Cavernosal Nerve Stimulation Research Articles

The therapeutic effect of ALT-711 on erectile function in rats treated with high-level AGEs (advanced glycation end products) containing diet.

To investigate, if advanced glycation end products (AGEs) are involved in erectile dysfunction (ED) and also ALT-711, a cross-link breaker of AGEs, has the therapeutic potential against the development of ED in rats treated with high concentrated AGEs including food. For this purpose, 30 male Harlan Spraque-Dawley rats randomly were divided into three groups; (1) control rats treated with regular diet, (2) rats treated with high-level of AGE specific diet for 6 months, and (3) rats having AGE-diet treated with ALT-711 for the final 3 months of 6 months of AGE-diet period. Erectile response to cavernosal nerve stimulation (CNS), protein expression of neuronal nitric oxide synthase (nNOS) and levels of AGEs, Malondialdehyde (MDA), cyclic guanosine monophosphate (cGMP) were determined in penile tissues. Erectile responses to CNS and penile nNOS and cGMP content were significantly reduced, while AGEs and MDA were elevated in penises of Group-2. Treatment with ALT-711 reversed ED and depletion of both nNOS and cGMP. Additionally, ALT-711 treatment reduced penile tissue AGEs and MDA expression. In present study: rats without any co-morbidity such as diabetes mellitus (DM) and chronic renal failure (CRF) were treated with high-level AGEs containing food. Our results suggest that ALT-711 may be an interesting and promising approach in the treatment of AGEs-related ED.

Decreased expression of pigment epithelium-derived factor within the penile tissues contributes to erectile dysfunction in diabetic rats.

Increased production of reactive oxygen species (ROS) and inflammation are major contributors to the development and progression of diabetes-associated erectile dysfunction (DMED). As an endogenous antioxidant and anti-inflammatory factor, the potential implication of pigment epithelium-derived factor (PEDF) in DMED has not been revealed. To assess the potential antioxidant and anti-inflammatory functions of PEDF in DMED, we first demonstrated that PEDF was significantly decreased at the levels of the mRNA and protein in the penis of diabetic rats compared with normal controls. To test the hypothesis that decreased the penile levels of PEDF are associated with oxidative stress and inflammation in DMED, an adenovirus expressing PEDF (Ad-PEDF) or the same titer of control virus (Ad-GFP) was intracavernously administered at 2 weeks after diabetic onset. After 6 weeks of treatment, we found that administration of Ad-PEDF could significantly increase erectile response to cavernosal nerve stimulation in the diabetic rats by restoring the endothelial NO synthase (eNOS), P-eNOS, and neuronal NO synthase (nNOS) protein levels to the standard levels represented in normal rats and by suppressing the levels of tumor necrosis factor-α (TNF-α) and oxidative stress. In conclusion, the present data indicated that the antioxidant and anti-inflammatory potential of PEDF plays important role in restoring erectile function by the inhibition of oxidative stress and TNF-α production.

164 The Effects of Multiple Adipose-Derived Stem Cell Intracorporeal Injections on Erectile Dysfunction in a Rat Model of Cavernosal Nerve Injury

Nerve injury after radical prostatectomy leads to erectile dysfunction in over half of treated patients. Despite contemporary advancements, current therapies are inefficient. Recently, experiments utilizing stem cell therapy have shown promising outcomes. In this study, using a rat model of cavernosal nerve injury (CNI), we sought to discover the effect of intracorporal injection (IC) of adipose-derived stem cells (ADSC) on erectile function (EF). Sprague-Dawly rats were randomized into four groups of rats (n=8/group): 1) EXP-1 group in which the animals underwent laparotomy (Lap) with CNI and IC injection of ADSC at the time of surgery. 2) EXP-2 group in which the rats underwent Lap with CNI and IC injection of ADSC both at the time of surgery and three weeks post CNI. 3) Crush group underwent Lap with CNI, and 4) The Sham control group underwent Lap and immediate closure. Six weeks after CNI, all four groups received EF evaluation via cavernosal nerve stimulation at 2.5V, 5V, and 7.5V and measurement of the intracorporal pressure response. Penile and major pelvic ganglion tissue was harvested for immunohistochemical (IHC) analysis.

