores on IIEF-5, SEP-2, SEP-3, and GPAS before and after combination therapy were measured., Results: After 4 weeks of combination therapy, the mean IIEF-5 score increased significantly over baseline from 9.0 to 17.6 (P < 0.001). Of the 34 subjects with a SEP-2 response of "no" at baseline, 27 (79%) responded "yes" after combination therapy (P < 0.001). Of the 50 subjects with a SEP-3 response of "no" at baseline, 35 (70%) responded "yes" after combination therapy (P < 0.001). Furthermore, of the 42 subjects with a GPAS response of "not at all" or "slightly" improved at baseline, 31 (74%) responded "moderately" or "greatly" improved after combination therapy (P < 0.001). One subject (1.5%) experienced device-related intermittent penile pain, which resolved after 4 days without any action., Conclusions: Statistically significant improvements over baseline were seen in IIEF-5, SEP-2, SEP-3, and GPAS measures following 4 weeks of combination therapy of PDE5i and VED. This study supports the use of PDE5i with VED in men in whom PDE5i alone failed. This combination therapy may be offered to patients not satisfied with PDE5i alone before being switched to more invasive alternatives.

Radical prostatectomy (RP) remains the standard treatment for men with clinically localized prostate cancer, despite the range of alternative treatment modalities. Even with significant advances in surgical technique and superb results for cancer control and preservation of urinary function, erectile dysfunction (ED) following RP is a common complication. This is mainly attributed to temporary cavernous nerve damage (neuropraxia) resulting in penile hypoxia, smooth muscle apoptosis, fibrosis and veno-occlusive dysfunction. One of the most promising new approaches is the concept of early penile rehabilitation, which is thought to prevent ED after RP by countering post-RP pathophysiological changes during the period of neural recovery. Various treatments, such as vacuum constriction devices, intraurethral and intracorporal alprostadil, and phosphodiesterase type 5 (PDE5) inhibitors, might serve to facilitate recovery of erectile function. PDE5 inhibitors are considered as the first-line treatment for early penile rehabilitation, with superior erectile function outcomes compared to placebo. Definitive conclusions regarding the success of penile rehabilitation cannot be drawn at this time because of differences in study design, data acquisition, and definitions of potency. Continued prospective, rigorous study is needed to develop and bring forward this important field and to establish the best evidence basis for counseling and treating patients suffering from ED after RP.

Erectile dysfunction (ED) following treatment for clinically localized prostate cancer, particularly radical prostatectomy (RP), is a major quality of life issue that remains unsatisfactorily addressed. With the introduction and use of cavernous nerve-sparing procedures over the past 25 years, many men recover erections postoperatively that enable sexual intercourse unlike in the prior surgical era, when permanent ED postoperatively was certain. Despite this advance, 26-100% of these patients may never recover normal erectile function (EF). Recent advances in the understanding of ED after RP have stimulated great attention to develop penile rehabilitation programs and neuromodulation. The purpose of penile rehabilitation is to prevent adverse corpus cavernosal tissue structural alterations and thereby maximize the chances of recovering functional erections. Rehabilitation programs are common in clinical practice, but there is no definitive evidence to support their efficacy. Neuromodulation represents another strategy for promoting erection recovery postoperatively. This therapy involves the application of neuroprotective interventions, conceivably targeting biological elements involved in the erection response that are affected by neuropathic injury. Well-conducted, controlled trials with adequate follow-up are required in order to determine the erection preservative benefits of these therapeutic strategies. The purpose of this essay is to describe the mechanisms related to post-RP ED, assess the need for penile rehabilitation and neuromodulation following surgery, and analyze the basic science and clinical trial evidence associated with these applications for preserving EF following prostate cancer treatment.

Erectile dysfunction (ED) is a common men's health problem characterized by the consistent inability to sustain an erection sufficient for sexual intercourse. Basic science research on erectile 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, neurogenic dysfunction, or both. The constitutive forms of nitric oxide synthase (NOS, endothelial [eNOS] and neuronal [nNOS]) are important enzymes involved in the production of nitric oxide (NO) and thus regulate penile vascular homeostasis. Given the effect of endothelial- and neuronal-derived NO in penile vascular biology, a great deal of research over the past decade has focused on the role of NO synthesis from the endothelium and nitrergic nerve terminal in normal erectile physiology, as well as in disease states. Loss of the functional integrity of the endothelium and subsequent endothelial dysfunction plays an integral role in the occurrence of ED. Therefore, molecular mechanisms involved in dysregulation of these NOS isoforms in the development of ED are essential to discovering the pathogenesis of ED in various disease states. This communication reviews the role of eNOS and nNOS in erectile physiology and discusses the alterations in eNOS and nNOS via posttranslation modification in various vascular diseases of the penis.

