Udenafil Enhances the Recovery of Erectile Function and Ameliorates the Pathophysiological Consequences of Cavernous Nerve Resection

IntroductionRadical prostatectomy is the treatment of choice for prostate cancer patients. Despite the introduction of nerve-sparing surgical techniques, its success is not entirely guaranteed and the majority of patients report compromised erectile function following surgical procedures.AimThis study was performed to investigate the effect of repeated dosing of udenafil, a novel phosphodiesterase type 5 inhibitor, on penile hypoxia and fibrosis induced by bilateral cavernous nerve resection (BCNR) in rats.MethodsThirty male Sprague-Dawley rats (300–320 g) were used in this study. The animals were divided into three groups; group I consisted of sham-operated animals (N = 10), animals in group II underwent BCNR alone (N = 10), and animals in group III were orally treated with 10 mg/kg udenafil b.i.d. for 8 weeks following BCNR (N = 10).Main Outcome MeasuresThe expression of transforming growth factor-β1, hypoxia-inducible factor-1α, endothelial nitric oxide synthase, neuronal nitric oxide synthase, and endothelin B receptor in penile tissue was examined at gene level. Additionally, erectile function, measured by intracavernous pressure (ICP), and pathological changes in the corpus cavernosum were examined.ResultsWhile fibrosis, apoptosis, and the expression of TGF-β1, HIF-1α, and ET_B were significantly increased, and the expression of eNOS and nNOS were significantly decreased in group II, compared with the sham-operated animals, repeated dosing of udenafil significantly ameliorated these changes. Erectile function was profoundly impaired in animals that underwent BCNR alone, and udenafil treatment significantly attenuated this impairment as measured by ICP.ConclusionsThese results demonstrate that long-term administration of udenafil ameliorates penile hypoxia and fibrosis induced by cavernous nerve resection. This study also suggests the potential beneficial role of repeated dosing of udenafil in the recovery of erectile function in patients with neuronal erectile dysfunction. Lee C-H, Shin J-H, Ahn G-J, Kang K-K, Ahn B-O, and Yoo M. Udenafil enhances the recovery of erectile function and ameliorates the pathophysiological consequences of cavernous nerve resection.     

Endothelial Antioxidant Administration Ameliorates the Erectile Response to PDE5 Regardless of the Extension of the Atherosclerotic Process

IntroductionThe lack of phosphodiesterase type 5 inhibitor effects in patients with erectile dysfunction (ED) of arterial origin may be caused by an endothelial dysfunction that causes a series of biochemical alterations leading to a reduced nitric oxide (NO) bioavailability and increased oxidative stress.AimThe aim of this study was to evaluate the effects of the treatment with endothelial antioxidant compounds (EAC) on the erectile response to sildenafil in patients with arterial ED already treated with sildenafil (100 mg twice a week for 8 weeks).Mean Outcome MeasuresA patient was considered responsive when the 5-item International Index of Erectile Function questionnaire score increased by >5 points.MethodsFifty-three patients with arterial ED, hypertension, and diabetes mellitus were randomly given, for 8 weeks, EAC (1 dose/day) and, after a wash out of 8 weeks, sildenafil (100 mg) plus EAC. The patients were divided into the following four groups: A (N = 12): patients with ED alone; B (N = 14): patients with ED plus atheromasic plaques and/or increased intima-media thickness of common carotid arteries; C (N = 14): patients with ED plus lower limb artery abnormalities; and D (N = 13): patients with ED plus carotid and lower limb artery abnormalities.ResultsThe administration of EAC plus sildenafil resulted in a significantly higher number of responsive patients (N = 36, 68%) compared with sildenafil alone (N = 24, 45%) or EAC alone (N = 17, 32%). The percentage of patients who successfully responded to the combined treatment increased in the various groups. It was 83%, 64%, 71%, and 54%, respectively, for groups A, B, C, and D. Furthermore, patients treated with EAC and sildenafil reached a successful response in a shorter length of time (3 weeks) compared with patients responsive to sildenafil (5.2 weeks) or EAC (5.7 weeks) alone.ConclusionEAC administration to patients with arterial ED improved the success rate to sildenafil. These data suggest that, in such patients, a combined treatment may be considered to increase bioavailable NO and to neutralize radical oxygen species, which in turn inactive NO. Vicari E, La Vignera S, Condorelli R, and Calogero AE. Endothelial antioxidant administration ameliorates the erectile response to PDE5 regardless of the extension of the atherosclerotic process.     

