Penile Arteries Research Articles

PD40-01 3 YEAR OUTCOMES OF THE ZEN TRIAL: THE MEDTRONIC ZOTAROLIMUS-ELUTING PERIPHERAL STENT SYSTEM FOR THE TREATMENT OF ED IN MALES WITH SUB-OPTIMAL RESPONSE TO PDE5 INHIBITORS

You have accessJournal of UrologySexual Function/Dysfunction/Andrology: Surgical Therapy II1 Apr 2015PD40-01 3 YEAR OUTCOMES OF THE ZEN TRIAL: THE MEDTRONIC ZOTAROLIMUS-ELUTING PERIPHERAL STENT SYSTEM FOR THE TREATMENT OF ED IN MALES WITH SUB-OPTIMAL RESPONSE TO PDE5 INHIBITORS Tobias Kohler and Irwin Goldstein Tobias KohlerTobias Kohler More articles by this author and Irwin GoldsteinIrwin Goldstein More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2015.02.2435AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES We report 3 year safety, feasibility and outcomes of zotarolimus−eluting stent implantation in focal atherosclerotic lesions of the internal pudendal arteries (IPAs) among men with erectile dysfunction (ED) and a suboptimal response to phosphodiesterase−5 inhibitors. METHODS We performed a prospective, multicenter, single-armed safety and feasibility trial of 30 male subjects > 18 years with atherosclerotic ED and a suboptimal response to phosphodiesterase-5 inhibitors. A novel combination of clinical, duplex ultrasound, and invasive angiographic factors were used to determine eligibility for stent therapy. Key inclusion criteria included IIEF-6 < 21 with at least 4 weeks of PDE5i use, ultrasound PSVs < 30 cm/sec bilaterally, and angiographic stenosis of one or both IPAs. Key exclusion criteria included non-vascular causes of ED, venous leak as seen on penile Doppler (EDV > 5 cm/sec), and non target lesions of > 70% stenosis in common iliac or common penile artery. The primary safety end point was any major adverse event 30 days after the procedure. The primary feasibility end point was improvement in the IIEF-6 (Erectile Dysfunction Domain) score of 4 points or more. RESULTS A total of 383 subjects were screened of which there was a 92% screen failure rate. Forty-five lesions were treated with stents in 30 subjects. Procedural success was 100% with no major adverse events through follow-up. The primary feasibility end point (IIEF-6 +4) was achieved by 81% of intention-to treat subjects (17/21) at 1 year, 58% (11/19) at 2 years and 39% (5/13) at three years. 5 patients were stented outside the pudendal artery. Per protocol outcomes revealed IIEF improvement by 4 points in 84% (16/19)at 1 year, 61% (11/18) at 2 years and 36% (4/11) at 3 years. Changes in IIEF6 scores from baseline for the per protocol group were + 18.6 (95% CI = 11.8-25.5) at one year, + 14.7 (6.3-23.2) at 2 years, and + 7.8 at 3 years (-0.3 - 16). Mean peak systolic velocity on penile Doppler increased from 16.4 cm/s at baseline to 32.4 cm/sec at 1 year. Angiographic binary restonosis (>50% lumen diameter stenosis) was found in 11/32 lesions (34.4%). CONCLUSIONS Among patients with ED and limited response with pharmacologic therapy, percutaneous stent revascularization of the internal pudendal artery is safe and appears promising. However, significant challenges remain in determining and screening for the appropriate patient treatment population, optimizing procedural techniques for placement, and preventing stent restenosis. © 2015 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 193Issue 4SApril 2015Page: e835 Advertisement Copyright & Permissions© 2015 by American Urological Association Education and Research, Inc.MetricsAuthor Information Tobias Kohler More articles by this author Irwin Goldstein More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

PD22-03 HOW DIMINISHED CAVERNOSAL ARTERIAL BLOOD FLOW AFFECTS THE SUCCESS OF ANASTAMOTIC URETHROPLASTY AFTER PELVIC FRACTURE URETHRAL INJURY