Introduction: Immunophilin ligands function by binding to receptor proteins such as FK506 binding proteins (FKBPs). FKBPs are studied for their roles in neuroprotection., Aim: Compare the effect of FK506 (FK) and rapamycin (RAP) on erectile function (EF) recovery and FKBP expressions in penis and major pelvic ganglion (MPG) after cavernous nerve (CN) injury., Methods: Adult male rats were divided into four groups: sham surgery (CN exposure only) + vehicle; bilateral CN injury (BCNI; bilateral crush, 3 minutes with hemostat clamp) + vehicle; BCNI + FK (5 mg/kg/day, 5 days, sc); and BCNI + RAP (2 mg/kg/day, 5 days, sc). At both 24 hours (Day 1) or 1 week (Day 7) after BCNI, EF was assessed by intracavernosal pressure measurement and FKBPs 12, 38, 52, and 65 expressions were evaluated by Western blot analysis in collected penises and MPGs., Main Outcome Measures: EF and change in protein expressions of FKBPs in the rat penis and MPG after BCNI with and without immunophilin ligand treatment., Results: Both FK- and RAP-treated rats had preserved EF compared with vehicle-treated rats after BCNI. FKBPs changed variably following injury and treatment. In particular, in the penis at Day 1, FKBP 38 expression was decreased after BCNI and both FK and RAP attenuated this decrease. In MPG at Day 1, FKBP 38 expression was also decreased after BCNI and FK attenuated the decrease, while at Day 7, FKBP 38 expression was still decreased and RAP attenuated the decrease. Also, in the penis at Day 1, FKBP 65 expression decreased after BCNI and FK attenuated the decrease. In the MPG, FKBP 65 expression increased at both Days 1 and 7 with FK treatment., Conclusions: Improved EF after BCNI, as shown with RAP, further suggests a role of immunophilin ligands as a protective therapy of CN injury associated erectile dysfunction. Our findings also suggest that select FKBPs, such as FKBP 38 and FKBP 65, may mediate these effects.

The field of erectile dysfunction (ED) management over time has witnessed assorted interventions to enable men to perform sexual intercourse. In recent times, major progress in ED research has led to increasingly effective treatments based on a refined knowledge of the scientific basis for penile erection. Current concepts suggest that therapeutic prospects on the horizon include novel pharmacotherapies, growth factor therapy, gene therapy, and regenerative medicine. The purpose of this review is to present the foundations for future therapies in ED management.

Introduction: A scientific explanation remains elusive for many presentations of recurrent ischemic priapism., Aim: The aim of this article was to evaluate the possible clinical association between idiopathic priapism and anxiety disorders., Methods: Twenty-one patients without identifiable, presumed etiologies for their priapism disorders presented consecutively to a single practitioner's clinical practice and underwent clinical history evaluation and management over a 2(1/2)-year interval., Main Outcome Measures: The main outcome is the documentation of patient demographics and clinical profiles relating to medical history and priapism presentations., Results: Anxiety disorders including generalized anxiety, attention-deficit hyperactivity disorder, and obsessive-compulsive disorder were self-reported in 10 patients., Conclusions: The possible association between idiopathic priapism and anxiety disorders lends support for a central neurobiologic pathophysiology for the erectile disorder. Further neuropsychiatric studies of this clinical population is required to confirm the hypothesis.

Purpose: Angiotensin II is a known mediator of smooth muscle vasoconstriction and fibrosis. It up-regulates thrombospondin-1, a major activator of latent transforming growth factor-beta. Transforming growth factor-beta induces vascular fibrosis via intracellular SMAD signaling pathways. We evaluated the effect of treatment with the angiotensin II type 1 receptor antagonist losartan on erectile function in the rat following bilateral cavernous nerve injury., Materials and Methods: A total of 36 adult male rats were divided equally into 6 groups, including group 1-sham surgery with cavernous nerve exposure only plus vehicle, group 2-sham surgery plus oral low dose losartan (10 mg/kg per day), group 3-sham surgery plus high dose losartan (40 mg/kg per day), group 4-bilateral cavernous nerve injury (3-minute crush using a hemostat clamp) plus vehicle, group 5-bilateral cavernous nerve injury plus low dose losartan and group 6-bilateral cavernous nerve injury plus high dose losartan. Seven days following surgery erectile function was measured by electrically stimulating the cavernous nerves and monitoring intracavernous pressure. Penile tissue was collected for Western blot analysis of fibronectin, transforming growth factor-beta, thrombospondin-1, alpha-actin, and phosphorylated and total SMAD2 and SMAD3 expression., Results: Erectile function was significantly decreased after bilateral cavernous nerve injury compared with that after sham surgery (p <0.01). Low and high dose losartan preserved erectile function after bilateral cavernous nerve injury compared to that in vehicle controls (p <0.01 and <0.05, respectively). Fibronectin, pSMAD2, pSMAD3, transforming growth factor-beta-1, thrombospondin-1 and alpha-actin expression was up-regulated, and total SMAD2 and SMAD3 expression was down-regulated in the penis after bilateral cavernous nerve injury. Each dose of losartan after bilateral cavernous nerve injury significantly attenuated the up-regulated expression of fibronectin (p <0.01), pSMAD2 (p <0.05) and thrombospondin-1 (p <0.05), and up-regulated total SMAD2 (p <0.05)., Conclusions: These data suggest that fibrotic activators in the penis may cause decreased erectile function after bilateral cavernous nerve injury. Angiotensin II type 1 receptor antagonism may counteract this effect and promote erectile function preservation for conditions associated with penile fibrosis.

