Animal model of high cholesterol atherosclerotic erectile dysfunction and mechanism of atherosclerotic erectile dysfunction

Aim: To establish the animal model of atherosclerotic erectile dysfunction (ED) induced by high cholesterol diet and explore the mechanism of atherosclerotic ED. Methods: Thirty male rabbits were divided at random into two groups: the normal diet (ND)group (n=10) and the high cholesterol (HCH) group fed with 1.5% cholesterol diet (n=20). Serum total cholesterol, plaque areas of the ascending aorta,     

Improvement of erectile function by Korean red ginseng (Panax ginseng) in a male rat model of metabolic syndrome

The seriousness of metabolic syndrome is not due to the disease itself but its promotion of other diseases, such as erectile dysfunction and cardiovascular and cerebrovascular diseases. We investigated the effects of Korean red ginseng (KRG, Panax ginseng) extract on erectile function in a rat model of metabolic syndrome. We divided the rats into three groups: control, metabolic syndrome+normal saline (N/S) and metabolic syndrome+KRG. To determine the occurrence of metabolic syndrome in all groups, body weight and various biochemical parameters (e.g., blood glucose, insulin, cholesterol) were measured, and the intra-abdominal glucose tolerance test was performed. To investigate penile erection, the peak intracavernosal pressure (ICP), mean arterial pressure (MAP) and Masson''s trichrome stain were evaluated. Erectile function was also investigated by measuring the cyclic guanosine monophosphate (cGMP) levels of the corpus cavernosum. We found that the various biochemical parameters and body weight were similar in the metabolic syndrome+KRG group and the control group, although the values were slightly higher. The peak ICP/MAP ratio of the metabolic syndrome+N/S group was markedly decreased compared to the other groups. The cGMP level of the corpus cavernosum in the metabolic syndrome+N/S group was significantly lower than that of the other groups. As demonstrated in this model of metabolic syndrome with erectile dysfunction, KRG may improve erectile function.     

Chronic inhibition of nitric‐oxide synthase induces hypertension and erectile dysfunction in the rat that is not reversed by sildenafil

Study Type – Aetiology (case control)
Level of Evidence 3b

OBJECTIVE

To evaluate the effect of N(G)‐nitro‐l ‐arginine methyl ester (L‐NAME)‐induced hypertension (HT) on erectile function in the rat and determine if the phosphodiesterase (PDE)‐5 inhibitor, sildenafil, can reverse the effects of nitric oxide (NO) deficiency, as HT is a risk factor for erectile dysfunction (ED) and the NO synthase (NOS) inhibitor L‐NAME induces NO‐deficient HT.

MATERIALS AND METHODS

Thirty‐six adult Sprague‐Dawley male rats were divided into three groups, i.e. a control, L‐NAME‐HT (40 mg/rat/day in the drinking water for 4 weeks), and sildenafil‐treated L‐NAME‐HT (1.5 mg/rat/day sildenafil, by oral gavage concomitantly with L‐NAME). The erectile response expressed as a ratio of intracavernosal pressure (ICP)/mean arterial pressure (MAP), evaluated after electrical stimulation of the right cavernous nerve. The isometric tension of corpus cavernosum smooth muscle (CCSM) was measured in organ‐bath experiments. NOS expression was determined immunohistochemically for neuronal (n)NOS and by Western blot analysis for endothelial (e) and inducible (i) NOS protein. cGMP levels were evaluated by enzyme‐linked immunosorbent assay.

RESULTS

The erectile response was diminished in the HT group. Nitrergic and endothelium‐dependent relaxation was reduced, while the relaxation response to sodium nitroprusside and contractile response to phenylephrine were not altered in CCSM from L‐NAME‐treated rats. HT rats showed decreased expression of nNOS, whereas eNOS and iNOS protein expression was increased. Sildenafil partly restored endothelial and molecular changes in CCSM from HT rats, but did not reverse the decreased erectile response, even as cGMP levels returned to normal levels.