Metformin Treatment Improves Erectile Function in an Angiotensin II Model of Erectile Dysfunction

IntroductionIncreased angiotensin II (AngII) levels cause hypertension, which is a major risk factor for erectile dysfunction (ED). Studies have demonstrated that increased AngII levels in penile tissue are associated with ED. A recent study showed that metformin treatment restored nitric oxide synthase (NOS) protein expression in penile tissue in obese rats; however, whether metformin treatment can be beneficial and restore erectile function in a model of ED has not yet been established.AimThe goal of this study was to test the hypothesis that AngII induces ED by means of increased corpus cavernosum contraction, and that metformin treatment will reverse ED in AngII-treated rats.MethodsMale Sprague-Dawley rats were implanted with mini-osmotic pumps containing saline or AngII (70 ng/minute, 28 days). Animals were then treated with metformin or vehicle during the last week of AngII infusion.Main Outcome MeasuresIntracavernosal pressure; corpus cavernosum contraction and relaxation; nNOS protein expression; extracellular signal-regulated kinase (ERK1/2), AMP-activated protein kinase (AMPK), and eNOS protein expression and phosphorylation.ResultsAngII-induced ED was accompanied with an increase in corpus cavernosum contractility, decreased nitrergic relaxation, and increased ERK1/2 phosphorylation. Metformin treatment improved erectile function in the AngII-treated rats by reversing the increased contraction and decreased relaxation. Metformin treatment also resulted in an increase in eNOS phosphorylation at ser1177.ConclusionsMetformin treatment increased eNOS phosphorylation and improved erectile function in AngII hypertensive rats by reestablishing normal cavernosal smooth muscle tone. Labazi H, Wynne BM, Tostes R, and Webb RC. Metformin treatment improves erectile function in an angiotensin II model of erectile dysfunction. J Sex Med 2013;10:2154–2164.     

Centrally Mediated Erectile Dysfunction in Rats with Type 1 Diabetes: Role of Angiotensin II and Superoxide

IntroductionErectile dysfunction is a serious complication of diabetes mellitus. Apart from the peripheral actions, central mechanisms are also responsible for penile erection.AimThis study aims to determine the contribution of angiotensin (ANG) II in the dysfunction of central N-methyl-D-aspartic acid (NMDA)- and nitric oxide (NO)-induced erectile responses in streptozotocin-induced type 1 diabetic (T1D) rats.MethodsThree weeks after streptozotocin injections, rats were randomly treated with the angiotensin-converting enzyme inhibitor-enalapril, or the ANG II type 1 receptor blocker, losartan, or the superoxide dismutase mimetic, tempol, or vehicle via chronic intracerebroventricular infusion by osmotic mini-pump for 2 weeks.Main Outcome MeasureCentral NMDA receptor stimulation or the administration of the NO donor, sodium nitroprusside (SNP)-induced penile erectile responses and concurrent behavioral responses were monitored in conscious rats.ResultsTwo weeks of enalapril, losartan, or tempol treatment significantly improved the erectile responses to central microinjection of both NMDA and SNP in the paraventricular nucleus (PVN) of conscious T1D rats (NMDA responses—T1D+enalapril: 1.7 ± 0.6, T1D+losartan: 2.0 ± 0.3, T1D+tempol: 2.0 ± 0.6 vs. T1D+vehicle: 0.6 ± 0.3 penile erections/rat in the first 20 minutes, P < 0.05; SNP responses—T1D+enalapril: 0.9 ± 0.3, T1D+losartan: 1.3 ± 0.3, T1D+tempol: 1.4 ± 0.4 vs. T1D+vehicle: 0.4 ± 0.2 penile erections/rat in the first 20 minutes, P < 0.05). Concurrent behavioral responses including yawning and stretching, induced by central NMDA and SNP microinjections, were also significantly increased in T1D rats after enalapril, losartan, or tempol treatments. Neuronal NO synthase expression within the PVN was also significantly increased, and superoxide production was reduced in T1D rats after these treatments.ConclusionsThese data strongly support the contention that enhanced ANG II mechanism/s within the PVN of T1D rats contributes to the dysfunction of central NMDA-induced erectile responses in T1D rats via stimulation of superoxide. Zheng H, Liu X, and Patel KP. Centrally mediated erectile dysfunction in rats with type 1 diabetes: Role of angiotensin II and superoxide. J Sex Med 2013;10:2165–2176.     

Morphological and Functional Evidence for the Contribution of the Pudendal Artery in Aging-Induced Erectile Dysfunction