Analysis of erectile responses to H2S donors in the anesthetized rat.

Hydrogen sulfide (H2S) is a biologically active endogenous gasotransmitter formed in penile tissue that has been shown to relax isolated cavernosal smooth muscle. In the present study, erectile responses to the H2S donors sodium sulfide (Na2S) and sodium hydrosulfide (NaHS) were investigated in the anesthetized rat. Intracavernosal injections of Na2S in doses of 0.03-1 mg/kg increased intracavernosal pressure and transiently decreased mean arterial pressure in a dose-dependent manner. Blood pressure responses to Na2S were rapid in onset and short in duration. Responses to Na2S and NaHS were similar at doses up to 0.3 mg/kg, after which a plateau in the erectile response to NaHS was reached. Increases in intracavernosal pressure in response to Na2S were attenuated by tetraethylammonium (K(+) channel inhibitor) and iberiotoxin (large-conductance Ca(2+)-activated K(+) channel inhibitor), whereas glybenclamide [ATP-sensitive K(+) (KATP) channel inhibitor] and inhibitors of nitric oxide (NO) synthase, cyclooxygenase, and cytochrome P-450 epoxygenase had no effect. These data indicate that erectile responses to Na2S are mediated by a tetraethylammonium- and iberiotoxin-sensitive mechanism and that KATP channels, NO, or arachidonic acid metabolites are not involved. Na2S did not alter erectile responses to sodium nitroprusside (NO donor) or cavernosal nerve stimulation, indicating that neither NO nor cGMP metabolism are altered. Thus, Na2S has erectile activity mediated by large-conductance Ca(2+)-activated K(+) channels. It is suggested that strategies that increase H2S formation in penile tissue may be useful in the treatment of erectile dysfunction when NO bioavailability, KATP channel function, or poor responses to PGE1 are present.

Analysis of erectile responses to bradykinin in the anesthetized rat.

The kallikrein-kinin system is expressed in the corpus cavernosa, and bradykinin (BK) relaxes isolated corpora cavernosal strips. However, erectile responses to BK in the rat have not been investigated in vivo. In the present study, responses to intracorporal (ic) injections of BK were investigated in the anesthetized rat. BK, in doses of 1-100 μg/kg ic, produced dose-related increases in intracavernosal pressure (ICP) and dose-related deceases in mean arterial pressure (MAP). When decreases in MAP were prevented by intravenous injections of angiotensin II (Ang II), increases in ICP, in response to BK, were enhanced. Increases in ICP, ICP/MAP ratio, and area under the curve and decreases in MAP in response to BK were inhibited by the kinin B2 receptor antagonist HOE-140 and enhanced by the angiotensin-converting enzyme (ACE) inhibitor captopril and by Ang-(1-7). Increases in ICP, in response to BK, were not attenuated by the nitric oxide (NO) synthase inhibitor (N(ω)-nitro-L-arginine methyl ester) or the soluble guanylate cyclase inhibitor (1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one) but were attenuated by the cyclooxygenase inhibitor, sodium meclofenamate. Decreases in MAP were not attenuated by either inhibitor. These data suggest that erectile responses are mediated by kinin B2 receptors and modulated by decreases in MAP. These data indicate that ACE is important in the inactivation of BK and that erectile and hypotensive responses are independent of NO in the penis or the systemic vascular bed. Erectile responses to cavernosal nerve stimulation are not altered by BK or HOE-140, suggesting that BK and B2 receptors do not modulate nerve-mediated erectile responses under physiologic conditions. These data suggest that erectile responses to BK are mediated, in part, by the release of cyclooxygenase products.