CONCLUSIONS

Sildenafil treatment did not correct the ED in L‐NAME‐treated HT rats. Under sustained high blood pressure, up‐regulation of PDE5 expression failed to reverse the depletion of neuronal NO and/or impaired nNOS activity. However, endothelium‐dependent relaxation was restored. Drug targeting of neuronal dysfunction might delay the onset of ED in HT.     

Improvement in erectile function in men with organic erectile dysfunction by correction of elevated cholesterol levels: a clinical observation

PURPOSE: We determined that use of a statin drug to lower cholesterol would improve erectile function in men who have hypercholesterolemia as the only risk factor for erectile dysfunction (ED). MATERIALS AND METHODS: A total of 18 men were determined to have increased cholesterol as the only risk factor for ED by history, system review, physical examination and laboratory analysis. Nine of these men agreed to participate in the study. Organic ED was verified by abnormal nocturnal penile tumescence and rigidity testing with the RigiScan (UroHealth Systems, Inc., Laguna Niguel, California) and Sexual Health Inventory in Men questionnaire. Subjects were given atorvastatin with a goal decrease of total cholesterol to less than 200 mg/dl and low-density lipoprotein cholesterol to less than 120 mg/dl. RigiScan measurements were compared before and after treatment with atrovastatin. RESULTS: Mean age +/- SD was 49.7 +/- 7.4 years. Mean length of treatment with atrorvastatin was 3.7 +/- 2.1 months. Clinically 8 of the 9 men had improved erection adequate for penetration during sexual intercourse. Mean questionnaire scores improved from 14.2 to 20.7 (p <0.001). Mean total and low-density lipoprotein cholesterol decreased significantly after treatment (p <0.001). RigiScan measurements showed an increased average penile rigidity at the base (p <0.001) and tip (p <0.005) after treatment with atorvastatin. CONCLUSIONS: Erectile function improves in men with hypercholesterolemia as the only risk factor for ED when treated with atorvastatin. Treating hypercholesterolemia may improve ED, while promoting primary cardiac prevention.     

Early onset of fibrosis within the arterial media in a rat model of type 2 diabetes mellitus with erectile dysfunction

OBJECTIVES

To determine, in the obese Zucker fa/fa rat (OZR), whether the loss in smooth muscle cells (SMCs) as well as the increase in fibrosis that occurs within the corpora cavernosa accompanying corporal veno‐occlusive dysfunction (CVOD), also occurs within the media of the arterial tree.

MATERIALS AND METHODS

The penis and aorta from both 7‐month‐old male diabetic OZR (5 months of diabetes) and aged‐matched nondiabetic lean Zucker rats (LZR) rats were harvested (eight per group). The penis and aorta were subjected to histo‐ or immnohistochemistry, followed by quantitative image analysis (QIA) to determine the contents of SMC, collagen and the pro‐fibrotic transforming growth factor (TGF)β1. The turnover of SMCs was assessed by terminal deoxynucleotidyl transferase‐mediated dUTP‐biotin nick‐end labelling (TUNEL) and proliferating cell nuclear antigen (PCNA) assays. Quantitative Western blots determined calponin (SMC marker) and PCNA, and hydroxyproline was used for collagen. In vitro relaxation of corporal strips was measured.

RESULTS

In vitro relaxation of corporal tissue from OZR was considerably less than in the LZR. In the media of the penile dorsal artery (PDA) of OZR, there was a considerable reduction in the SMC content and the SMC/collagen ratio, as well as an increase in apoptosis, but there were no changes in PCNA or TGFβ1 expression, or in the intima‐media/lumen ratio. In the aorta of the OZR, in contrast to the PDA, there was a reduction in PCNA as well as a more pronounced decrease in the SMC/collagen ratio, mainly from an increase in collagen, but there were no changes in TGFβ1 or the wall/lumen morphometry. In the OZR, Western blots of aortic tissue confirmed the decrease in PCNA and a reduction in the SMC marker calponin.

CONCLUSIONS

These data show that 5 months after the onset of hyperglycaemia in the OZR, the rats develop both abnormal corporal SMC relaxation and a generalized fibrosis of the arterial media of both the large and small diameter vessels. It is possible that this pan‐fibrosis of the media of the arterial system might contribute to the diabetes‐related ED that occurs during this period in this rat model.     