IntroductionAging increases the risk of both erectile dysfunction (ED) and cardiovascular disease. These conditions have similar etiologies and commonly coexist. One unifying concept is the role of arterial insufficiency which is a primary factor in the onset of age-related ED.AimBased on the novel finding that the pudendal arteries contribute 70% of the total penile vascular resistance, our objective was to morphometrically and functionally characterize this vessel in young and old normotensive rats.MethodsErectile function was monitored in 15- and 77-week Sprague-Dawley rats using the apomorphine bioassay (80 mg/kg, s.c.). Anesthetized animals were perfusion-fixed, aortic, renal, and internal pudendal arteries were excised, embedded, sectioned, stained, and morphometrically assessed using light microscopy. Hearts were excised, separated, and weighed prior to perfusion. Contractile and relaxation responses to acetylcholine (ACh) and phenylephrine (PE) were assessed by wire myograph.Main Outcome MeasuresErectile function, morphological measurements, concentration response curves to ACh and PE.ResultsWith age, there were marked decreases in erectile responses compared to younger rats (2.8 ± 0.87 vs. 0.3 ± 0.58). The pudendal arteries had a relatively small lumen (303 ± 13.8 µm) and a thick medial layer (47 ± 2.2 µm). In aged pudendal arteries, the lumen diameter did not change, and yet the medial layer, cross sectional area, and extracellular matrix were markedly increased. In contrast, the lumen diameter and wall thickness of the aorta and renal arteries in aged rats increased proportionally. An increase in small, round, smooth muscle cells was seen in aged pudendal arteries. Functionally, there were no differences in contractile responses to PE; however, ACh-induced relaxation decreased with age.ConclusionsIn aged rats, erectile function was severely diminished when pudendal arteries had undergone marked phenotypic changes. Specifically, there was endothelial dysfunction and pathological remodeling of this vessel with age, characterized by medial thickening, impaired vasodilation and significantly reduced capacity for penile blood flow. Hannan JL, Blaser MC, Oldfield L, Pang JJ, Adams SM, Pang SC, and Adams MA. Morphological and functional evidence for the contribution of the pudendal artery in aging-induced erectile dysfunction.     

Effect of BKCa Channel Opener LDD175 on Erectile Function in an In Vivo Diabetic Rat Model

IntroductionThe development of novel therapeutic options is imperative in patients with erectile dysfunction, especially those non-responsive to phosphodiesterase type 5 inhibitors. LDD175, a potent BKCa channel opener, has a relaxation effect on the in vitro cavernosal smooth muscle strip.AimTo investigate the effect of LDD175 on erectile function using in vivo animal disease model.MethodsMale Sprague-Dawley rats were assigned to a normal control group and seven diabetic groups: diabetic control, sildenafil (1 and 5 mg/kg), LDD175 (5 and 10 mg/kg), LDD175 5 mg/kg plus sildenafil 1 mg/kg, and LDD175 10 mg/kg plus tetraethylammonium.Main Outcome MeasuresIntracavernosal pressure (ICP), ratio of ICP to mean arterial pressure (MAP), and the area under curve of ICP/MAP of eight groups were compared using in vivo pelvic nerve stimulation.ResultsThe ICP, ICP/MAP ratio, and area under curve of the ICP/MAP ratio of the normal control rats increased with an increase in electrical field stimulation voltage. All parameters in the diabetic control group were significantly lower than those in the normal control rats, with an electrical field stimulation ranging from 1 to 5 V (P < .05). LDD175 improved the erectile response in diabetic rats in a dose-dependent manner. The combination of sildenafil (1 mg/kg) and LDD175 (5 mg/kg) showed a significant additive effect (P < .05) on the improvement of erectile function compared with sildenafil (1 mg/kg) alone. The enhancement of erectile function by LDD175 was completely blocked by tetraethylammonium.ConclusionThe results showed that the BKCa channel opener LDD175 improved erectile function in an in vivo diabetic rat model. Furthermore, combination therapy of LDD175 and sildenafil had an additive effect on the improvement of erectile function in diabetic rats. LDD175 could be a new candidate for the treatment of erectile dysfunction.     

ORIGINAL RESEARCH—PSYCHOLOGY: Integrated Sildenafil and Cognitive-Behavior Sex Therapy for Psychogenic Erectile Dysfunction: A Pilot Study

IntroductionMen with psychogenic erectile dysfunction (ED) present a challenge to physicians. Treatment with pharmacological agents alone does not address the complexities of the causative or resulting psychological issues.AimTo evaluate the effectiveness of an integrative treatment protocol (ITP) with sildenafil and cognitive-behavior sex therapy (CBST) compared with sildenafil alone for men with psychogenic ED.Main Outcome MeasuresChange from baseline on the International Index of Erectile Function (IIEF) in the domains of erectile function and sexual satisfaction to demonstrate improved sexual functioning and confidence.MethodsMen with psychogenic ED and female partners were randomized to receive either sildenafil alone or an ITP with sildenafil and CBST for the first 4 weeks. In the last 4 weeks, couples in the sildenafil group added CBST sessions to their regimen; patients in the ITP group continued the combined therapy. The IIEF questionnaire was used to compare erectile function and overall satisfaction serially at pretreatment, 4, and 8 weeks. Couples who met the success criteria in both domains after the first 4 weeks received no further treatment.ResultsFifty-three couples constituted the study population. After the first 4 weeks of sildenafil and ITP, 48% of men met criteria for success on erectile function and 65.5% for satisfaction compared to men on sildenafil alone with 29% and 37.5% success rates, respectively. After the last 4 weeks, integration of CBST with sildenafil resulted in a 58% success rate for erectile function which was comparable to the 66% rate for the initial drug/ITP group; satisfaction rates for men were 45% and 75%, respectively.ConclusionsCBST was shown to have a positive influence when used throughout the entire 8 weeks of the ITP or added to the sildenafil in the last 4 weeks. Although patients in both treatment regimens had significant improvements in the IIEF domain scores confirming efficacy of sildenafil, those in the CBST and drug regimen achieved higher rates of clinical success within the first 4 weeks of therapy. Banner LL, and Anderson RU. Integrated sildenafil and cognitive-behavior sex therapy for psychogenic erectile dysfunction: A pilot study.     