MP52-13 THE EFFECT OF PARTIAL BLADDER OUTLET OBSTRUCTION (PBOO) SEVERITY AND HYPERCHOLESTEROLEMIA ON ERECTILE FUNCTION IN RATS

You have accessJournal of UrologySexual Function/Dysfunction/Andrology: Basic Research I1 Apr 2015MP52-13 THE EFFECT OF PARTIAL BLADDER OUTLET OBSTRUCTION (PBOO) SEVERITY AND HYPERCHOLESTEROLEMIA ON ERECTILE FUNCTION IN RATS Serap Gur, Nur Bayatli, and Didem Yilmaz Serap GurSerap Gur More articles by this author , Nur BayatliNur Bayatli More articles by this author , and Didem YilmazDidem Yilmaz More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2015.02.1730AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Erectile dysfunction (ED) and lower urinary tract symptoms (LUTS) caused by benign prostatic hyperplasia (BPH) are commonly coexist and very prevalent in men aged over 50 years. One of the leading theories of this interrelation is atherosclerosis-induced pelvic injury. We investigated the degree of partial bladder outlet obstruction (PBOO) induced by a ligation (with 5F or 4F catheter [c]) of the bladder neck and the role of atherosclerosis induced by hypercholesterolemic diet (HCD) on erectile function in rats. METHODS A total of 96 Sprague-Dawley male rats were divided into 6 groups: 1) Sham-operated; 2) PBOO (5Fc); 3) PBOO (4Fc); 4) HCD 5)HCD-PBOO (5Fc) and 6) HCD-PBOO (4Fc). HCD groups were fed 4% cholesterol and PBOO groups were subjected by ligation of the urethra for 6 wk. Erectile response was measured using cavernosal nerve stimulation by evaluating ratios of intracavernosal pressure (ICP)/mean arterial pressure. The relaxant and contractile properties of corpus cavernosum smooth muscle (CCSM) strips were evaluated in tissue baths. Immunohistochemical (IHC) staining for neuronal nitric oxide synthase (nNOS), endothelial NOS (eNOS), Rho-activated kinase (ROCK) and collagen deposition was performed. RESULTS The weight of bladder enhanced gradually in obstructed and combination groups and peaked in HCD-PBOO (4F)(Table). Relaxant and contractile responses of CCSM decreased depending on the severity of PBOO with HCD (Table). Rho-kinase inhibitor Y-27632 (10 μM) inhibited peak and sustained contractile responses to phenylephrine in groups (Table). We found lower nNOS, eNOS, higher Rho-kinase and collagen expressions in PBOO and combined groups. CONCLUSIONS The PBOO caused the more marked ED manifesting by considerable lowering of erectile response and the shift HCD in rats promoted. Our results suggest that the PBOO causes the functional and molecular changes, penile remodeling, accumulation of extracellular collagen in penile tissue, which may become more stressed with the HCD. The management of atherosclerosis may be beneficial in the treatment and continued research are needed for PBOO with HCD and will undoubtedly contribute to the future development of novel therapies for LUTS and ED. Sham-control PBOO(5F) PBOO(4F) HCD HCD-PBOO(5F) HCD- PBOO(4F) Bladder weight (g) 0.12 ± 0.01 0.25 ± 0.008*** 0.34 ± 0.004*** 0.53 ± 0.02*** 0.67 ± 0.004***### 0.91 ± 0.01 ***††† ICP/MAP (7.5V) 1.15 ± 0.06 0.66 ± 0.007*** 0.50 ± 0.020*** 0.52 ± 0.010*** 0.32 ± 0.01***### 0.10 ± 0.002***††† ACh (10-3M) 91.5 ± 1.5 78.9 ± 0.7*** 63.7 ± 2.5*** 46.7 ± 1.3*** 18.9 ± 1.1*** ### 6.2 ± 0.2*** ††† EFS relaxation (20Hz) 96.7 ±1.4 86.9 ± 1.6* 70.5 ± 2.1*** 62.6 ± 0.5*** 55.3 ± 1.9***### 16.6 ± 1.6***††† SNP (10-3M) 100 ± 0 100 ± 0 97.4 ± 0.9 91.4 ± 0.3 81.4 ± 0.3*** ### 66.1 ± 0.3*** ††† EFS contraction (40Hz) 69.5 ± 0.2 51.4 ± 0.8*** 43.8 ± 0.1*** 39.6 ± 0.02*** 29.0 ± 0.3***### 18.4 ± 0.9***††† Phe (10-3M) 90.9 ± 4.4 60.3 ± 2.6*** 43.5 ± 1.3*** 36.7 ± 0.8*** 28.1 ± 1.1***### 13.0 ± 1.1***††† Y-27 632(1μM) 100 ± 0 93.8 ± 0.3 43.5 ± 0.2*** 36.7 ± 0.5*** 28.13 ± 1.1***### 13.0 ± 0.8***††† Data are mean ± SEM (n=12-15). *p<0.05, **p<0.01, ***p<0.001 vs sham-control; ###p<0.001 vs PBOO (5F) and †††p<0.001 vs PBOO (4F). © 2015 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 193Issue 4SApril 2015Page: e632 Advertisement Copyright & Permissions© 2015 by American Urological Association Education and Research, Inc.MetricsAuthor Information Serap Gur More articles by this author Nur Bayatli More articles by this author Didem Yilmaz More articles by this author Expand All Advertisement Advertisement PDF DownloadLoading ...