Enhanced effects of salidroside on erectile function and corpora cavernosa autophagy in a cavernous nerve injury rat model

We explored the efficacy and mechanisms of salidroside treatment for erectile dysfunction induced by bilateral cavernous nerve injury (BCNI). Forty male rats were divided into four groups as follows: sham (cavernous nerves exposed only) (S); BCNI (M); BCNI + rapamycin (M + rapamycin); and BCNI + salidroside (M + salidroside). Erectile function in the rats was measured by intracavernosal pressure. Penile tissue was harvested for transmission electron microscopy, immunohistochemistry, immunofluorescence, Masson's trichrome staining, haematoxylin–eosin staining, TdT-mediated dUTP Nick End Labeling and western blotting. The M group exhibited a decrease in erectile responses and increased apoptosis and fibrosis compared to these in the S group. Meanwhile, nerve content and the penile atrophy index were also decreased in the M group. Treatment with salidroside and rapamycin for 3 weeks partially restored erectile function and significantly attenuated corporal apoptosis, fibrosis, nerve content and penile atrophy in the M group. Moreover, the autophagy level was further enhanced in the M + salidroside group, which was the same as that in the positive observation group (M + rapamycin). Salidroside treatment not only improved erectile function in rats with BCNI, but also inhibited apoptosis and fibrosis and ameliorated the loss of nerve content and endothelial and corpus cavernosum smooth muscle cells by promoting protective autophagy.     

Changes in erectile organ structure and function in a rat model of chronic prostatitis/chronic pelvic pain syndrome

There is a growing recognition of the association between chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) and erectile dysfunction (ED); however, most of the reports are based on questionnaires which cannot distinguish between organic and functional ED. The purpose of this study was to determine the exact relationship between CP/CPPS and ED, and to investigate the changes in erectile organ structure and function in a rat model of CP/CPPS. We established a rat model of experimental autoimmune prostatitis (EAP), which is a valid model for CP/CPPS. Erectile function in EAP and normal rats was comparable after cavernous nerve electrostimulation. The serum testosterone and oestradiol levels, ultrastructure of the corpus cavernosum and expression of endothelial nitric oxide synthase and neuronal nitric oxide synthase in the two groups were similar; however, there was a decrease in smooth muscle‐to‐collagen ratio and alpha‐smooth muscle actin expression and an increase in transforming growth factor‐beta 1 expression was observed in EAP rats. Thus, organic ED may not exist in EAP rats. We speculate that ED complained by patients with CP/CPPS may be psychological, which could be caused by impairment in the quality of life; however, further studies are needed to fully understand the potential mechanisms underlying the penile fibrosis in EAP rats.     

Dopamine D2 receptors in the basolateral amygdala modulate erectile function in a rat model of nonorganic erectile dysfunction

Nonorganic erectile dysfunction is a problem with unknown central mechanisms. Changes in brain activity in the amygdala have been observed in human patients. This study aimed to investigate the dopamine system in the basolateral amygdala of male rats with nonorganic erectile dysfunction. We applied chronic mild stress to induce nonorganic erectile dysfunction. After exposure to chronic mild stress, the sucrose consumption test, sexual behaviour test and apomorphine test were used to select depression‐like rats with erectile dysfunction as nonorganic erectile dysfunction model rats. The sexual behaviour of these rats after central infusion of a dopamine D1/D2 receptor agonist/antagonist was observed. The expression levels of dopamine D1/D2 receptors and tyrosine hydroxylase in the basolateral amygdala were also measured. The result of the sucrose consumption test, sexual behaviour test and apomorphine test indicated a successful nonorganic erectile dysfunction model. Central infusion of a dopamine D2 receptor agonist increased intromission ratio in model rats. Lower expression levels of tyrosine hydroxylase and the dopamine D2 receptor in the basolateral amygdala were observed in rats with nonorganic erectile dysfunction. These results suggest that impairment of the dopamine D2 receptor pathway in the basolateral amygdala may contribute to the development of nonorganic erectile dysfunction.     