The Female Factor: Predicting Compliance with a Post-Prostatectomy Erectile Preservation Program

IntroductionEarly post-radical prostatectomy (RP) erectile preservation (EP) therapy may be critical to preserve erections after surgery.AimTo assess if pre-RP female sexual function predicts of partner compliance with an EP protocol.Main Outcome MeasuresCompliance, defined as use of localized penile EP therapy (intracavernosal injections [ICIs], vacuum erection device [VED], or alprostadil) at 3 and 6 months after RP.MethodsRecords of patients enrolled in our EP program from April 2007 to June 2008 were reviewed. Before surgery, patients completed the Sexual Health Inventory for Men (SHIM) and their female partners completed the Female Sexual Function Index (FSFI) questionnaire. Prior to surgery, patients were advised to take sildenafil 25 mg every nightly and use a 250-µg alprostadil suppository three times/week. At 1 month, additional daily use of a VED was encouraged. All patients unable to achieve erections sufficient for penetration were encouraged to initiate ICI of Trimix (phentolamine, papaverine, and PGE1) twice weekly after 3 months following surgery. Data were analyzed using binary logistic regression analysis holding all input variables constant.ResultsTwenty-nine patients had preoperative SHIM > 7 and pre-RP partner FSFI data available. After a 4-week follow-up, compliance with alprostadil suppository declined and both ICI and VED usage increased. At 6 months, six (25.0%) patients had return of natural erectile function and 22 (91.7%) were achieving assisted erections. Higher preoperative partner FSFI scores were associated with greater compliance to the localized penile therapy component of our EP protocol (risk ratio 3.8, P = 0.05).ConclusionsPreoperative female sexual function correlated with greater partner compliance with the localized component of our EP protocol. Consideration of a female partner's preoperative sexual function in predicting patient erectile function recovery after RP is warranted. Future studies are necessary to determine the clinical significance of this factor. Moskovic DJ, Mohamed O, Sathyamoorthy K, Miles BJ, Link RE, Lipshultz LI, and Khera M. The female factor: Predicting compliance with a post-prostatectomy erectile preservation program.     

Effect of a Local Delivery of Triiodothyronine (T3) Within Neuroregenerative Guide on Recovery of Erectile Function in a Rat-Model of Cavernous Nerve Injury

IntroductionA promoting effect of thyroid hormones has been established on the maturation of central and peripheral nervous systems. However, effects on autonomic nerves have never been experimentally investigated.AimTo assess the effect of a local treatment combining silicone guides and local administration of Triiodothyronine (T3) on the erectile function and the histological neuroregeneration of crushed cavernous nerves (CNs) in rats.MethodsForty-five rats were divided into five equal groups: SHAM surgery, guide without crush, crush, crush + guide, crush + guide + T3. All surgical procedures were bilateral. CNs were crushed with microvascular bulldog clamp of 100 g/cm². A silicone guide was placed around the nerves. The guides were filled with T3 neuroregenerative solution.Main Outcome MeasuresErectile function was assessed 10 weeks post-operatively. Intra-cavernous pressure (ICP) and mean arterial pressure (MAP) were monitored during electrical stimulation of CNs at various frequencies. The main outcome was hardness of erection defined as ΔICP/MAP. Fluorescent immunohistochemical analysis of CNs was performed to assess regeneration of nerves morphologically.ResultsElectrophysiological data showed increased recovery of erectile function in the group with guide + T3 neuroregenerative solution compared with the empty guide. Immunohistochemical analysis of cavernous nerves demonstrated in morphology that regenerated axons were straighter in nerves with guide and more regular if guides had been filled with T3.ConclusionThe use of guides prevented axonal sprouting, facilitated functional neuroregeneration and enabled a local delivery of thyroid hormones. Triiodothyronine improved neuroregeneration and recovery of erectile function after a nerve-sparing–like injury in a rat model. Bessede T, Alsaid B, Ferretti L, Pierre M, Bernabé J, Giuliano F, Karam I, Benoît G, and Droupy S. Effect of a local delivery of triiodothyronine (T3) within neuroregenerative guide on recovery of erectile function in a rat-model of cavernous nerve injury.     