Introduction: Current surgical shunting procedures for major ischemic priapism do not always effectively resolve acute presentations of this disorder., Aim: To evaluate a modification of the Al-Ghorab distal penile corporoglanular shunt surgery for ischemic priapism., Methods: Three previously potent men (48, 43, 40 years of age) presented with major ischemic priapism episodes (5, 2, and 6 days in duration, respectively), which were refractory to clinical management including sympathomimetic intracavernosal treatments, intracorporal aspiration and saline irrigation, and penile shunt surgery attempts. We offered a surgical technique for facilitating corporal blood evacuation by retrograde insertion of a cavernosal dilator through the excised tunical windows of the distal corpora cavernosa after transglanular incision., Main Outcome Measures: Clinical evaluation of priapism resolution and erection recovery., Results: All men achieved successful resolution of priapism, with meaningful erection recovery assessable in one man. Conclusions. The modified Al-Ghorab corporoglanular shunt surgery appears to offer an advantageous management approach to resolve ischemic priapism, particularly for cases refractory to first-line management.

Introduction: Immunophilin ligands provide potentially new alternatives for the treatment of erectile dysfunction (ED), which occurs after injury of the cavernous nerves (CNs)., Aim: To review and update current knowledge of the neurotrophic effects and likely mechanism of action of immunophilin proteins with emphasis on the FK506-binding protein (FKBP) subfamily and the role of immunophilin ligands for the treatment of CN injury-induced ED., Methods: Review of available reports of studies investigating the effects and neurotrophic mechanisms of immunophilin ligands involved in erectile function recovery in rodent models of CN injury., Main Outcome Measures: Erection parameters and molecular correlations associated with CN injury and functional recovery., Results: Treatment with prototype immunosuppressive immunophilin ligands FK506 (FK) and rapamycin (Rapa) improve erectile function in animal models of CN injury. Similarly, non-immunosuppressive analogs such as GPI-1046 and FK1706 are effective in recovery of erections after CN injury. Neuronal nitric oxide may influence the erection recovery effects of immunophilin ligands after CN injury. FKBPs 38 and 65 expression changes in the penis and its innervation coincide with the neurotrophic effects of immunophilin ligands. Antioxidative actions of immunophilin ligands contribute to their neurotrophic effects. Immunophilins are localized to nerves coursing in human prostate and penile tissue., Conclusions: The findings support the hypothesis that immunophilin ligands, working through specific receptor mechanisms that are specific to injured CN, are potentially useful to sustain erectile function in men following radical prostatectomy.

Introduction: Recurrent ischemic priapism likely has a neurogenic basis for some clinical presentations., Aim: To describe a phenomenon of resolved recurrent ischemic priapism in a patient following celiac plexus block for recurrent upper abdominal pain., Methods: The case report profiled a 44-year-old Caucasian man who developed recurrent ischemic priapism after retroperitoneal surgery. He had failed multiple conventional interventions for his priapism. After he underwent a celiac plexus block for recurrent upper abdominal pain, his recurrent priapism episodes immediately stopped., Main Outcome Measures: Clinical history regarding priapism occurrences., Results: The patient obtained a resolution of his priapism after celiac plexus block, without recurrences at a 6-month follow-up assessment., Conclusions: Celiac plexus block successfully led to resolution of recurrent ischemic priapism of probable neurogenic origin associated with spinal nerve outflow injury.