You have accessJournal of UrologyTrauma/Reconstruction: Urethral Reconstruction (including Stricture) III1 Apr 2015PD22-03 HOW DIMINISHED CAVERNOSAL ARTERIAL BLOOD FLOW AFFECTS THE SUCCESS OF ANASTAMOTIC URETHROPLASTY AFTER PELVIC FRACTURE URETHRAL INJURY Craig Hunter, Walid Shahrour, Pankaj Joshi, Sandesh Surana, Vikram shah Batra, and Sanjay Kulkarni Craig HunterCraig Hunter More articles by this author , Walid ShahrourWalid Shahrour More articles by this author , Pankaj JoshiPankaj Joshi More articles by this author , Sandesh SuranaSandesh Surana More articles by this author , Vikram shah BatraVikram shah Batra More articles by this author , and Sanjay KulkarniSanjay Kulkarni More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2015.02.1445AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES The vascular supply to the urethra is of paramount importance to urethra. Pelvic Fracture Urethral Injury (PFUI) is often accompanied by vascular injury. For patients with erectile dysfunction and PFUI, it has been previously recommended to undergo a preoperative penile Doppler to investigate penile blood flow. In cases when arterial insufficiency (less than 25 ml/sec) is found, it has been recommended to undergo penile revascularization prior to urethroplasty. The aim of our study was to evaluate the success of urethroplasty in patients with diminished cavernosal arterial blood flow. We hypothesized that decreased cavernosal flow led to increase failure rates of anastomotic urethroplasty after PFUI. METHODS This is a retrospective review from Jan 2013 to September 2013 of those patients who underwent repair of pelvic fracture urethral defect and whom penile Doppler was available. All patients with pelvic fracture planning to undergo anastamotic urethroplasty obtain a penile Doppler, irrespective of their stated subjective erection abililty. All penile Doppler studies were performed by an outside imaging center, and reports were reviewed. Locally and worldwide, the radiologist is usually performing the study for erectile dysfuction, and as such the report is limited to the cavernosal artery; rarely is the flow of the dorsal penile artery flow reported. All patients underwent progressive perineal anastamotic urethroplasty. Failure was described as need for repeat urethroplasty, visual internal urethrotomy, urethal dilation, or need for indefinite urinary catheter. RESULTS From January 2013 to September 2013, 103 Pelvic fracture urethral defects were repaired at our institution. 65 patients with follow up and penile Doppler were available for review. Mean age of patient was 26 years (range 17 to 52), and mean follow up of 16 months (range 12 to 21). Among the 65 patients, 14 (25%) had a documented cavernosal artery flow of less than 25 ml/sec bilaterally. Of those 16 patients with documented poor flow, 12 (75%) had successful urethroplasty. 39 of the 49 (80%) patients with adequate flow had successful urethroplasty. CONCLUSIONS Diminished cavernosal artery flow rates are not predictive of success or failure in PFUI repair. Patients with severe cavernosal artery insufficiency have adequate successful anastamotic urethroplasty after PFUI. A prospective evaluation of the Dorsal Penile Artery may prove to have a more significant correlation to success after PFUI. © 2015 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 193Issue 4SApril 2015Page: e477 Advertisement Copyright & Permissions© 2015 by American Urological Association Education and Research, Inc.MetricsAuthor Information Craig Hunter More articles by this author Walid Shahrour More articles by this author Pankaj Joshi More articles by this author Sandesh Surana More articles by this author Vikram shah Batra More articles by this author Sanjay Kulkarni More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Retraction statement: A double-blind placebo-controlled study of the efficacy and safety of pentoxifylline in early chronic Peyronie's disease.

Study Type – Therapy (RCT) Level of Evidence 1b OBJECTIVE To analyse the safety and efficacy of pentoxifylline sustained-release (PTX-SR) treatment in patients with early chronic Peyronie’s disease (PD). PATIENTS AND METHODS In all, 228 patients with a mean (sd) age of 51 (9) years who had early chronic PD were randomized to receive 400 mg PTX-SR (Apo-Pentoxifylline, Apotex Inc., Toronto, Canada) twice daily (group 1, 114) or similar regimen of placebo (group 2, 114) for 6 months. A medical history was taken and the men had a complete physical examination. The following variables were assessed before and after therapy: penile curvature and penile artery spectral traces (end-diastolic velocity, EDV, peak systolic velocity, PSV, and resistivity index, RI, of the right and left cavernous arteries assessed with dynamic penile duplex ultrasonography), plaque characteristics (assessed by penile X-ray and penile ultrasonography), pain (assessed by visual analogue scale), erectile function (assessed by the International Index of Erectile Function, IIEF questionnaire), treatment satisfaction (assessed by Erectile Dysfunction Inventory of Treatment Satisfaction questionnaire), and side-effects. Patient perception of penile curvature and plaque size, and mean weekly intercourse attempts were also assessed. RESULTS Overall, 36.9% of patients who received PTX-SR reported a positive response, vs only 4.5% in the placebo group. Of patients in PTX-SR group, 12 (11%) had disease progression, vs 46 (42%) in placebo group (P = 0.01). Improvement in penile curvature (P = 0.01), and plaque volume (P = 0.001) was significantly greater in patients treated with PTX-SR than placebo. The increase in IIEF total score was significantly higher in the PTX-SR group (P = 0.02). Mean PSV changes after therapy compared to baseline were statistically significant between PTX-SR (right, +11.4%, left, +11.7%) and placebo-treated (+0.2% and −4.2%, respectively) patients (both P = 0.04). CONCLUSIONS PTX-R was moderately effective in reducing penile curvature and plaque volume in patients with early chronic PD. Further studies with different treatment regimens are needed to better elucidate the beneficial effects of PTX-SR in PD.

FM19G11 reverses endothelial dysfunction in rat and human arteries through stimulation of the PI3K/Akt/eNOS pathway, independently of mTOR/HIF-1α activation.