Longitudinal studies of time‐dependent changes in both bladder and erectile function after streptozotocin‐induced diabetes in Fischer 344 male rats

OBJECTIVES

To provide sensitive physiological endpoints for the onset and long‐term progression of deficits induced by diabetes mellitus (DM) in bladder and erectile function in male rats, and to evaluate parallel changes in urogenital and nerve function induced by hyperglycaemia over a protracted period as a model for chronic deficits in patients with diabetes.

MATERIALS AND METHODS

The study comprised in 877 male, 3‐month‐old, Fischer 344 rats; 666 were injected intraperitoneally with 35 mg/kg streptozotocin (STZ) and divided into insulin‐treated and untreated diabetic groups. The rats were studied over 8 months and measurements made of both erectile and bladder function, as well as nerve conduction studies over the duration of the study.

RESULTS

There was an early (first month) abnormality of both erectile and bladder function that persisted through the 8 months of the study. The erectile dysfunction was manifest as reduced intracavernous pressure/blood pressure ratio, and the bladder dysfunction as a persistent increase in detrusor overactivity with no detrusor decompensation. Insulin treatment prevented or modified the abnormality in each organ. Hyperglycaemia caused a progressive decrease in caudal nerve conduction velocity. The mean digital sensory and tibial motor nerve conduction velocity did not deteriorate over time. Correlation measurements of nerve and organ function were not consistent.

CONCLUSIONS

The results of this extensive long‐term study show early and profound effects of hyperglycaemia on the smooth muscle of the penis and bladder, that were persistent and stable in surviving rats over the 8 months. The physiological changes did not correlate well with neurological measurements of those organs. Significantly, diverse smooth‐muscle cellular and subcellular events antedated the measured neurological manifestations of the hyperglycaemia by several months. Although autonomic diabetic neuropathy is a primary life‐threatening complication of long‐term diabetes in humans, this rat model of STZ‐induced diabetes showed that the rapid onset of physiological manifestations was based on many molecular changes in the smooth muscle cells in this model of type 1 DM.     

Transplantation of adipose tissue‐derived stem cell‐derived exosomes ameliorates erectile function in diabetic rats

Mesenchymal stem cells (MSCs) have been considered as an attractive tool for the therapy of diseases. Accumulating evidence indicates that the healing effects of MSCs are mainly related to paracrine action rather than transdifferentiation. Exosomes excreted from MSCs have emerged as physiologically relevant and powerful components of the MSC secretome. However, whether MSC‐derived exosomes can improve erectile function of streptozotocin‐induced diabetic rats and its mechanism remains unknown. Our previous work showed that adipose tissue‐derived stem cells (ADSCs) transplantation could increase endothelial and smooth muscle contents and improve erectile function of diabetic rats. In this study, ADSC‐derived exosomes (ADSC‐Exo) exhibited in vitro proangiogenic properties, induced the proliferation of endothelial cells and restored erectile function in vivo, as well as decreased fibrosis of corpus cavernosum. In further experiments, we found that ADSC‐Exo contained some proangiogenic (miR‐126, miR‐130a and miR‐132) microRNAs and an antifibrotic microRNA family (miR‐let7b and miR‐let7c). Thus, it is reasonable to postulate that ADSC‐Exo transports key functional miRNAs to target cells in a specific manner to improve functional recovery or to activate endogenous repair mechanisms. This proof‐of‐concept study provides a novel approach for the treatment of diabetic erectile dysfunction.     

Chronic administration of sildenafil improves erectile function in a rat model of chronic renal failure