Introduction: Female sexual arousal disorder (FSAD) is a major component of female sexual dysfunctions, affecting 25-70% of women. The mechanisms of FSAD are poorly understood. Estrogen contributes to the control of genital blood flow during the sexual response. Vascular effects of estrogen are mostly attributed to its regulation of endothelial nitric oxide (NO) production. However, the role of endothelial NO synthase (eNOS) and the mechanisms that regulate eNOS in female genital tract structures are largely unknown., Aim: To review available evidence of the mechanisms of eNOS regulation in female genital tract structures., Methods: This article reviews the literature that relates to the role of NO and eNOS in female sexual arousal and its modulation by estrogen., Main Outcome Measures: Association between female sexual arousal, NO, and eNOS., Results: The NO/cyclic guanosine monophosphate pathway is believed to have a primary role in the regulation of clitoral and vaginal blood flow, and smooth muscle relaxation during sexual arousal. Estrogen is critical for maintaining vaginal and clitoral blood flow and vaginal transudate production. Estrogen regulates eNOS by genomic mechanisms, involving augmented mRNA transcription and protein synthesis, and by non-genomic mechanisms, which occur without alterations in gene expression. However, limited studies have evaluated the physiological role of endothelial NO and the molecular mechanisms of eNOS regulation in the female genital tract., Conclusions: The effects of estrogen on increasing genital blood flow and smooth muscle relaxation have been attributed mostly to regulation of eNOS. However, the exact mechanisms of eNOS regulation in female genital tract structures and the molecular basis for the eNOS defect with aging and vascular diseases warrant further investigation.

Context: Erectile dysfunction (ED) after radical prostatectomy (RP) has a significant negative impact on a patient's health-related quality of life. Phosphodiesterase type 5 inhibitors (PDE5-Is) have recently been utilized not only as a treatment of ED in this population but also as a preventive strategy in penile rehabilitation programs., Objective: To elucidate the pathophysiologic mechanisms of post-RP ED, to assess the need for rehabilitation following surgery, and to analyze the basic scientific evidence and clinical applications of PDE5-Is for the prevention and treatment of ED., Evidence Acquisition: A systematic review of the literature using Medline, Cancerlit, and the Cochrane Library was conducted for the period between January 1997 and June 2008 using the keywords erectile dysfunction, radical prostatectomy, and phosphodiesterase inhibitors. Efficacy and safety of PDE5-Is in the randomized, placebo-controlled trials are evaluated in this review, and the limitations of the remaining studies are also discussed., Evidence Synthesis: Post-RP ED has many factors. Cavernosal nerve injury induces pro-apoptotic factors (ie, loss of smooth muscle) and pro-fibrotic factors (ie, an increase in collagen) within the corpora cavernosa. Cavernosal changes may also be attributed to poor oxygenation due to hemodynamic changes. Experimental data support the concept of cavernosal damage and suggest a protective role for daily dosage of a PDE5-I; however, similar data have not yet been replicated in humans. Penile rehabilitation programs are common in clinical practice, but there is no definitive evidence to support their use or the best treatment strategy. PDE5-Is are efficacious and safe in young patients with normal preoperative erectile function who have undergone bilateral nerve-sparing radical prostatectomy. On-demand use of a PDE5-I may be at least as efficacious as daily use. PDE5-I use in penile rehabilitation programs is not supported by rigorous level 1 evidence-based medicine., Conclusions: PDE5-Is are an efficacious and safe treatment for post-RP ED in properly selected patients. The experimental results on the protective role of daily dosages of PDE5-Is, while robust, have not been replicated in humans. With current human data, the role of a PDE5-I alone as a rehabilitation strategy is unclear and deserves further investigation.

Purpose: We determined the effect of passive secondhand cigarette smoke on 1) erectile function in vivo, 2) molecular mechanisms involved in penile vascular function, and 3) erectile function and penile molecular signaling in the presence of phosphodiesterase type 5 inhibitor therapy., Materials and Methods: Four groups of mice were used, including group 1--controls, group 2--mice exposed to 3 weeks of secondhand smoke (5 hours per day for 5 days per week), group 3--control plus sildenafil (100 mg/kg per day) and group 4--smoke exposed plus sildenafil (100 mg/kg per day). Cavernous nerve electrical stimulation and intracavernous injection of acetylcholine were done to assess erectile function. Constitutive and inducible nitric oxide synthase activity, reactive oxygen species generation, nitrotyrosine formation and superoxide anion levels were assessed., Results: Decreased erectile responses to cavernous nerve electrical stimulation and impaired endothelium dependent erectile responses to ACh in mice exposed to secondhand smoke were observed. Superoxide anion was increased in endothelial and corporeal smooth muscle cells of smoking mouse penises. In mice exposed to secondhand smoke constitutive nitric oxide synthase activity was decreased, and inducible nitric oxide synthase activity, reactive oxygen species generation and nitrotyrosine formation increased. Sildenafil therapy restored constitutive nitric oxide synthase activity in the penis of smoking mice, decreased inducible nitric oxide synthase activity, reactive oxygen species generation and nitrotyrosine formation, and improved erectile responses to cavernous nerve electrical stimulation and acetylcholine., Conclusions: Short-term exposure to secondhand smoke impairs erectile function through excessive penile reactive oxygen species signaling and inducible nitric oxide synthase activity. Decreased penile constitutive nitric oxide synthase activity may be attributable to the decreased endothelial nitric oxide synthase activity resulting from increased oxidative stress. Sildenafil therapy restored nitric oxide synthase activity and decreased reactive oxygen species signaling, resulting in improved erectile function.