FM19G11 up-regulates mammalian target of rapamycin (mTOR)/hypoxia inducible factor-1α (HIF-1α) and PI3K/Akt pathways, which are involved in endothelial function. We evaluated the effects of FM19G11 on defective endothelial vasodilatation in arteries from rats and humans and investigated the mechanisms involved. Effects of chronic in vivo administration of FM19G11 on aortic endothelial vasodilatation were evaluated together with ex vivo treatment in aortic and mesenteric arteries from control and insulin-resistant rats (IRR). Its effects on vasodilator responses of penile arteries (HPRAs) and corpus cavernosum (HCC) from men with vasculogenic erectile dysfunction (ED) (model of human endothelial dysfunction) were also evaluated. Vascular expression of phosphorylated-endothelial NOS (p-eNOS), phosphorylated-Akt (p-Akt) and HIF-1α was determined by immunodetection and cGMP by elisa. Chronic administration of FM19G11 reversed the impaired endothelial vasodilatation in IRR. Ex vivo treatment with FM19G11 also significantly improved endothelium-dependent vasodilatation in aorta and mesenteric arteries from IRR. These effects were accompanied by the restoration of p-eNOS and cGMP levels in IRR aorta and were prevented by either NOS or PI3K inhibition. p-Akt and p-eNOS contents were increased by FM19G11 in aortic endothelium of IRR. FM19G11-induced restoration of endothelial vasodilatation was unaffected by mTOR/HIF-1α inhibitors. FM19G11 also restored endothelial vasodilatation in HPRA and HCC from ED patients. Stimulation of the PI3K/Akt/eNOS pathway by FM19G11 alleviates impaired NO-mediated endothelial vasodilatation in rat and human arteries independently of mTOR/HIF-1α activation. This pharmacological strategy could be beneficial for managing pathological conditions associated with endothelial dysfunction, such as ED.

Chapter 3 - Anatomy and physiology of genital organs – men

Male sexual functions involve a number of organs and structures in genitalia whose role is to produce fertilizing gametes and to allow female-partner insemination. The testes belong to the reproductive and endocrine systems as they synthesize spermatozoa and androgens, and are under finely regulated hormonal control by the hypothalamopituitary axis. Sexual responses are controlled by a complex and coordinated interplay of both the somatic and the autonomic nervous system in multiple components of the brain, spinal cord, and relevant peripheral organs. Erectile bodies are an essential element of the penis and engorgement of the penis with blood leads to penile tumescence. Blood engorgement is due to relaxation of smooth-muscle cells of erectile tissue and endothelium of the penile arteries. The penis gains additional rigidity when the ischiocavernosus muscles contract. Stimuli from peripheral and/or central origins activate particular spinal nuclei, causing penile erection. Ejaculation consists of two phases, emission and expulsion, which correspond, respectively, to secretion of the different components of the semen by sex glands and forceful expulsion of semen due to rhythmic contractions of the bulbospongiosus muscle. A spinal generator of ejaculation integrates genital stimuli and sexual cues and, when the excitatory threshold is reached, triggers ejaculation by orchestrating the activation of autonomic and somatic pathways commanding the peripheral events of ejaculation.

Endothelin-1 contributes to endothelial dysfunction and enhanced vasoconstriction through augmented superoxide production in penile arteries from insulin-resistant obese rats: role of ET(A) and ET(B) receptors.

We assessed whether endothelin-1 (ET-1) inhibits NO and contributes to endothelial dysfunction in penile arteries in a model of insulin resistance-associated erectile dysfunction (ED). Vascular function was assessed in penile arteries, from obese (OZR) and lean (LZR) Zucker rats, mounted in microvascular myographs. Changes in basal and stimulated levels of superoxide (O2 (-) ) were detected by lucigenin-enhanced chemiluminescence and ET receptor expression was determined by immunohistochemistry. ET-1 stimulated acute O2 (-) production that was blunted by tempol and the NADPH oxidase inhibitor, apocynin, but markedly enhanced in obese animals. ET-1 inhibited the vasorelaxant effects of ACh and of the NO donor S-nitroso-N-acetyl-DL-penicillamine in arteries from both LZR and OZR. Selective ETA (BQ123) or ETB receptor (BQ788) antagonists reduced both basal and ET-1-stimulated superoxide generation and reversed ET-1-induced inhibition of NO-mediated relaxations in OZR, while only BQ-123 antagonized ET-1 actions in LZR. ET-1-induced vasoconstriction was markedly enhanced by NO synthase blockade and reduced by endothelium removal and apocynin. In endothelium-denuded penile arteries, apocynin blunted augmented ET-1-induced contractions in OZR. Both ETA and ETB receptors were expressed in smooth muscle and the endothelial layer and up-regulated in arteries from OZR. ET-1 stimulates ETA -mediated NADPH oxidase-dependent ROS generation, which inhibits endothelial NO bioavailability and contributes to ET-1-induced contraction in healthy penile arteries. Enhanced vascular expression of ETB receptors contributes to augmented ROS production, endothelial dysfunction and increased vasoconstriction in erectile tissue from insulin-resistant obese rats. Hence, antagonism of ETB receptors might improve the ED associated with insulin-resistant states.

Screening of new compounds for the management of erectile dysfunction

Objective/Background: Erectile dysfunction, a male sexual dysfunction generally develops due to impairment of relaxation of penile smooth muscles and arteries. Inhibitors of phosphodiesterase type 5 (PDE5) enzyme like in sildenafil, vardenafil, tadalafil etc. are in clinical use for the management of erectile dysfunction. Ongoing research focuses on development of potent medicine with fewer side effects. Objective of this article is to discuss and demonstrate procedures available to screen new compounds for the management of erectile dysfunction. Methodology: Many animal models (mice, rat, cat, rabbit, dog etc.) are available to screen new chemical compounds for increasing erectile function. In vitro (using isolated corpus cavernosum smooth muscle of penile tissue) and in vivo (measuring intracavernosal pressure) studies may be performed for screening new compounds. In this article, we discuss about two such screening procedures using rat as an animal model. Results and discussion: Compounds those relax isolated rat corpus cavernosum smooth muscles significantly in vitro may increase penile erection in humans. Similarly, the compounds those increase intracavernosal pressure by relaxing erectile smooth muscle and penile arteries in rat may increase erectile function in humans. Conclusion: Rat is a suitable model for screening new compounds to manage erectile dysfunction. Key words: Corpus cavernosum smooth muscle, intracavernosal pressure, mean arterial pressure.