The relationship between erectile dysfunction (ED) and chronic renal failure (CRF) has been reported in several studies. This study aimed to investigate whether the chronic use of sildenafil could enhance the erectile capacity in CRF-induced rats. In addition, we assessed the effect of that treatment on certain molecules, which have been suggested to play crucial roles in erectile physiology and CRF-related ED as well. Three groups of animals were utilized: (1) age-matched control rats, (2) CRF-induced rats, (3) CRF-induced rats treated with chronic administration of sildenafil (5 mg kg⁻¹ p.o. for 6 weeks [treatment started after 6 weeks of CRF induction]). At 3 months, all animals underwent cavernosal nerve stimulation (CNS) to assess erectile function. Penile tissue advanced glycation end products (AGE''s)/5-hydroxymethyl-2-furaldehyde, malondialdehyde (MDA), cGMP (ELISA), inducible nitric oxide synthase (iNOS) and neuronal NOS (nNOS) (Western blot) analyses were performed in all rat groups. CRF-induced rats had a significant decrease in erectile function when compared to control rats (P < 0.05). The increase in both intracavernosal pressure (ICP) and area under the curve of CRF-induced rats treated with sildenafil (Group 3) was greater than CRF-induced rats (Group 2). Additionally, sildenafil treatment decreased AGE, MDA and iNOS levels, while it preserved nNOS and cGMP contents in CRF-induced penile tissue. Decreased AGE, MDA, iNOS and increased nNOS, cGMP levels at the sildenafil-treated group increased both ICP and Total ICP to CNS, which led to improve erectile function in CRF-induced rats. The results of the present study revealed the therapeutic effect of chronic sildenafil administration on erectile function in CRF-induced rats.     

Effects of hydrogen sulphide donor,sodium hydrosulphide treatment on the erectile dysfunction in L‐NAME‐induced hypertensive rats

Men with hypertension often develop erectile dysfunction (ED). The present study aimed to examine the effects of sodium hydrosulphide (NaHS), a hydrogen (H₂S) donor, treatment on ED in nitric oxide synthase (NOS) inhibitor (L‐NAME)‐induced hypertensive rats. Forty adult Sprague‐Dawley rats were divided into four groups: control, NaHS (0.037 mg kg day^?1)‐treated control, L‐NAME‐induced hypertension (40 mg kg day^?1) and NaHS‐treated L‐NAME‐induced hypertension. The ratio of intracavernosal pressure to mean arterial pressure and isometric tension of corpus cavernosum (CC) were measured. The penile expression of endothelial and neuronal NOS (eNOS and nNOS), inflammation markers [nuclear factor kappa B (NF‐κB) and inhibitor kappa B alpha (IκBα)], H₂S‐producing enzymes[cystathionine β‐synthase (CBS) and cystathionine γ‐lyase (CSE)], the smooth muscle/collagen ratio and H₂S concentrations were determined. The blood pressure was significantly increased in the hypertensive group, but not reversed by NaHS. The erectile response in hypertensive rats was partially prevented by NaHS. The relaxation response to electrical field stimulation was increased in CC from NaHS‐treated hypertensive rats. NaHS treatment restored decreased protein expression of eNOS, nNOS and CSE as well as smooth muscle/collagen ratio and H₂S levels and increased NF‐κB and IκBα protein expression in the penile tissue of hypertensive rats. NaHS promoted the recovery of erectile responses in hypertensive rats by improvement of neuronal function and downregulation of fibrosis and NF‐κB signalling.     

Effect of hydrogen sulphide‐donating sildenafil (ACS6) on erectile function and oxidative stress in rabbit isolated corpus cavernosum and in hypertensive rats

OBJECTIVE

To study the effect of the H₂S‐donating derivative of sildenafil (ACS6) compared to sildenafil citrate and sodium hydrosulphide (NaHS) on relaxation, superoxide formation and NADPH oxidase and type 5 phosphodiesterase (PDE5) expression in isolated rabbit cavernosal tissue and smooth muscle cells (CSMCs), and in vivo on indices of oxidative stress induced with buthionine sulphoximine (BSO).

MATERIALS AND METHODS

Relaxation was studied in an organ bath in response to carbachol and after incubation with interleukin‐1β for 12 h. CSMCs were incubated with tumour‐necrosis factor‐α or the thromboxane A₂ (TXA₂) analogue, U46619, with or with no sildenafil citrate, ACS6 or NaHS for 16 h. Superoxide formation and the expression of p47^phox (an active subunit of the NADPH oxidase complex) and PDE5 protein was then assessed using Western blotting. Rats were also treated with BSO (with or with no sildenafil citrate or ACS6) for 7 days; cavernosal cGMP, cAMP, glutathionine and plasma TXA₂ and 8‐isoprostane F_2α was measured by enzyme‐linked immunosorbent assay.