Vasculogenic Erectile Dysfunction and Metabolic Syndrome

IntroductionErectile dysfunction (ED), defined as the inability to achieve and/or maintain a penile erection sufficient for sexual intercourse, is a health problem affecting more than one-half of men between the age of 40 and 70 years.AimThe aim of the present study was to determine the potential factors affecting penile vascular flow and predictability of vascular flow in patients with ED.MethodsTotally 163 male patients between 29 and 82 years of age who were admitted to our outpatient clinic with complaints of ED were included. After a detailed medical history was obtained, all patients were asked to complete the International Index of Erectile Function (IIEF) questionnaire. Blood samples were obtained for measurements of serum cholesterol, triglycerides, and fasting blood glucose (FBG), and the body mass index (BMI) was calculated.Main Outcome MeasuresPenile color Doppler ultrasonography (PDU) was performed to evaluate flow patterns, Mann–Whitney U-test and Spearman correlation analyses were used to assess the relationship of PDU findings with hypertension, obesity (BMI ≥ 25 kg/m²), FBG, and cholesterol levels measurements.ResultsThe mean age, IIEF score, and BMI of the study population was 51.3 ± 12.1 years, 11.9 ± 6.1 and 28.5 ± 4.0 kg/m², respectively. When the vascular pathologies detected with PDU and the presence of risk factors were compared, no significant correlation was determined between arterial insufficiency and metabolic syndrome (MS), whereas there was a significant correlation between veno-occlusive dysfunction and MS.ConclusionThe prevalence of ED increases with advanced age and with the presence of a systemic disease. Basic evaluations may not always be sufficient for assessment of ED. In the presence of MS, the use of penile Doppler ultrasonography should be considered for the evaluation of penile vascular structures in ED patients. Koca O, Çal??kan S, Öztürk M?, Güne? M, K?l?ço?lu G, and Karaman MI. Vasculogenic erectile dysfunction and metabolic syndrome.     

Nebivolol Dilates Human Penile Arteries and Reverses Erectile Dysfunction in Diabetic Rats through Enhancement of Nitric Oxide Signaling

IntroductionTraditional beta-blockers have sometimes been associated with erectile dysfunction (ED). Nebivolol is a cardioselective β₁-adrenoceptor antagonist that promotes vasodilation through a nitric oxide (NO)-dependent mechanism.AimWe evaluated the effects of nebivolol on the NO/cyclic guanosine monophosphate (cGMP) signaling pathway, on erectile function and dysfunction, and in human penile vascular tissues.MethodsErectile response to cavernosal nerve electrical stimulation in control and diabetes-induced ED rats were evaluated, along with serum nitrite/nitrate (NOx) concentration and plasma/tissue cGMP levels. Endothelium-dependent and sildenafil-induced relaxation of isolated human corpus cavernosum (HCC) and human penile resistance arteries (HPRA) were also determined.Main Outcome MeasuresThe effects of nebivolol on erectile function and dysfunction and on NO/cGMP-mediated responses.ResultsTreatment with nebivolol significantly potentiated erectile response in control rats, regardless of its effects on blood pressure. Nebivolol increased NOx and plasma cGMP by 3-fold and 2.75-fold, respectively, and significantly augmented the elevation of plasma cGMP produced by sildenafil. Nebivolol enhanced endothelium-dependent and sildenafil-induced relaxations of HCC tissue, and produced endothelium-dependent vasodilation of HPRA. Nebivolol, but not atenolol, significantly improved erectile response in diabetic rats (51.6%, 53.2%, and 87.1% of response at 3 Hz in nondiabetic rats, for vehicle-treated, atenolol-treated, and nebivolol-treated diabetic rats, respectively); after sildenafil administration, ED was completely reversed in nebivolol-treated diabetic rats (69.6% and 112% for diabetic rats treated with sildenafil and nebivolol plus sildenafil, respectively). Accordingly, nebivolol restored systemic NOx levels and cGMP content in penile tissue from these animals.ConclusionsNebivolol in vivo activated the NO/cGMP pathway, enhanced erectile response and reversed ED in diabetic rats. Moreover, nebivolol in vitro potentiated NO/cGMP-mediated relaxation of human erectile tissues. These effects may account for the low incidence of ED in nebivolol-treated hypertensive patients. Nebivolol therefore may have utility in the treatment of ED, particularly ED associated with diabetes. Angulo J, Wright HM, Cuevas P, González-Corrochano R, Fernández A, Cuevas B, La Fuente JM, Gupta S, and de Tejada IS. Nebivolol dilates human penile arteries and reverses erectile dysfunction in diabetic rats through enhancement of nitric oxide signaling.     

Comparison of Penile Size and Erectile Function after High-intensity Focused Ultrasound and Targeted Cryoablation for Localized Prostate Cancer: A Prospective Pilot Study