AB25. What would YES (Morning Erection/Sleep-related Erection) be without NO (Nitric Oxide) induced by Teststerone?

As you know, for penile erection, a sufficient amount of testosterone-induced nitric oxide is needed in the smooth muscle of the penile arterial wall. With aging, LOH syndrome and so on, the serum testosterone level decreases, resulting in a decline of penile erectile function. Furthermore, it is known that the enzyme PDE5 in the penile artery wall also inhibits that function. Even so, it may be safe to say that decreasing testosterone is the major factor for erectile dysfunction, excepting severe diabetic arterial sclerosis. Currently, however, almost all doctors treat ED cases with a PDE5-Inhibitor only. From my understanding of the above-mentioned mechanism of erection, I think this medical treatment is not scientific and only a half measure. Cases in which PDE5-inhibitors alone are effective are limited to those in which sufficient NO is maintained to barely induce erection unless inhibited by PDE5. Aging males, especially, have lower NO levels caused by low testosterone. These cases cannot be cured satisfactorily by PDE5 inhibitors alone, even if the men can somehow achieve sexual intercourse. Therefore, I cannot understand or agree with the treatment method using a PDE5-Inhibitoralone without checking the testosterone level. Furthermore, simple temporal recovery of sexual activity does not revitalize the male fundamental physiology, that is, sleep-related erection and morning erection. And a more important problem is that latent psychological disorders should be thoroughly investigated for patients consulting about so-called ED. It is even said that it is lucky for a patient to have a chance to consult about ED, since it means that the doctor will check for other disorders; for example, metabolic syndrome so on. More aged men are beginning to feel loss of motivation and poor physiological condition after the climacteric stage, with loss of morning erection, even if they do not express complaints. These problems are mostly caused by a decline in testosterone, which latently accelerates arterial sclerosis and vascular disorders, shortening the male life span. Such patients with low levels of free testosterone complaining of ED should be treated with testosterone substitution and a PDE9-inhibitor (especially long-acting Cialis) for a period of at least 2-3 months. This treatment will restore the male physiological functions of sleep-related erection and morning erection and as well as treating many symptoms of LOH syndrome at the same time. However, the most important effect of revitalization of male physiology is surely the restoration of the self-actualization and dignity of maleness to patients. That should be considered the most clinically significant outcome.

Endothelin A (ETA) Receptors Are Involved in Augmented Adrenergic Vasoconstriction and Blunted Nitric Oxide-Mediated Relaxation of Penile Arteries from Insulin-Resistant Obese Zucker Rats

Endothelin 1 (ET-1) levels and receptors are up-regulated in the erectile tissue of diabetic patients and animal models of erectile dysfunction (ED). The present study assessed the role of ET-1 receptors in the impaired adrenergic vasoconstriction and nitrergic relaxation of penile arteries from a rat model of insulin resistance. The effect of ET receptor antagonists was evaluated on the contractile responses to electrical field stimulation (EFS) of penile arteries from obese Zucker rats (OZRs) compared with lean Zucker rats (LZRs). ET receptor expression was determined by immunohistochemistry. Changes in neural nitrergic relaxation and adrenergic vasoconstriction and the expression of ET receptors in perivascular nerves were assessed. ET-1 (10(-10) M) enhanced EFS-induced vasoconstriction, and treatment with the adrenergic neurotoxin guanethidine reduced the contractions induced by ET-1 in penile arteries from both LZRs and OZRs, thus supporting the hypothesis that ET-1 releases noradrenaline from adrenergic nerves. ET-1 antagonized neural nitric oxide (NO)-mediated relaxant responses in LZR arteries, antagonizing relaxations induced by the NO donor S-nitroso-N-acetylpenicillamine to a larger extent in arteries from OZRs. ET(A) and ET(B) receptors were expressed in perivascular fibers colocalized with the neuronal marker protein gene product 9.5 in penile arteries from OZRs. The ET(A) receptor antagonist BQ-123 reversed the enhancing effect of ET-1 on the vasoconstriction elicited by EFS and the ET-1-induced inhibition of nitrergic relaxations in LZRs, restoring them to control levels in penile arteries of OZRs. ET-1 enhances adrenergic vasoconstriction through presynaptic ET(A) receptors and antagonizes neural NO-mediated relaxation through postsynaptic smooth muscle ET(A) receptors in penile arteries from OZRs, which likely contributes to the augmented vasoconstriction and blunted nitrergic relaxation of erectile tissue under conditions of insulin resistance.

Safety and six-month durability of angioplasty for isolated penile artery stenoses in patients with erectile dysfunction: a first-in-man study.