RESULTS

ACS6 and sildenafil citrate relaxed cavernosal smooth muscle equipotently; NaHS alone had little effect at up to 100 µm . The formation of superoxide and expression of p47^phox and PDE5 was reduced by ACS6, sildenafil citrate and NaHS (order of potency: ACS6 > sildenafil citrate > NaHS). The effects of ACS6 were blocked by inhibitors of protein kinase A (PKA) and PKG. In rats treated with BSO, both ASC6 and sildenafil citrate reduced the increased plasma levels of TXA₂ and 8‐isoprostane F_2α but increased cGMP, cAMP and glutathionine levels in corpus cavernosum.

CONCLUSIONS

By virtue of a dual action on PKA and PKG activation, ACS6 not only promotes erection, acutely, but might also have a long‐term beneficial effect through inhibition of oxidative stress and downregulation of PDE5.     

Cavernous smooth muscle hyperplasia in a rat model of hyperlipidaemia-associated erectile dysfunction

Study Type – Aetiology (case control) Level of Evidence 3b What’s known on the subject? and what does the study add? Increased cavernous smooth muscle content has been repeatedly observed in rat models of hyperlipidaemia – associated erectile dysfunction. This study shows that the increased smooth muscle content is due to hyperplasia.

OBJECTIVE

? To investigate the structural changes, including possible smooth muscle hyperplasia, in the penis of a hyperlipidaemia‐associated erectile dysfunction (ED) animal model.

MATERIALS AND METHODS

? Hyperlipidaemia was induced in rats through a high‐fat diet. ? Penile tissues of normal and hyperlipidaemic rats were stained with Alexa‐488‐conjugated phalloidin and/or with antibodies against rat endothelial cell antigen, neuronal nitric oxide synthase (nNOS), and collagen type IV (Col‐IV) before image and statistical analyses were carried out. ? The main outcome measures were the smooth muscle, endothelial, Col‐IV and nNOS content of the corpus cavernosum.

RESULTS

? Phalloidin intensely stained all smooth muscle in the penis, revealing the circular and longitudinal components of cavernous smooth muscle (CSM). ? The CSM content was significantly higher in the hyperlipidaemic than in the normal rats (P < 0.05). ? Cell numbers in both circular and longitudinal CSM were significantly higher in the hyperlipidaemic than in the normal rats (P < 0.05). ? Cavernous endothelial content was significantly lower in hyperlipidaemic than in normal rats (P < 0.05). ? nNOS‐positive nerves within the dorsal nerves, around the dorsal arteries, and in the corpora cavernosa were all significantly lower in the hyperlipidaemic than in the normal rats (P < 0.05).

CONCLUSIONS

? Hyperlipidaemia is associated with reduced nNOS‐positive nerves, reduced endothelium, and increased CSM in the penis. ? The increased CSM is attributable to hyperplasia. ? These structural changes may explain why hyperlipidaemic men are more likely to develop ED.     

Pentoxifylline promotes recovery of erectile function in a rat model of postprostatectomy erectile dysfunction

Background

Cavernous nerve (CN) injury during radical prostatectomy (RP) causes CN degeneration and secondary penile fibrosis and smooth muscle cell (SMC) apoptosis. Pentoxifylline (PTX) is a phosphodiesterase inhibitor that further inhibits multiple cytokine pathways involved in nerve degeneration, apoptosis, and fibrosis.

Objectives

To evaluate whether PTX enhances erectile function in a rat model of CN injury.

Design, Setting and Interventions

Forty male Sprague-Dawley rats underwent CN crush injury and were randomized to oral gavage feeding of phosphate-buffered saline (vehicle) or PTX 25, PTX 50, or PTX 100 mg/kg per day. Ten animals underwent sham surgery and received vehicle treatment. Treatment continued for 28 d, followed by a wash-out period of 72 h. An additional eight rats underwent resection of the major pelvic ganglion (MPG) for tissue culture and examination of direct effects of PTX on neurite sprouting.