MP52-05 BILATERAL CAVERNOUS NERVE INJURY INDUCES TEMPORAL INCREASE OF TNF-α AND RECRUITMENT OF MACROPHAGES IN THE MAJOR PELVIC GANGLION IN VIVO.

INTRODUCTION AND OBJECTIVES: In addition to a loss of nitrergic function, cavernous nerve injury (CNI) in rats and radical prostatectomy in men result in an enhancement of adrenergic-neurogenic contractions of cavernosal tissue. Our aim was to evaluate the modulation of a-adrenergic system as a strategy to relieve erectile dysfunction (ED) and functional cavernosal alterations induced by CNI in rats. The effects of a-adrenergic blockade on neurogenic relaxation of human corpus cavernosum (HCC) were also evaluated. METHODS: Bilateral crush CNI (BCNI) was induced in anesthetized rats that were randomly selected to receive or not the non-selective a-blocker, phentolamine (1 mg/kg/day; PHENT) or the selective a1A-blocker, silodosine (0.1 mg/kg/day; SILOD) in drinking water for 4 weeks. Erectile responses to cavernosal nerve stimulation and neurogenic responses of corpus cavernosum to electrical field stimulation (EFS) in organ chambers were then evaluated. HCC from ED patients were obtained at the time of penile prosthesis implantation and nitrergic responses to EFS were determined. RESULTS: Chronic treatment with SILOD significantly improved erectile responses, partially recovered nitrergic relaxations and normalized neurogenic contractions (Table). Chronic a-blockade with PHENT or SILOD allowed for a significant potentiation of erectile responses in BCNI rats after acute administration of the PDE5 inhibitor tadalafil (0.3 mg/kg; i.v.). Treatment of HCC with PHENT (1 mM) slightly increased nitrergic relaxations and enhanced the potentiating effects of tadalafil (30 nM) on these responses. CONCLUSIONS: a-adrenergic modulation, especially selective a1A-blockade, improves erectile and cavernosal functions after BCNI. Modulation of adrenergic system, mainly in combination strategies, could have a role in the management of ED after RP.