Obstructive pelvic arterial lesions are highly prevalent in patients with erectile dysfunction and commonly located in penile artery segments. In this first-in-man study, we intended to assess the safety and feasibility of balloon angioplasty for isolated penile artery stenoses in patients with erectile dysfunction. Twenty-five patients with erectile dysfunction and isolated penile artery stenoses (unilateral stenosis ≥70% or bilateral stenoses ≥50%) identified by pelvic computed tomographic angiography were enrolled. A total of 20 patients (mean age 61 years [range, 48-79 years]) underwent balloon angioplasty. Three patients had bilateral penile artery stenoses. Procedural success was achieved in all 23 penile arteries, with an average balloon size of 1.6 mm (range, 1.00-2.25 mm). The average International Index for Erectile Function-5 (IIEF-5) score improved from 10.0±5.2 at baseline to 15.2±6.7 (p<0.001) at one month and 15.2±6.3 (p<0.001) at six months. Clinical success (change in the IIEF-5 score ≥4 or normalisation of erectile function [IIEF-5 ≥22]) was achieved in 15 (75%), 13 (65%), and 12 (60%) patients at one, three, and six months, respectively. There were no adverse events through follow-up. For the first time we demonstrated that penile artery angioplasty is safe and can achieve clinically significant improvement in erectile function in 60% of patients with erectile dysfunction and isolated penile artery stenoses.

Nebivolol potentiates the efficacy of PDE5 inhibitors to relax corpus cavernosum and penile arteries from diabetic patients by enhancing the NO/cGMP pathway.

The efficacy of oral pharmacotherapy for erectile dysfunction (ED) (i.e., type 5 phosphodiesterase[PDE5] inhibitors) is significantly reduced in diabetic patients. Nebivolol is a selective β1-blocker used for treatinghy pertension that has been shown to increase the efficacy of sildenafil to reverse ED in diabetic rats. To evaluate the effects of nebivolol on the efficacy of the PDE5 inhibitors, sildenafil, tadalafil, and vardenafil to relax human corpus cavernosum (HCC) and vasodilate human penile resistance arteries (HPRA) from diabetic patients with ED (DMED). The influence of nebivolol on the capacity of these three PDE5 inhibitors to stimulate cyclic guanosine monophosphate (cGMP) production in HCC was also evaluated. HCC and HPRA were obtained from organ donors without ED (NEND; n = 18) or patients with diabetes undergoing penile prosthesis implantation (DMED; n = 19). Relaxations of HCC strips and HPRA to sildenafil,tadalafil, and vardenafil were evaluated in organ chambers and wire myographs. cGMP content in HCC was determined by ether extraction and quantification by ELISA. Effects of nebivolol on PDE5 inhibitor-induced relaxation of HCC, vasodilation ofHPRA and cGMP accumulation in HCC. Treatment with nebivolol (1 μM) significantly potentiated sildenafil-, tadalafil- and vardenafil-induced relaxations of HCC and vasodilations of HPRA from both NEND and DMED. Enhancement of relaxant capacity by nebivolol resulted in reversion of the impairment of PDE5 inhibition-induced responses in DMED and it was accompanied by enhancing the ability of PDE5 inhibitors to increase cGMP in HCC restoring reduced cGMP levelsin HCC from DMED. Nebivolol potentiated the capacity of PDE5 inhibitors to relax vascular structures of erectile tissue from diabetic patients by enhancing the nitric oxide (NO)/cGMP pathway in these tissues. These effects suggest a potential therapeutic utility of nebivolol as an adjunct to PDE5 inhibitors for the treatment of ED associated with diabetes.

MP47-10 NO/CGMP-MEDIATED RELAXATION INDUCED BY INSULIN IN HUMAN CORPUS CAVERNOSUM AND PENILE ARTERIES IS IMPAIRED IN ERECTILE DYSFUNCTION.