Purpose: We investigated changes in serum biomarkers of vascular function after short-term, continuous sildenafil dosing in men with type 2 diabetes with erectile dysfunction., Materials and Methods: Men with erectile dysfunction associated with type 2 diabetes mellitus were randomized to receive continuous, daily sildenafil (50 mg for 1 week run-in and 100 mg for 3 weeks) (148), or placebo (144) for 4 weeks (phase I) and then sildenafil (25, 50 or 100 mg) on demand for 12 weeks (phase II). Blood draws at baseline and after phases I and II were analyzed for cyclic guanosine monophosphate (endothelial function marker), 8-isoprostane (oxidative stress marker), and interleukin-6 and interleukin-8 (inflammatory cytokines). Primary and secondary erectile function outcome variables were affirmative responses on Sexual Encounter Profile question 3 (ability to maintain erection sufficient for sexual intercourse) and Erection Hardness Score, respectively., Results: Serum cyclic guanosine monophosphate levels were increased in the sildenafil group relative to the placebo group at 4 (p <0.01) and 16 (p <0.05) weeks, correlating with affirmative responses to Sexual Encounter Profile question 3 at the 4-week interval only (p <0.05). Serum 8-isoprostane levels were decreased to a nonsignificant degree in the sildenafil group at 4 weeks with no further change at 16 weeks, whereas interleukin-6 and interleukin-8 levels were unchanged at either interval, and these levels were unassociated with erectile function outcomes., Conclusions: These data suggest that short-term, continuous sildenafil treatment causes systemic endothelial function to be enhanced and remain so for a duration after its discontinuation. However, they do not indicate any influence of this treatment on systemic oxidative stress or inflammation, or an effect on long-term erectile function improvement.

Objectives: To evaluate the effect of the fibrin sealant, Evicel, on the neuroregulatory control of penile erections in an experimental rat model., Methods: 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., Results: 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., Conclusion: 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.

Introduction: Erectile dysfunction persists as a major functional complication of nerve-sparing radical prostatectomy., Aim: To evaluate retrospectively the potential benefit of erythropoietin administration to improve erectile function recovery following radical prostatectomy., Methods: Preoperatively potent patients who underwent nerve-sparing radical retropubic prostatectomy between March 2005 and February 2006 elected to receive erythropoietin treatment (40,000 IU subcutaneously, single injection on their preoperative day; treatment group, N = 15). A contemporaneous clinically matched cohort comprising patients who elected postoperative standard surveillance only served for comparison (control group, N = 21). Phosphodiesterase type 5 (PDE5) inhibitor "on-demand" use was applied. Potency evaluations were monitored by International Index of Erectile Function-5 questionnaires administered preoperatively and at 3, 6, and 12 months postoperatively., Main Outcome Measure: Erection recovery., Results: Health comorbidities as well as erectile function status were demonstrated to be no different between groups at baseline. Erythropoietin-treated patients demonstrated significantly higher postoperative International Index of Erectile Function-5 questionnaire scores than control group patients at 3, 6, and 12 months postoperatively with or without use of PDE5 inhibitors (P < 0.05). At 12 months postoperatively, the percentages of patients performing sexual activity were 87% and 68% of erythropoietin-treated and control patients, respectively (P = 0.213), although the erythropoietin-treated patients had a significantly greater ability to perform sexual intercourse with minimal or no difficulty (P < 0.05)., Conclusion: Erythropoietin administration on the preoperative day before undergoing nerve-sparing radical prostatectomy in men reporting normal erectile function preoperatively may confer improved erectile function recovery postoperatively.

The 5 alpha-reductase inhibitors, which inhibit conversion of testosterone to dihydrotestosterone, are used for miscellaneous clinical applications, including the treatment of benign prostatic hyperplasia and male pattern hair loss, and for possible reduction of the risk of prostate cancer. Erectile dysfunction has been associated with 5 alpha-reductase inhibitors. Overall, reports in the literature suggest rates of erectile dysfunction to be between 0.8%-33% in men using these medications. However, randomized controlled studies report the rates of erectile dysfunction to be between 0.8%-15.8%. The possible risk association is that these medications impact androgen function, which is understood to contribute to normal erectile physiology. The 5 alpha-reductase inhibitors result in a drop in median serum dihydrotestosterone levels by 60%-93% within 2 years, but there is no major change in testosterone levels. In this review, we surveyed studies on erectile dysfunction in patients treated with 5 alpha-reductase inhibitors and critically examined the evidence that associates 5 alpha-reductase inhibitors and erectile dysfunction. We conclude that 5 alpha-reductase inhibitors do not lead to erectile dysfunction to a significant degree, and we support the position that dihydrotestosterone is less relevant than testosterone in erectile function.