MP52-04 SELECTIVE α1A-ADRENERGIC MODULATION ENHANCES ERECTILE RESPONSES IN RATS AFTER CAVERNOUS NERVE INJURY AND IMPROVES NEUROGENIC AND PDE5 INHIBITOR RESPONSES IN HUMAN AND RAT CAVERNOSAL TISSUE

INTRODUCTION AND OBJECTIVES: In addition to a loss of nitrergic function, cavernous nerve injury (CNI) in rats and radical prostatectomy in men result in an enhancement of adrenergic-neurogenic contractions of cavernosal tissue. Our aim was to evaluate the modulation of a-adrenergic system as a strategy to relieve erectile dysfunction (ED) and functional cavernosal alterations induced by CNI in rats. The effects of a-adrenergic blockade on neurogenic relaxation of human corpus cavernosum (HCC) were also evaluated. METHODS: Bilateral crush CNI (BCNI) was induced in anesthetized rats that were randomly selected to receive or not the non-selective a-blocker, phentolamine (1 mg/kg/day; PHENT) or the selective a1A-blocker, silodosine (0.1 mg/kg/day; SILOD) in drinking water for 4 weeks. Erectile responses to cavernosal nerve stimulation and neurogenic responses of corpus cavernosum to electrical field stimulation (EFS) in organ chambers were then evaluated. HCC from ED patients were obtained at the time of penile prosthesis implantation and nitrergic responses to EFS were determined. RESULTS: Chronic treatment with SILOD significantly improved erectile responses, partially recovered nitrergic relaxations and normalized neurogenic contractions (Table). Chronic a-blockade with PHENT or SILOD allowed for a significant potentiation of erectile responses in BCNI rats after acute administration of the PDE5 inhibitor tadalafil (0.3 mg/kg; i.v.). Treatment of HCC with PHENT (1 mM) slightly increased nitrergic relaxations and enhanced the potentiating effects of tadalafil (30 nM) on these responses. CONCLUSIONS: a-adrenergic modulation, especially selective a1A-blockade, improves erectile and cavernosal functions after BCNI. Modulation of adrenergic system, mainly in combination strategies, could have a role in the management of ED after RP.

Ginsenoside Rg3 improves erectile function in streptozotocin-induced diabetic rats.

Ginsenoside Rg3 is one of the active ingredients isolated from Panax ginseng C.A. Meyer. Previous studies demonstrated that Rg3 has antioxidant and neuroprotective abilities. The purpose of this study was to evaluate the protective effect of Rg3 on erectile function in streptozotocin (STZ)-induced diabetic rats. Two-month-old Sprague-Dawley male rats received a one-time intraperitoneal (IP) STZ (60 mg/kg) or vehicle injection after a 16-hour fast. Three days later, rats were randomly divided into four groups and were treated with daily gavage feedings of a mix of distilled saline water and 0.5% carboxymethylcellulose or Rg3 dissolved in the mix at doses of 10 mg/kg and 100 mg/kg for 3 months. A sham group underwent IP injection of saline followed by daily gavage of the above mix for 3 months. Erectile function was assessed by cavernosal nerve electrostimulation at 3 months. The penis was then harvested and deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) was performed. Western blot was performed to examine cleaved caspase-3, platelet endothelial cell adhesion molecule (PECAM)-1, and smooth muscle actin (SMA). Neural regeneration was measured by nicotinamide adenine dinucleotide phosphate (NADPH)-diaphorase staining. Superoxide dismutase (SOD) and malondialdehyde (MDA) levels were detected by colorimetry. In the negative control group, the functional evaluation showed a lower mean intracavernosal pressure (ICP) with cavernosal nerve stimulation than in the sham group; there was a significant change in the expression of cleaved caspase-3, bcl-2, bcl-xl, PECAM-1, and SMA, as well as in the SOD and MDA production in the corpus cavernosum. Histological analysis of specimens stained for NADPH showed a significant change in the staining quality of the neurons in the dorsal nerves; TUNEL showed a greater apoptotic index in corpus cavernosum cells. With daily oral gavage with 100 mg/kg Rg3, the ICP/mean arterial pressure value was significantly higher than in the controls. The level of cleaved caspase-3, bcl-2, bcl-xl, PECAM-1, and SMA and the number of positively stained nerve fibers tended to revert to normal after Rg3 treatment. The apoptotic index in corpus cavernosum cells was lowered. Oral gavage with Rg3 appears to both prevent degeneration of neurons in the dorsal nerves and exert an antioxidant effect in the corpus cavernosum of rats.