You have accessJournal of UrologySexual Function/Dysfunction/Andrology: Basic Research II1 Apr 2014MP47-10 NO/CGMP-MEDIATED RELAXATION INDUCED BY INSULIN IN HUMAN CORPUS CAVERNOSUM AND PENILE ARTERIES IS IMPAIRED IN ERECTILE DYSFUNCTION. Juan I. Martínez-Salamanca, José M. La Fuente, Argentina Fernández, Eduardo Martínez-Salamanca, Pepe Cardoso, Joaquín Carballido, and Javier Angulo Juan I. Martínez-SalamancaJuan I. Martínez-Salamanca More articles by this author , José M. La FuenteJosé M. La Fuente More articles by this author , Argentina FernándezArgentina Fernández More articles by this author , Eduardo Martínez-SalamancaEduardo Martínez-Salamanca More articles by this author , Pepe CardosoPepe Cardoso More articles by this author , Joaquín CarballidoJoaquín Carballido More articles by this author , and Javier AnguloJavier Angulo More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2014.02.1463AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail Introduction and Objectives In addition to regulate glucose homeostasis, insulin has been demonstrated to influence vascular function at local level. However, the influence of insulin in human erectile tissue is not well defined. The aim of this work was to characterize the effects of insulin in human corpus cavernosum (HCC) and penile resistance arteries (HPRA) analyzing its interactions with NO/cGMP pathway and the influence of erectile dysfunction (ED). Methods HCC and HPRA were obtained from organ donors (NoED) and patients with erectile dysfunction (ED) who gave informed consent at the time of penile prosthesis implantation. HCC and HPRA were mounted in organ chambers and wire myographs, respectively, for isometric tension recording. cGMP was determined in HCC homogenates by ELISA. Results Insulin caused concentration-dependent relaxation of HCC (n=20) and vasodilation of HPRA (n=32) (pD2 7.40±0.33 and 7.21±0.32, respectively; Emax 64.0±6.1% and 59.3±5.3%, respectively). Insulin-induced relaxation of HCC was impaired in ED patients (53.0±7.4%) with respect to NoED (80.7±7.5%, p<0.01). Responses in NoED were inhibited by guanylyl cyclase inhibition with 20μM ODQ while responses in ED were potentiated by PDE5 inhibition with 30nM tadalafil. NO/cGMP contribution was confirmed by cGMP elevation (3.18±0.54 fold increase) after exposure to 1μM insulin. Involvement of endothelium was suggested by the marked difference between vasodilation in HPRA with <25% relaxation to 10μM acetylcholine (ACh) and HPRA with >40% relaxation to ACh (47.0±6.8 vs. 68.7±7.5, p<0.01). Treatment with insulin (10nM) improved endothelium-dependent relaxation in HCC, especially in ED patients with diabetes (52.3±11.5% vs. 81.1±5.4%, p<0.05). Conclusions Insulin causes human penile smooth muscle relaxations that are mediated by NO/cGMP pathway, contributed by endothelium, and impaired by the presence of ED. Insulin also participates in the regulation of endothelial function in erectile tissue. Altered regulation of penile smooth muscle tone by insulin could contribute to ED in metabolic disorders. © 2014FiguresReferencesRelatedDetails Volume 191Issue 4SApril 2014Page: e522 Advertisement Copyright & Permissions© 2014MetricsAuthor Information Juan I. Martínez-Salamanca More articles by this author José M. La Fuente More articles by this author Argentina Fernández More articles by this author Eduardo Martínez-Salamanca More articles by this author Pepe Cardoso More articles by this author Joaquín Carballido More articles by this author Javier Angulo More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

MP47-14 PIOGLITAZONE IS PROTECTIVE AGAINST POST-PROSTATECTOMY ERECTILE DYSFUNCTION

INTRODUCTION AND OBJECTIVES: Penile smooth muscle tone is finely tuned by neurogenic stimuli. Alteration of neurogenic regulation could cause an imbalance in favour of contractile stimuli and compromise erection. We have previously observed that calcium-activated potassium channel (KCa) stimulation enhances vasodilatory capacity of PDE5 inhibitors in human penile arteries. The aim of this work was to evaluate the impact of KCa modulation on the neurogenic regulation of cavernosal smooth muscle tone in rats and humans. METHODS: Rat corpus cavernosum (RCC) was obtained from thirty 12-16 weeks old male Sprague-Dawley rats. Human corpus cavernosum (HCC) strips were obtained from 20 patients with erectile dysfunction (ED) who gave informed consent at the time of penile prosthesis implantation. RCC and HCC were mounted in organ chambers and responses to electrical field stimulation (EFS) were evaluated. RESULTS: EFS caused reproducible, frequency-dependent contractions in RCC. Blockade of KCa with tertaethylammonium (TEA) markedly potentiated neurogenic contractions (16Hz, 67.2 3.2% vs. 105.6 4.6% at 5mM, p<0.001) but did not modify norepinephrineinduced contractions. By using specific KCa subtype blockers, largeconductance KCa (BK) appeared as responsible for modulation of neurogenic contractions. Stimulation of BK with NS1619 significantly inhibited EFS-induced contractions in RCC (67.5 5.4% vs. 39.3 5.8%, p<0.01 at 30mM). BK stimulation also caused a significant potentiation of EFS-induced relaxations in phenylephrine-contracted RCC treated with guanethidine and atropine (2 Hz, 31.8 6.9% vs. 64.9 6.7%, p<0.01). Similar results were obtained in HCC where TEA caused concentration-dependent enhancement of EFS-induced contractions (35.3 3.4% vs. 118.5 32.0% at 5mM, p<0.01) while BK activation with NS1619 (30mM) inhibited neurogenic contractions and potentiated neurogenic relaxations. CONCLUSIONS: BK participates in regulation of neurogenic control of cavernosal smooth muscle tone. Pharmacological stimulation of these channel would favor relaxant responses over contractile input in rat and human cavernosal tissue. Thus, BK stimulation could be a reasonable strategy for treating ED mainly in situations involving imbalanced regulation of neurogenic control.