Introduction: Erectile dysfunction remains a major functional complication of radical prostatectomy in the modern era despite surgical techniques to preserve the penile autonomic nerve supply., Aim: To develop and evaluate a neurostimulation system for cavernous nerve electrical stimulation for future use as a chronic implantation device that neurotrophically promotes erectile function recovery following radical prostatectomy., Method: After radical retropubic prostatectomy, the neurovascular bundle was stimulated using a temporarily placed electrode array of an implantable neurostimulation system (20 Hz frequency, 260 micro seconds pulse width, 5 mA-60 mA amplitude up to 10 minutes), and penile circumference increases were measured., Main Outcome Measure: Increase in penile circumference. Results. Among 12 men (mean age 60.3 years) enrolled in this study, 6 (50%) demonstrated measurable increases in penile circumference in response to cavernous nerve stimulation. Among these six men, the mean increase was 5.0 mm (range 1.6 mm to 7.0 mm). Temporary surgical placement of the device was done with relative ease, and there was no evidence of injury to the neurovascular bundle. Conclusions. A chronic implantable nerve stimulation system for cavernous nerve stimulation having possible neuromodulatory effects on the recovery of penile erections after radical prostatectomy is feasible.

Objectives: To demonstrate the use of optical coherence tomography (OCT) for imaging of the cavernous nerve (CN) and periprostatic tissues. The rates of nerve preservation and postoperative potency after radical prostatectomy might improve with better identification of the CN using emerging intraoperative imaging modalities. OCT is an imaging modality that allows for real-time, high-resolution, cross-sectional imaging of tissues., Methods: Seven male Sprague-Dawley rats underwent surgery using a midline celiotomy to expose the bladder, prostate, and seminal vesicles. The CNs and major pelvic ganglion were identified. Visual identification of the CN was further confirmed by electrical stimulation with simultaneous intracorporeal pressure measurements. OCT images of the CN, major pelvic ganglion, bladder, prostate, and seminal vesicles were acquired and correlated directly with the histologic findings. Once a baseline technique for the scanning and interpretation of the acquired images was established using the rat model, OCT was used to image ex vivo human prostatectomy specimens., Results: OCT provided unique imaging characteristics, differentiating the CN from the bladder, prostate, seminal vesicles, and periprostatic fat. OCT images of the CN and prostate correlated well with the histologic findings. OCT of ex vivo human prostatectomy specimens revealed findings similar to those with the rat experiments, with, however, less dramatic architecture visualized in part because of the thicker capsule and more dense stroma of human prostates., Conclusions: The results of our study have shown that OCT provides real-time, high-resolution imaging of the CN in the rat model with excellent correlation to the histologic findings. This study provides a basis for the intraoperative use of this emerging technology during nerve-sparing prostatectomy.

The proposal that exposures to environmental or occupational substances may affect erection ability is a tenable one and would add to a growing list of pathogenic risk factors associated with erectile dysfunction. Several lines of evidence gained by clinical epidemiologic and biomedical research investigations lend support. Several environmental toxicants to include lead, organic solvents, and pesticides have been implicated as possibly hazardous agents. Effects on the nervous and hormonal systems have been proposed as the leading mechanisms by which environmental toxicants adversely impact erectile function. Synthesis of the current evidence supports a possible risk association between environmental exposures and erectile dysfunction. However, scientific support is lacking to establish a direct causal association at this time. More scientific work is needed to identify specific environmental agents that may harm erectile function and define their exact mechanisms of action in this regard.

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.

Introduction: Hypertension is a risk factor for erectile dysfunction (ED). The pathophysiologic basis of ED in hypertension remains largely unknown., Aim: The goal of this study was to test the hypothesis that increased nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity contributes to the development of hypertension-associated ED., Methods: Male Sprague-Dawley rats were implanted with osmotic pumps containing saline or angiotensin II (Ang II, 70 ng/min) for 28 days and treated with or without the NADPH oxidase inhibitor apocynin (10 mM) in the drinking water., Main Outcome Measures: Erectile function was examined by measuring the mean arterial blood pressure (MAP) and intracavernosal pressure (ICP) upon electrical stimulation of the cavernous nerve. Protein expression levels of NADPH oxidase subunits were analyzed by Western blot. Reactive oxygen species production was determined by dihydroethidium (DHE) staining and thiobarbituric acid reactive substances (TBARS) assay., Results: Maximum ICP (MaxICP) and ICP area under the curve, which were normalized by MAP, were significantly reduced in Ang II-infused hypertensive rats compared to that of normotensive rats (P < 0.05). Protein expression of NADPH oxidase subunit p47(phox) was significantly increased by 30% in Ang II-infused hypertensive rat penes along with increased DHE staining and TBARS levels (P < 0.05) when compared to that of controls. There were no significant changes in p67(phox) or gp91(phox) protein expression. Apocynin reduced NADPH oxidase protein expression and TBARS levels as well as improved MaxICP and ICP area under curve in Ang II-infused hypertensive rats (P < 0.05)., Conclusions: These data suggest that activation of NADPH oxidase is a molecular mechanism for hypertension-associated ED. Apocynin treatment exerted protective effects on erectile function through inhibition of NADPH oxidase activity, thereby reducing oxidative stress in Ang II-infused hypertensive rats. This is the first study to identify the importance of NADPH oxidase in the regulation of erectile function in vivo.