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.

Chronic Escitalopram Treatment Induces Erectile Dysfunction by Decreasing Nitric Oxide Bioavailability Mediated by Increased Nicotinamide Adenine Dinucleotide Phosphate Oxidase Activity and Reactive Oxygen Species Production

To investigate the effects of escitalopram, a selective serotonin reuptake inhibitor, on erectile and penile vascular function in the rat. The effect of chronic treatment with escitalopram (0.286 mg/kg/day) on change in intracavernosal pressure, maximum intracavernosal pressure/mean arterial pressure, and area under the intracavernosal pressure curve in response to cavernosal nerve stimulation was measured. The effect of chronic escitalopram treatment on endothelial-dependent relaxant responses was investigated in isolated mesenteric and internal pudendal resistance arteries. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity and nitric oxide synthase levels were determined with enzymatic assay and Western blot, respectively. Chronic treatment with escitalopram resulted in a significant reduction in the erectile response to cavernosal nerve stimulation without an effect on the response to intracavernosal injection of the nitric oxide donor sodium nitroprusside. The decrease in erectile function was associated with marked increases in NADPH oxidase activity in the corpora cavernosa. Treatment with escitalopram also caused a significant reduction in the relaxant response to acetylcholine in isolated internal pudendal and mesenteric resistance arteries without altering the response to sodium nitroprusside. The decreased response to acetylcholine in the isolated vascular segments was associated with a marked increase in NADPH oxidase activity that was corrected by treatment with the NAPDH oxidase inhibitor apocynin. The inhibitory effects of escitalopram on erectile and vascular function were not accompanied by a change in endothelial nitric oxide synthase, neuronal nitric oxide synthase, inducible nitric oxide synthase expression, or endothelial nitric oxide synthase activity, suggesting that the inhibitory effect is caused by a decrease in nitric oxide bioavailability mediated by increased NADPH oxidase and reactive oxygen species production.

Nitric Oxide-Releasing Polymeric Microspheres Improve Diabetes-Related Erectile Dysfunction

We have used a long-acting nitric oxide (NO)-releasing polymer to develop injectable biodegradable microspheres capable of localized NO release over prolonged periods of time. The aim of this study was to evaluate the therapeutic potential of these microspheres for diabetes-related erectile dysfunction (ED) in the rat model. NO-releasing microspheres were incubated in physiologic buffer, and in vitro NO release was measured using a Griess assay. To ensure no migration, microspheres were fluorescently tagged and injected into the corpus cavernosum of adult rats, and fluorescent imaging was performed weekly for 4 weeks, at which point rats were sacrificed. To assess physiologic efficacy, diabetes was induced in 40 rats using streptozotocin (STZ), whereas 10 rats were kept as age-matched controls. Diabetic rats were divided into four groups: no treatment, sildenafil, NO-releasing microspheres, and combination therapy. For each rat, the cavernosal nerve (CN) was stimulated at various voltages, and intracavernosal pressure (ICP) and mean arterial pressure (MAP) were measured via corpus cavernosum and carotid artery catheterization, respectively. Long-term efficacy was determined by injecting diabetic rats with microspheres and measuring erectile response at predetermined intervals for up to 5 weeks. Erectile response was determined via calculation of mean peak ICP/MAP and area under curve (AUC) for each experimental group. Under physiologic conditions in vitro, microspheres continued NO release for up to 4 weeks. Fluorescent imaging revealed no detectable signal in tissues besides cavernosal tissue at 4 weeks postinjection. Upon CN stimulation, peak ICP/MAP ratio and AUC of diabetic rats improved significantly (P < 0.05) in microsphere and combination therapy groups compared with no treatment and sildenafil groups. In long-term efficacy studies, microspheres augmented the effect of sildenafil for 3 weeks following injection (P < 0.05). NO-releasing microspheres significantly improved erectile response in diabetic rats for 3 weeks and hence offer a promising approach to ED therapy, either as monotherapy or combination therapy.