MP47-13 CALCIUM-ACTIVATED POTASSIUM CHANNEL (KCA) STIMULATION MODULATES NEUROGENIC CONTRACTION AND FAVOURS NEUROGENIC RELAXATION IN RAT AND HUMAN CORPUS CAVERNOSUM

You have accessJournal of UrologySexual Function/Dysfunction/Andrology: Basic Research II1 Apr 2014MP47-13 CALCIUM-ACTIVATED POTASSIUM CHANNEL (KCA) STIMULATION MODULATES NEUROGENIC CONTRACTION AND FAVOURS NEUROGENIC RELAXATION IN RAT AND HUMAN CORPUS CAVERNOSUM Juan I. Martínez-Salamanca, José M. La Fuente, Argentina Fernández, Eduardo Martínez-Salamanca, Joaquín Carballido, and Javier Angulo Juan I. Martínez-SalamancaJuan I. Martínez-Salamanca More articles by this author , José M. La FuenteJosé M. La Fuente More articles by this author , Argentina FernándezArgentina Fernández More articles by this author , Eduardo Martínez-SalamancaEduardo Martínez-Salamanca More articles by this author , Joaquín CarballidoJoaquín Carballido More articles by this author , and Javier AnguloJavier Angulo More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2014.02.1466AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail Introduction and Objectives Penile smooth muscle tone is finely tuned by neurogenic stimuli. Alteration of neurogenic regulation could cause an imbalance in favour of contractile stimuli and compromise erection. We have previously observed that calcium-activated potassium channel (KCa) stimulation enhances vasodilatory capacity of PDE5 inhibitors in human penile arteries. The aim of this work was to evaluate the impact of KCa modulation on the neurogenic regulation of cavernosal smooth muscle tone in rats and humans. Methods Rat corpus cavernosum (RCC) was obtained from thirty 12-16 weeks old male Sprague-Dawley rats. Human corpus cavernosum (HCC) strips were obtained from 20 patients with erectile dysfunction (ED) who gave informed consent at the time of penile prosthesis implantation. RCC and HCC were mounted in organ chambers and responses to electrical field stimulation (EFS) were evaluated. Results EFS caused reproducible, frequency-dependent contractions in RCC. Blockade of KCa with tertaethylammonium (TEA) markedly potentiated neurogenic contractions (16Hz, 67.2±3.2% vs. 105.6±4.6% at 5mM, p<0.001) but did not modify norepinephrine-induced contractions. By using specific KCa subtype blockers, large-conductance KCa (BK) appeared as responsible for modulation of neurogenic contractions. Stimulation of BK with NS1619 significantly inhibited EFS-induced contractions in RCC (67.5±5.4% vs. 39.3±5.8%, p<0.01 at 30μM). BK stimulation also caused a significant potentiation of EFS-induced relaxations in phenylephrine-contracted RCC treated with guanethidine and atropine (2 Hz, 31.8±6.9% vs. 64.9±6.7%, p<0.01). Similar results were obtained in HCC where TEA caused concentration-dependent enhancement of EFS-induced contractions (35.3±3.4% vs. 118.5±32.0% at 5mM, p<0.01) while BK activation with NS1619 (30μM) inhibited neurogenic contractions and potentiated neurogenic relaxations. Conclusions BK participates in regulation of neurogenic control of cavernosal smooth muscle tone. Pharmacological stimulation of these channel would favor relaxant responses over contractile input in rat and human cavernosal tissue. Thus, BK stimulation could be a reasonable strategy for treating ED mainly in situations involving imbalanced regulation of neurogenic control. © 2014FiguresReferencesRelatedDetails Volume 191Issue 4SApril 2014Page: e523 Advertisement Copyright & Permissions© 2014MetricsAuthor Information Juan I. Martínez-Salamanca More articles by this author José M. La Fuente More articles by this author Argentina Fernández More articles by this author Eduardo Martínez-Salamanca More articles by this author Joaquín Carballido More articles by this author Javier Angulo More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Dynamic tissue perfusion measurement in the reproductive organs of the female and male dogs

Abstract The aim of this study was to investigate the usefulness of new software Pixel Flux (PXFX) for clinical evaluation of tissue perfusion in the field of reproduction in dogs. The experiment was performed on six adult Beagle dogs. Different organs and tissues of the animals were examined with the MyLab25 Gold ultrasound system. Blood flow in the ovary, testicle, prostate, the ramification of the penile artery, and the network of blood vessels of the pampiniform plexus were examined with the use of colour coded Doppler technique, and obtained data was evaluated with the PXFX software. The more objective digital evaluation of data obtained with colour Doppler sonography through the application of dynamic tissue perfusion measurements provides new opportunities for diagnosis, as well as continuous monitoring of the function of the examined tissues and organs. The use of PXFX software is strongly indicated as a tool in small animal practice as an additional method for evaluation of tissue perfusion, especially in the cases when other methods like pulsed wave Doppler techniques are difficult to be performed

Nebivolol Potentiates the Efficacy of PDE5 Inhibitors to Relax Corpus Cavernosum and Penile Arteries from Diabetic Patients by Enhancing the NO/cGMP Pathway

Nebivolol Potentiates the Efficacy of PDE5 Inhibitors to Relax Corpus Cavernosum and Penile Arteries from Diabetic Patients by Enhancing the NO/cGMP Pathway