Measurements

Intracavernous pressure recording on CN electrostimulation, immunohistologic examination of the penis and the CN distal to the injury site, and length of neurite sprouts in MPG culture.

Results

Daily oral gavage feeding of PTX resulted in significant improvement of erectile function compared to vehicle treatment in all treated groups. After treatment with PTX 50 and PTX 100 mg/kg per day, the expression of neuronal nitric oxide synthase in the dorsal penile nerve was significantly higher than in vehicle-treated rats. Furthermore, PTX treatment prevented collagen deposition and SMC loss in the corpus cavernosum. In the CN, signs of Wallerian degeneration were ameliorated by PTX treatment. MPG culture in medium containing PTX resulted in a significant increase of neurite length.

Conclusions

PTX treatment following CN injury in rats improved erectile recovery, enhanced nerve regeneration, and preserved the corpus cavernosum microarchitecture. The clinical availability of this compound merits application in penile rehabilitation studies following RP in the near future.     

A new experimental rat model of erectile dysfunction and lower urinary tract symptoms associated with benign prostatic hyperplasia: the testosterone‐supplemented spontaneously hypertensive rat

What's known on the subject? and What does the study add? Lower urinary tract symptoms (LUTS) resulting from benign prostatic hyperplasia (BPH) and erectile dysfunction (ED) are common problems in the aging male population. Moreover, several recent studies have shown that ED is closely associated with the presence and severity of LUTS independently of co‐morbidities. However, the pathophysiological mechanisms linking LUTS/BPH and ED remain largely unexplored. The major difficulty in studying such relationships between ED and LUTS/BPH, and of exploring the impact of new therapeutic approaches for both LUTS/BPH and ED, is the lack of experimental model combining ED, prostate enlargement and bladder dysfunction all at once. The present study describes a new model of BPH, the SHR supplemented with testosterone which is the first animal model which displays all at once the key features of BPH: prostate enlargement and an increased sympathetic tone of bladder outlet mimicking the static and the dynamic components of voiding symptoms of BPH, a significant impairment of bladder function which reflects the storage symptoms of BPH and finally, ED. This model could be very relevant to better characterize the close relationship that exists between BPH/LUTS and ED, and to evaluate new therapeutic strategies for BPH together with their side effect profile on sexual function on the same animal, thus allowing a reduction of the number of animals to be used in such studies. Study Type – Aetiology (case control) Level of Evidence 3b

OBJECTIVE

• ? To design a new experimental model combining erectile dysfunction, prostate enlargement and urodynamic impairment characteristic of lower urinary tract symptoms (LUTS) associated with benign prostate hyperplasia (BPH).

MATERIALS AND METHODS

• ? Three groups of animals (12‐week‐old; n= 7/group) were considered: Wistar Kyoto (control) rats (WKY), untreated spontaneously hypertensive rats (SHR) and SHR treated with testosterone (SHR‐T, 3 mg/kg/day) for 3 weeks.
• ? Cystometry experiments and evaluation of erectile function were performed. Prostate enlargement was evaluated.

RESULTS

• ? SHR displayed a significant decrease in the intercontraction interval (ICI) and in the voided volume (VV) whereas non‐voiding contractions (NVC) were increased. SHR‐T exhibited a further decreased ICI and VV and an increased frequency of NVC.
• ? Erectile responses to electrical stimulation of the cavernous nerve were significantly impaired in both SHR (?66%) and SHR‐T (?58%).
• ? The prostate weight was similar in WKY and SHR, but significantly increased in SHR‐T.

CONCLUSIONS

• ? The testosterone‐supplemented SHR represents an experimental model for urodynamic impairment combining both static and dynamic components of voiding symptoms with erectile dysfunction and prostate enlargement.
• ? This model is suitable for the assessment of sexual side effects of LUTS/BPH treatments and efficacy of new therapeutic agents in LUTS/BPH and associated erectile dysfunction.