The sGC activator BAY 60-2770 has potent erectile activity in the rat

Nitric oxide (NO) is the principal mediator of penile erection, and soluble guanylate cyclase (sGC) is the receptor for NO. In pathophysiological conditions when sGC is inactivated and not responsive to NO or sGC stimulators a new class of agents called sGC activators increase the activity of NO-insensitive sGC and produce erection. The aim of this study was to investigate erectile responses to BAY 60-2770, a sGC activator, under physiological and pathophysiological conditions. In the present study increases in intracavernosal pressure (ICP) in response to intracavernosal (ic) injections of BAY 60-2770 were investigated under baseline conditions, when sGC was inhibited by 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), when nitric oxide synthase (NOS) was inhibited by N-nitro-L-arginine methyl ester (L-NAME), and after cavernosal nerve crush injury. Under baseline conditions ic injections of BAY 60-2770 increase ICP, ICP/mean arterial pressure (MAP), and area under the ICP curve (AUC) and produce small decreases in MAP at the highest doses studied. BAY 60-2770 was very potent in its ability to induce erection and responses to BAY 60-2770 were enhanced by ODQ which attenuates erectile responses to sodium nitroprusside (SNP), diethylamine NONOate (DEA/NO), and cavernosal nerve stimulation. Responses to BAY 60-2770 were not altered by L-NAME or cavernosal nerve crush injury. These data indicate that BAY 60-2770 has potent erectile activity that is enhanced by ODQ and show that responses to BAY 60-2770 are not attenuated by NOS inhibition or cavernosal nerve injury. These results suggest that BAY 60-2770 would be effective in the treatment of erectile dysfunction when NO bioavailability is reduced, after pelvic nerve injury, and when sGC is oxidized.

Analysis of Erectile Responses to BAY 41-8543 and Muscarinic Receptor Stimulation in the Rat

Soluble guanylate cyclase (sGC) is the receptor for nitric oxide (NO) and in pathophysiologic conditions where NO formation or bioavailability is impaired, erectile dysfunction (ED) occurs. The aim of this study was to investigate erectile responses to the sGC stimulator BAY 41-8543 in physiologic and pathophysiologic conditions. Increases in intracavernosal pressure (ICP) in response to intracavernosal (ic) injections of BAY 41-8543 were investigated in the anesthetized rat. Increases in ICP/MAP in response to ic injections of BAY 41-8543 and the interaction of BAY 41-8543 with exogenous and endogenously released NO were investigated and the effect of the sGC stimulator on cavernosal nerve injury was assessed. The mechanism of the increase in ICP/MAP in response to ic injection of acetylcholine was investigated. The ic injections of BAY 41-8543 increased ICP/MAP and the duration of the response. BAY 41-8543 was less potent than sodium nitroprusside (SNP) and ic injections of BAY 41-8543 and SNP produced a larger response than the algebraic sum of responses to either agent alone. Simultaneous ic injection of BAY 41-8543 and cavernosal nerve stimulation produced a greater response than either intervention alone. Atropine and cavernosal nerve crush injury decreased the response to nerve stimulation and ic injection of BAY 41-8543 restored the response. These data show that BAY 41-8543 has significant erectile activity and can synergize with exogenous and endogenously released NO. This study shows that atropine and nerve crush attenuate the response to cavernosal nerve stimulation and that BAY 41-8543 can restore the response. The results with atropine, L-NAME and hexamethonium indicate that the response to ic injection of acetylcholine is mediated by muscarinic receptors and the release of NO with no significant role for nicotinic receptors. These results suggest that BAY 41-8543 would be useful in the treatment of ED.