IntroductionErectile dysfunction (ED) represents a common quality-of-life issue of any treatment used for prostate cancer, including high-intensity focused ultrasound (HIFU) and targeted cryoablation of the prostate (TCAP). There is a paucity of comparative studies regarding the difference in the erectile function and penile size of patients undergoing HIFU or TCAP.AimThe aim of this study is to compare the erectile function and penile size of patients undergoing HIFU or TCAP.MethodsPatients with a preoperative erectile function domain of the International Index of Erectile Function (IIEF-EF) score ≥26 were prospectively included. All patients were preoperatively evaluated by IIEF-EF and penile color Doppler ultrasound. Penile length and circumference were measured in flaccidity and at maximum erection. At 6, 12, 18, 24, 36 months after surgery, patients were assessed with the same protocol.Main Outcome MeasuresIIEF-EF score, penile color Doppler ultrasound, penile length, and circumference at different time points.ResultsThere were 55 patients in the HIFU group and 47 in the TCAP group. At each time point, there were significant differences in mean IIEF-EF scores and penile color Doppler results between the two groups. At 36 months, TCAP patients experienced lower erectile function recovery rate compared with HIFU patients (TCAP = 46.8%; HIFU = 65.5%; P = 0.021). No significant decreases in penile length and circumference were found in the two groups (all P values ≥0.05).ConclusionsOur data demonstrate TCAP caused significantly decreased erectile function than HIFU. We found no change in penile size after HIFU or TCAP. The option of HIFU may be more attractive to the patient who wants to avoid ED afterward, to maintain their quality of life. Li L-Y, Lin Z, Yang M, Gao X, Xia T-L, and Ding T. Comparison of penile size and erectile function after high-intensity focused ultrasound and targeted cryoablation for localized prostate cancer: A prospective pilot study.     

Novel water-soluble curcumin derivative mediating erectile signaling

IntroductionCurcumin is an inducer of heme oxygenase enzyme-1 (HO-1) that is involved in erectile signaling via elevating cyclic guanosine monophosphate (cGMP)levels.AimTo assess the effect of oral administration of a water-soluble long-acting curcumin derivative on erectile signaling.MethodsTwo hundred and thirty six male white albino rats were divided into four groups; group 1 (N = 20) includes control. Group 2 (N = 72) was equally divided into four subgroups; subgroup 1 received pure curcumin (10 mg/kg), subgroup 2 received the long-acting curcumin derivative (2 mg/kg), subgroup 3 received the long-acting curcumin derivative (10 mg/kg), and subgroup 4 received sildenafil (4 mg/kg). Subgroups were sacrificed after the first, second, and third hour. Group 3 (N = 72) was equally divided into the same four subgroups already mentioned and were sacrificed after 24 hours, 48 hours, and 1 week. Group 4 (N = 72) was subjected to intracavernosal pressure (ICP) measurements 1 hour following oral administration of the same previous doses in the same rat subgroups.Main Outcome MeasureCavernous tissue HO enzyme activity, cGMP, and ICP.ResultsIn group 2, there was a significant progressive maintained elevation of HO activity and cGMP tissue levels starting from the first hour in subgroups 3 and 4, whereas, the rise in HO activity and cGMP started from second hour regarding the other rat subgroups. Sildenafil effect decreased after 3 hours. In group 3, there was a significant maintained elevation of HO activity and cGMP tissue levels extended to 1 week as compared to controls for all rat subgroups that received both forms of curcumin. In group 4, long-acting curcumin derivative exhibited more significant potentiation of intracavernosal pressure as compared to control and to the pure curcumin.ConclusionWater-soluble long-acting curcumin derivative could mediate erectile function via upregulating cavernous tissue cGMP. Abdel Aziz MT, El Asmer MF, Rezq A, Kumosani TA, Mostafa S, Mostafa T, Atta H, Abdel Aziz Wassef M, Fouad HH, Rashed L, Sabry D, Hassouna AA, Senbel A, and Abdel Aziz A. Novel water-soluble curcumin derivative mediating erectile signaling     

Erectile Dysfunction in Young Non-Obese Type II Diabetic Goto-Kakizaki Rats is Associated with Decreased eNOS Phosphorylation at Ser1177

IntroductionDiabetes mellitus (DM) is a risk factor for erectile dysfunction (ED). Although type 2 DM is responsible for 90–95% diabetes cases, type 1 DM experimental models are commonly used to study diabetes-associated ED.AimGoto-Kakizaki (GK) rat model is relevant to ED studies since the great majority of patients with type 2 diabetes display mild deficits in glucose-stimulated insulin secretion, insulin resistance, and hyperglycemia. We hypothesized that GK rats display ED which is associated with decreased nitric oxide (NO) bioavailability.MethodsWistar and GK rats were used at 10 and 18 weeks of age. Changes in the ratio of intracavernosal pressure/mean arterial pressure (ICP/MAP) after electrical stimulation of cavernosal nerve were determined in vivo. Cavernosal contractility was induced by electrical field stimulation (EFS) and phenylephrine (PE). In addition, nonadrenergic-noncholinergic (NANC)- and sodium nitroprusside (SNP)-induced relaxation were determined. Cavernosal neuronal nitric oxide synthase (nNOS) and endothelial nitric oxide synthase (eNOS) mRNA and protein expression were also measured.Main Outcome MeasureGK diabetic rats display ED associated with decreased cavernosal expression of eNOS protein.ResultsGK rats at 10 and 18 weeks demonstrated impaired erectile function represented by decreased ICP/MAP responses. Ten-week-old GK animals displayed increased PE responses and no changes in EFS-induced contraction. Conversely, contractile responses to EFS and PE were decreased in cavernosal tissue from GK rats at 18 weeks of age. Moreover, GK rats at 18 weeks of age displayed increased NANC-mediated relaxation, but not to SNP. In addition, ED was associated with decreased eNOS protein expression at both ages.ConclusionAlthough GK rats display ED, they exhibit changes in cavernosal reactivity that would facilitate erectile responses. These results are in contrast to those described in other experimental diabetes models. This may be due to compensatory mechanisms in cavernosal tissue to overcome restricted pre-penile arterial blood supply or impaired veno-occlusive mechanisms. Carneiro FS, Giachini FRC, Carneiro ZN, Lima VV, Ergul A, Webb RC, and Tostes RC. Erectile dysfunction in young non-obese type II diabetic Goto-Kakizaki rats is associated with decreased eNOS phosphorylation at Ser¹¹⁷⁷.     