     

Safety and efficacy of sildenafil citrate in treating erectile dysfunction in patients with combat‐related post‐traumatic stress disorder: a double‐blind,randomized and placebo‐controlled study

OBJECTIVE

To evaluate the safety and efficacy of sildenafil citrate for treating erectile dysfunction (ED) in patients with combat‐related post‐traumatic stress disorder (PTSD).

PATIENTS AND METHODS

In all, 266 combat‐exposed war veterans with ED (aged 37–59 years) were recruited. They met the Diagnostic and Statistical Manual of Mental Disorders‐IV criteria for PTSD according to the Structured Clinical Interview for Patients, Investigator Version. The patients were also evaluated with the Clinician‐Administered PTSD Scale, both to establish the diagnosis of PTSD and to measure symptom severity. Only patients with psychogenic ED were included in the study. Patients with comorbid conditions (diabetes mellitus, hypercholesterolaemia, hypertension, Peyronie’s disease) and smokers of more than five cigarettes daily were excluded. The patients were randomly divided into a group of 133 who received 100 mg of on‐demand sildenafil 0.75–2 h before sexual stimulation, and 133 who received placebo. Patients were asked to use ≥16 doses or attempts at home. The efficacy of the treatments was assessed every four attempts during treatment, and at the end of the study, using responses to the 15‐question International Index of Erectile Function (IIEF), Sexual Encounter Profile diary questions 2 and 3, Erectile Dysfunction Inventory of Treatment Satisfaction questionnaire, patients’ event logs of sexual activity, and a Global Assessment Question about erections.

RESULTS

Sildenafil did not produce significantly and substantially greater improvement than placebo in each of the primary and secondary outcome measures (P = 0.08). A normal EF domain score (≥26) at endpoint was reported by 13 (9.8%), and 11 (8.3%) of patients on the sildenafil and placebo regimens, respectively (P = 0.09). Patients treated with sildenafil had no statistically significantly greater improvement in the five sexual function domains of the IIEF questionnaire than those treated with placebo (P = 0.08). The incidences of treatment‐emergent adverse events were significantly greater in the sildenafil arm than in the placebo group (P = 0.01).

CONCLUSIONS

Sildenafil is no better than placebo in treating PTSD‐emergent ED. Further randomized clinical trials are warranted in combat veterans and other populations with PTSD to better elucidate the role of phosphodiesterase type 5 inhibitors in treating PTSD‐emergent ED.     

Investigation of a complex plant extract for mild to moderate erectile dysfunction in a randomized,double‐blind,placebo‐controlled,parallel‐arm study

Study Type – Therapy (RCT)
Level of Evidence 1b

OBJECTIVE

To assess the effects of a complex plant extract (Prelox®, a formulation of pine bark extract and l ‐arginine aspartate; Horphag Research UK Ltd, London, UK) on erectile dysfunction (ED) in men, as sexual desire typically persists in ageing men, while their erectile and endothelial function gradually declines.

PATIENTS AND METHODS

In this double‐blind, placebo‐controlled study we assessed the effects of Prelox in 124 patients (aged 30–50 years) with moderate ED over an investigational period of 6 months. The International Index Of Erectile Function (IIEF) was used to quantify changes in sexual function.

RESULTS

The erectile domain of the IIEF (questions 1–5 plus 15) improved with Prelox from a baseline mean (sd ) score of 15.2 (6.6) to 25.2 (2.1) after 3 months and 27.1 (2.1) after 6 months of treatment. In the placebo group there was an increase from a baseline score of 15.1 (7.0) to 19.1 (3.0) and 19.0 (3.1) after 3 and 6 months, respectively. The effects with Prelox were statistically significant compared with placebo (P < 0.05). Mean (sd ) total plasma testosterone levels increased significantly from 15.9 (2.3) to 18.9 (2.6) nmol/L (P < 0.05) after 6 months with Prelox, compared to an increase from 16.9 (2.4) to 17.3 (2.3) nmol/L in the placebo group.

CONCLUSION

This study shows that Prelox is effective for improving erectile function, and that this effect persists on continuous therapy for up to 6 months. Moreover, there is some evidence that erectile function continues to improve the longer the therapy is used.