Background and Purpose: Laser nerve stimulation has recently been studied in neuroscience as an alternative to electrical stimulation. Its advantages include noncontact stimulation, better spatial selectivity, and elimination of electrical stimulation artifacts. This study explored laser stimulation of the rat cavernous nerves as a potential alternative to electrical nerve mapping during nerve-sparing radical prostatectomy., Materials and Methods: The cavernous nerves were surgically exposed in 10 male rats. A thulium fiber laser stimulated the nerves, with a wavelength of 1870 nm, pulse energy of 7.5 mJ, radiant exposure of 1 J/cm2, pulse duration of 2.5 msec, pulse rate of 10 Hz, and 1-mm laser spot diameter, for a stimulation time of 60 sec., Results and Conclusion: A significant increase in the intracavernosal pressure was detected on laser stimulation, with pressure returning to baseline values after stimulation ceased. This study demonstrates the feasibility of noncontact stimulation of the cavernous nerves using near-infrared laser radiation.

Objective: To determine if FK506-binding proteins (FKBPs) are localized to the autonomic nerve supply of the human penis because FK506 (an immunosuppressant drug) has been linked to enhanced nerve regeneration after nerve injury and neurodegenerative diseases by binding to FKBPs, a select group of immunophilins., Materials and Methods: Human lower genitourinary tract specimens were obtained and embedded in paraffin wax. The tissue was sectioned (10 microm) and processed for immunohistochemistry using antibodies for FKBPs 12, 38, 52, 65, 135 and neuronal nitric oxide synthase (nNOS). To confirm specificity of the antibody, we processed some tissue in the absence of primary antibody, with mouse or rabbit IgG, and with a blocking peptide for FKBP12., Results: In the pelvis, immunoreactivity for all the FKBPs and nNOS was localized to the periprostatic ganglia although FKBP12 was the only FKBP localized to nerve bundles in this location. In penile tissue, immunoreactivity for all five FKBPs and nNOS was localized to nerves, although immunoreactivity for FKBP38 was minimal. The FKBPs were also evident in epithelial, endothelial and smooth muscle cells of the prostate and penis. Negative controls did not produce staining., Conclusions: Identification and localization of immunophilins to nerves coursing in prostate and penile tissue suggest a likely molecular basis to apply immunophilin ligand therapy to protect or regenerate cavernosal nerves. Our findings support the hypothesis that immunosuppressant drugs such as FK506, working via specific receptor mechanisms, are potentially useful to sustain erectile function in men after radical prostatectomy.

Introduction: Diet and exercise affect endothelial function in the penis, but the molecular mechanisms underlying their effects are not understood., Aims: We evaluated endothelial nitric oxide synthase (eNOS) interaction with its negative regulator caveolin-1 and eNOS uncoupling as molecular targets in the penis associated with the beneficial effects of low-fat diet and chronic exercise., Methods: The penes were obtained from adult male Yucatan pigs fed a normal-fat or high-fat diet on exercised or sedentary regimen for 24 weeks. Markers of endothelial function (guanosine 3',5'-monophosphate [cGMP] production), endothelial dysfunction (eNOS uncoupling and eNOS interaction with caveolin-1), and oxidative stress (thiobarbituric acid reactive substances [TBARS]) were measured in the penes. The concentrations of cGMP and TBARS were determined using commercial kits. eNOS uncoupling was determined by low-temperature sodium dodecyl sulfate polyacrylamide gel electrophoresis. eNOS binding to caveolin-1, eNOS phosphorylation (Ser-1177), and protein expression of eNOS and caveolin-1 were measured by Western blot analysis in penes purified for NOS and in homogenates, respectively., Main Outcome Measures: Molecular parameters of endothelial function including eNOS regulatory function., Results: Relative to normal-fat diet, high-fat diet significantly (P < 0.05) reduced cGMP levels and significantly (P < 0.05) increased eNOS uncoupling, eNOS binding to caveolin-1, and TBARS production in the penis of sedentary pigs. Exercise of pigs on high-fat diet reversed (P < 0.05) the abnormalities in cGMP levels, eNOS uncoupling, and eNOS binding to caveolin-1, but not TBARS levels. Exercise of pigs on normal-fat diet did not affect any of these parameters. Protein expressions of caveolin-1, phosphorylated (Ser-1177), and total eNOS were unaffected by diet or exercise., Conclusion: Low-fat diet and chronic exercise preserve endothelial function in the pig penis by sustaining active eNOS in its dimeric form and by limiting eNOS interaction with its negative regulator caveolin-1.