Edaravone ameliorates diabetes-induced dysfunction of NO-induced relaxation in corpus cavernosum smooth muscle in the rat

IntroductionDiabetes mellitus (DM) represents a major risk factor for erectile dysfunction (ED). Although the etiology of diabetes-induced ED is multifactorial and still unknown, reactive oxygen species are thought to be one of the key factors.AimThe aim of this article is to investigate whether administration of edaravone, a free radical scavenger, could prevent type 1 diabetes-induced dysfunction of nitric oxide (NO)-induced relaxation in corpus cavernosum smooth muscle in the rat.MethodsSix-week-old male Wistar rats were randomly divided into three groups. One group was treated with citrate-phosphate buffer plus normal saline (group Cont), whereas in the other two groups, diabetes was induced by streptozotocin (50 mg/kg intraperitoneally [i.p.]). Subsequently, the diabetic rats were treated for 4 weeks either with edaravone (10 mg/kg/day, i.p.; group DM + E) or with normal saline (group DM).Main Outcome MeasuresSerum glucose and malondialdehyde levels as well as penile cyclic guanosine monophosphate (cGMP) concentrations were determined, and penile function was estimated by organ bath studies with norepinephrine-mediated contractions and acetylcholine-mediated relaxations. The participation mRNA levels of muscarinic M₃ receptors, neuronal nitrous oxide synthase (nNOS), endothelial NOS (eNOS) and inducible NOS (iNOS), and participation protein levels of nNOS, eNOS, phosphorylated nNOS, and phosphorylated eNOS were investigated by quantitative real-time polymerase chain reaction (PCR) and immunoblot analysis, respectively.ResultsTreatment with edaravone prevented partially but significantly the decreased body and penile weight induced by diabetes. Treatment with edaravone significantly improved the increased diabetes-induced malondialdehyde levels, the decreased penile cGMP concentrations, the increased diabetes-induced norepinephrine-mediated contractions, and the decreased acetylcholine-mediated relaxation. Although there were no significant differences in expression levels of mRNAs in nNOS, diabetes-induced upregulation of muscarinic M₃ receptor and iNOS mRNAs as well as diabetes-induced downregulations of eNOS, phosphorylated nNOS, and phosphorylated eNOS were significantly prevented by edaravone.ConclusionsEdaravone decreases the oxidative insult in the penile corpus cavernosum by ameliorating the NO–NOS system and thus preventing partially the developing ED in DM in the rat. Ohmasa F, Saito M, Tsounapi P, Dimitriadis F, Inoue S, Shomori K, Shimizu S, Kinoshita Y, and Satoh K. Edaravone ameliorates diabetes-induced dysfunction of NO-induced relaxation in corpus cavernosum smooth muscle in the rat.     

Vardenafil Improves Penile Erection in Type 2 Diabetes Mellitus Patients with Erectile Dysfunction: Role of Tropomyosin

IntroductionEvidences have been suggested that phosphodiesterase type 5 (PDE5) inhibition promotes vasculoprotective benefits in patients with cardiovascular diseases.AimThe aim of this study is to analyze the systemic effect of PDE5 inhibition in type 2 diabetes mellitus patients with erectile dysfunction (ED) determining changes in the expression levels of plasma proteins.MethodsSeventeen patients with controlled type 2 diabetes mellitus and ED were included in the study. Patients received vardenafil hydrochloride 20 mg on demand during 12 weeks. At the beginning and 12 weeks after vardenafil administration, plasma samples were collected and analyzed using proteomics.Main Outcome MeasuresInternational Index of Erectile Function-Erectile Function Domain (IIEF-EFD) and plasma protein expression before and after vardenafil administration. Nitrate/nitrite release, PDE5, and soluble guanylate cyclase (sGC) expression and cyclic guanosine monophosphate (cGMP) content in cultured bovine aortic endothelial cells (BAECs).ResultsThe IIEF-EFD score was markedly improved after 12 weeks of vardenafil administration. Plasma levels of alpha 1-antitrypsin isotypes 4 and 6 and β-tropomyosin were decreased, whereas apolipoprotein AI isoype 5 was increased 12 weeks after vardenafil administration. Only β-tropomyosin plasma levels were inversely correlated with IIEF-EFD score. Tropomyosin has been added to cultured BAECs and after 24 hours reduced the protein expression level of sGC-β₁ subunit and decreased the cGMP content. Tropomyosin did not modify PDE5 expression and nitric oxide release in BAECs as compared with control BAECs. Vardenafil (10 μg/mL) did not modify sGC-β₁ subunit expression in tropomyosin + vardenafil-incubated BAECs; however, vardenafil significantly reversed the reduction of cGMP content induced by tropomyosin.ConclusionVardenafil administration improved erectile functionality in controlled type 2 diabetes mellitus patients with ED, which was associated with reduction of circulating plasma β-tropomyosin levels. Tropomyosin affected by itself the cGMP generating system suggesting a possible new mechanism involved in ED. Vardenafil reversed the reduction effect of cGMP content elicited by tropomyosin in BAECs. Zamorano-León JJ, Olivier C, de las Heras N, Mateos-Cáceres PJ, Brime Menéndez R,Rodríguez-Sierra P, Martín Palacios N, Manso LSJ, Modrego J, Segura A, Macaya C, and López-Farré AJ. Vardenafil improves penile erection in type 2 diabetes mellitus patients with erectile dysfunction: Role of tropomyosin. J Sex Med 2013;10:3110–3120.     