Chapter 16 - Sexual dysfunction in diabetes

We aimed to summarize the etiology, clinical characteristics, diagnosis, and possible treatment options of sexual dysfunction in diabetic patients of both sexes. Details of dysfunction in diabetic women are less conclusive than in men due to the lack of standardized evaluation of sexual function in women. Male sexual dysfunction is a common complication of diabetes, including abnormalities of orgasmic/ejaculatory function and desire/libido in addition to penile erection. The prevalence of erectile dysfunction (ED) among diabetic men varies from 35% to 75%. Diabetes-induced ED has a multifactorial etiology including metabolic, neurologic, vascular, hormonal, and psychological components. ED should be regarded as the first sign of cardiovascular disease because it can be present before development of symptomatic coronary artery disease, as larger coronary vessels better tolerate the same amount of plaque compared to smaller penile arteries. The diagnosis of ED is based on validated questionnaires and determination of functional and organic abnormalities. First-, second- and third-line therapy may be applied. Phosphodiesterase-5 (PDE-5) inhibitor treatment from the first-line options leads to smooth muscle relaxation in the corpus cavernosum and enhancement in blood flow, resulting in erection during sexual stimulus. The use of PDE-5 inhibitors in the presence of oral nitrates is strictly contraindicated in diabetic men, as in nondiabetic subjects. All PDE-5 inhibitors have been evaluated for ED in diabetic patients with convincing efficacy data. Second-line therapy includes intracavernosal, trans- or intraurethral administration of vasoactive drugs or application of a vacuum device. Third-line therapies are the implantation of penile prosthesis and penile revascularization.

Impaired Endothelin Calcium Signaling Coupled to Endothelin Type B Receptors in Penile Arteries from Insulin-Resistant Obese Zucker Rats

Erectile dysfunction is considered as an early sign of subclinical vascular disease and endothelial dysfunction and a highly prevalent condition in diabetic patients. The current study assessed whether impaired vascular effects of endothelin (ET)-1 may contribute to the vascular dysfunction of penile arteries from a rat model of insulin resistance. The effect of ETA and ETB receptor antagonists was assessed on the intracellular Ca(2+) [Ca(2+) ]i and contractile responses to ET-1 in penile arteries from obese Zucker rats (OZR) and lean Zucker rats (LZR), and ET receptor expression in the arterial wall was assessed by immunohistochemistry. Changes in ET-1 [Ca(2+) ]i and vasoconstriction and ET receptor expression were evaluated in penile arteries from insulin-resistant rats. ET-1-induced vasoconstriction was associated with a higher increase in smooth muscle [Ca(2+) ]i in penile arteries from OZR compared with LZR. Removal of the endothelium inhibited and enhanced contractions to the lowest and highest doses of ET-1, respectively, mainly in OZR. The selective ETA receptor antagonist BQ-123 inhibited ET-1 vasoconstriction and [Ca(2+) ]i response in both LZR and OZR. The ETB receptor antagonist BQ-788 had little effect in healthy arteries but markedly inhibited ET-1-induced increases in [Ca(2+) ]i and vasoconstriction in arteries from OZR. ETA receptors were located on the smooth muscle and endothelium of penile arteries, whereas ETB receptors were found on the arterial endothelium in LZR and OZR, and also on the smooth muscle in OZR, immunostaining for both receptors being higher in OZR. Penile arteries from OZR exhibit an impaired ET-1 Ca(2+) signaling along with changes in the ET receptor profile. Thus, whereas ET-1 contraction and the associated [Ca(2+) ]i increase are mediated by smooth muscle ETA receptors in healthy arteries, ETB receptors contribute to contraction and are coupled to the augmented ET-1 [Ca(2+) ]i response under conditions of insulin resistance.

What is the origin of the arterial vascularization of the corpora cavernosa? A computer‐assisted anatomic dissection study

The purpose of this study was to identify the microscopic arterial vascularization of the corpora cavernosa (CC) of the penis using computer-assisted anatomic dissection (CAAD), determine the contribution of the different penile arteries towards this vascularization, detail the nature of cavernospongiosum shunts, and locate the anastomoses between these different arteries. Tissue specimens were taken from five donors who donated their bodies to science. The specimens were fixed in 10% formalin and sliced into a series of five 5-μm sections at intervals of 200μm. The first section was stained with hematoxylin-eosin or Masson's trichrome and the second with anti-protein S100. The cavernous artery of the penis is not the only source of arterial vascularization of the CC. In four of the five cases studied, we found two to four perforating branches arising from the dorsal arteries of the penis that join up with the cavernous artery of the penis or that are solely responsible for the vascularization of the distal third of the penis. The bulbo-urethral and urethral arteries are situated outside of the tunica albuginea of the corpus spongiosum on their lateral and dorsal sides. The anastomoses do not occur between the cavernous artery of the penis and the corpus spongiosum but between the cavernous artery of the penis and the urethral artery on the surface of the tunica albuginea. All of these arteries are accompanied by nerve branches. The CC were found to be vascularized by both cavernous and dorsal arteries of the penis. Intrapenile vascularization is organized around four arterial axes, which are anastomosed by multiple neurovascular shunts.

Role of androgen in the elderly. Male sexual dysfunction and androgen

Testosterone enhances DA release in the MPOA at rest and with sexual challenge, possibly by upregulating NOS, which increases NO and thereby increases DA release. Androgens have beneficial effects on endothelial cells and smooth-muscle cells. Testosterone and dihydrotestosterone may also relax penile artery and cavernous smooth muscle through their nongenomic effects. In rats, castration has been reported to decrease arterial flow, induce venous leakage, and reduce the erectile response to stimulation of the cavernous nerve. Hypogonadal patients in whom PDE5 inhibitor failed could be rescued by the administration of testosterone.