Introduction: Epidemiology can be defined as the population study of the occurrence of health and disease. The knowledge of the rates of occurrence of sexual dysfunctions and the primary risk factors for these conditions is very important to assist in assessing the risk and planning treatment and prevention programs in sexual medicine., Aim: Review modern studies of the prevalence and incidence of sexual dysfunction in an effort to establish a consensus concerning the frequency of occurrence of these conditions, and review the strengths and liabilities of design methodology in the field., Main Outcome Measure: Review of peer-reviewed literature., Results: The findings suggest that sexual dysfunctions are highly prevalent in our society worldwide, and that the occurrence of sexual dysfunctions increases directly with age for both men and women. There is also a strong support for the finding that although the frequency of symptoms increases with age, personal distress about those symptoms appears to diminish as individuals become older. An additional uniform result was that specific medical conditions and health behaviors represent major risk factors for sexual disorders, and that many of these health conditions also have a strong positive relationship with age., Conclusions: Progress has been made concerning both the number and quality of epidemiologic prevalence studies in sexual medicine; however, there is a paucity of studies of the incidence of these conditions. Because reliable incidence data are critical for prevention and treatment planning, the design and execution of the incidence trials should become a high priority for the field. In addition, repeated calls for the development of a new systematic and integrated diagnostic system in sexual medicine were also evident, because of the perception by many that the imprecision of our current diagnostic system represents the "rate-limiting step" for the epidemiology of the field. The review suggests that although much has been accomplished in the past 15-20 years, much remains to be done.

Introduction: Efforts to identify the health risk associations for priapism may reveal pathophysiologic mechanisms for the disorder and suggest a scientifically rational approach for correcting it., Aim: We describe a clinical presentation of idiopathic recurrent priapism in a patient with glucose-6-phosphate dehydrogenase (G6PD) deficiency and consider a possible nitric oxide (NO)-dependent mechanistic basis from which the medical condition causes priapism., Methods: The case report profiled a 35-year-old African-American man with G6PD deficiency who presented with a rapid progression of recurrent priapism episodes. He was outwardly healthy and did not have sickle cell disease or trait by hematologic screening. His management featured use of a long-term, continuous phosphodiesterase type 5 (PDE5) inhibitor therapeutic regimen., Main Outcome Measures: Clinical history data and response to PDE5 inhibitor therapy., Results: After a 3-month duration of PDE5 inhibitor therapy, priapism recurrences were sufficiently resolved and the patient discontinued therapy. At 18-month clinical follow-up, he experienced only minor priapism recurrences and retention of full erectile ability., Conclusions: G6PD deficiency offers an explanation for idiopathic priapism. The medical condition generates a pathophysiologic milieu consistent with aberrant NO signaling and heightened oxidative stress in the penis.

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.

Erectile dysfunction (ED) commonly results from endothelial dysfunction of the systemic vasculature. Although phosphodiesterase type 5 (PDE-5) inhibitors are effective at treating most cases of ED, they must be taken routinely and are ineffectual for a meaningful number of men. In recent years gene and stem cell-based therapies targeted at the penile endothelium have been gaining momentum in preclinical studies. These early studies reveal that gene and stem cell-based therapies may be both enduring and efficacious, and may eventually lead to a cure for ED. The following review will highlight our current understanding of endothelial-specific gene and stem cell-based therapies performed to date in a number of experimental animal models.

The cavernous nerves on the prostate surface are responsible for erectile function. Improved diagnostic techniques are necessary for identification of the nerves during prostate cancer surgery and preservation of sexual function after surgery. Electrical mapping of the nerves has been used as an intra-operative tool during prostate surgery, but it has proven inconsistent and unreliable. Non-contact optical stimulation of the cavernous nerves in the rat prostate has recently been demonstrated as a potential alternative to electrical nerve stimulation. The purpose of this study is to optimize the laser parameters to provide the maximum intracavernosal pressure response after optical nerve stimulation in the rat prostate. Optimal laser nerve stimulation parameters provided comparable response to electrical nerve stimulation. Optical nerve stimulation may represent a potential intra-operative diagnostic technique for use in laparoscopic and robotic nerve-sparing prostate cancer surgery.