Association Analysis of Endothelial Nitric Oxide Synthase G894T Gene Polymorphism and Erectile Dysfunction Complaints in a Population-Based Survey

IntroductionErectile dysfunction (ED) is a common disorder leading to a serious, negative impact on the quality of the patient's life. The gene encoding endothelial nitric oxide synthase (eNOS) is an interesting candidate gene for understanding the physiopathology of ED, as it is involved in the catalytic production of nitric oxide (NO), the neurotransmitter that plays a critical role in penile tumescence and erection.AimTo evaluate a potential association between the G894T polymorphism in the eNOS gene and ED complaints in a population-based sample in São Paulo, Brazil.Main Outcome MeasuresThe prevalence of ED complaints was estimated according to the answer to the question “How would you describe your ability to get and keep an erection that is adequate for satisfactory intercourse?” ED was considered to be present if the response was “sometimes” or “never.”MethodsA total of 449 men were enrolled in the study and answered an eight-item questionnaire to ascertain sexual performance/ED and satisfaction. The eNOS G894T polymorphism was genotyped using a standard polymerase chain reaction method.ResultsUnivariate analysis demonstrated that ED was associated with diabetes, hypertension, sleep apnea severity, increasing age and body mass index, as well as testosterone levels (P < 0.05). Forward multiple regression models indicated that age was the only independent factor associated with ED in this population (odds ratio = 1.09; 95% CI 1.06–1.11; P < 0.0001). Genotypic and allelic analyses provided no evidence for an association between this polymorphism and the risk for ED complaints in this sample. Population stratification did not affect the association test results.ConclusionsThis is the first study to examine the effect of polymorphisms in the eNOS gene and the risk for ED utilizing a case-control approach in the Brazilian population. Our results do not support a major role for eNOS gene polymorphisms in ED in this population. Andersen ML, Guindalini C, Santos-Silva R, Bittencourt LRA, and Tufik S. Association analysis of endothelial nitric oxide synthase G894T gene polymorphism and erectile dysfunction complaints in a population-based survey.     

Vascular and Chronological Age in Subjects with Erectile Dysfunction: A Cross-Sectional Study

IntroductionVascular age, as derived from the SCORE project algorithm for cardiovascular (CV) risk estimation, is an effective way for communicating CV risk. However, studies on its clinical correlates are scanty.AimTo evaluate if the difference between vascular and chronological age (Δage), in a population of subjects with erectile dysfunction (ED), can identify men with a worse risk profile.MethodsA consecutive series of 2,853 male patients attending the outpatient clinic for erectile dysfunction (ED) for the first time was retrospectively studied. Among them, 85.4% (n = 2,437) were free of previous MACE and were analyzed.Main Outcome MeasuresSeveral clinical, biochemical, and penile color Doppler parameters were studied. Vascular age was derived from the SCORE project algorithm, and the Δage was considered.ResultsHigher Δage is associated with several conventional (family history of CV diseases, hyperglycemia, elevated triglycerides, and increased prevalence of metabolic syndrome) and unconventional (severity of ED, frequency of sexual activity, alcohol abuse, lower education level, fatherhood, extramarital affairs, compensated hypogonadism, and low prolactin levels) risk factors. Δage is inversely related to penile color Doppler parameters, including flaccid and dynamic peak systolic velocity and flaccid acceleration (β = −0.125, −0.113, and −0.134, respectively, all P < 0.0001).ConclusionsIn subjects referring for ED without a personal history of CV events, Δage is associated with an adverse cardio-metabolic profile and worse penile color Doppler ultrasound parameters. Δage provides a simple method for identifying high-risk men that must undergo significant modification in their lifestyle and risk factors. In addition, it can be considered a simple, inexpensive, and safe surrogate marker of penile arterial damage.