The Selective Rho-kinase Inhibitor Azaindole-1 Has Long-lasting Erectile Activity in the Rat

To investigate the effects of the selective Rho-associated protein kinase (ROCK) inhibitor azaindole-1 on erectile function under physiologic and pathophysiologic conditions in the rat. The effect of intracavernosal (i.c.) injections of azaindole-1 on change in intracavernous pressure (ICP), ICP/mean arterial pressure (MAP), area under the curve (AUC), and response duration were investigated in the anesthetized rat under control conditions and when nonadrenergic noncholinergic neurotransmission and cholinergic function or soluble guanylyl cyclase (sGC) were inhibited or after cavernosal nerve crush injury. The i.c. injections of azaindole-1 produced dose-related increases in ICP/MAP and AUC that were long-lasting at the highest doses studied compared with the prototypical ROCK inhibitor fasudil. Erectile responses were not altered by 7-nitroindazole and atropine in doses that reduced the response to cavernosal nerve stimulation by 86%, indicating that they were independent of NO release by cavernosal nerves or activation of muscarinic receptors in the corpora cavernosa. Erectile responses to azaindole-1 were not altered by the sGC inhibitor ODQ in a dose that attenuated responses to the NO donor sodium nitroprusside, indicating that they were independent of an action on sGC. The erectile response to i.c. injections of azaindole-1 or Y-27632, which was reported to be NO/cyclic guanosine monophosphate-dependent, was not attenuated after cavernosal nerve crush injury. The present studies indicate that azaindole-1 has long-lasting erectile activity that is independent of NO release, muscarinic receptor, or sGC activation or the integrity of the cavernosal nerves.

Therapeutic effect of combination of alagebrium (ALT-711) and sildenafil on erectile function in diabetic rats

Recently, the relationship between advanced glycation end products (AGEs) and erectile dysfunction (ED) has been reported. The present study aimed to investigate whether a combination of an AGE cross-link breaker (alagebrium/ALT-711) and sildenafil could enhance the erectile capacity in streptozotocin (STZ) diabetic rats. Additionally, we assessed the effect of that treatment option on some molecules that have been suggested to have crucial roles in AGE-related ED pathways. Four groups of animals were utilized: (1) age-matched control rats, (2) STZ-induced diabetic rats (40 mg kg(-1) i.p.), (3) STZ rats+sildenafil (5 mg kg(-1) p.o.), (4) STZ rats treated with a combination of sildenafil (5 mg kg(-1) p.o)+alagebrium/ALT-711 (10 mg kg(-1) p.o.) for the final 1 month of the 2 months of diabetes period. At 2 months after i.p. injection of STZ, all animals underwent cavernosal nerve stimulation (CNS) to assess erectile function. Penile tissue AGEs, MDA (malondialdehyde), cyclic guanosine monophosphate (cGMP) (ELISA), endothelial nitric oxide (NO) synthase (eNOS), inducible NO synthase (iNOS) (western blot), nuclear factor (NF)-κB, mitogen-activated protein (MAP) kinase (immunohistochemistry) and apoptosis (terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling) analyses were performed in all groups of rats. STZ diabetic rats had a significant decrease in erectile function as determined by the peak intracavernosal pressure (ICP) and total ICP (area under the erectile curve) after CNS when compared with control rats (P<0.05). The increase in both ICP and area under the erectile curve of STZ diabetic rats treated with a combination of sildenafil+alagebrium/ALT-711 as well as in STZ diabetic rats treated with sildenafil alone was significantly greater than STZ diabetic rats. Additionally, combination treatment decreased AGE, MDA, iNOS, NF-κB, MAP kinase and apoptosis levels, whereas it preserved cGMP contents in diabetic penile tissue. Decreased AGE, MDA, iNOS, NF-κB, MAP kinase and increased cGMP levels at the combination (sildenafil+alagebrium/ALT-711) therapy group increased both the peak ICP and total ICP to CNS in the STZ diabetic rats, which was similar to the response observed in control rats. These results may explain the role of AGEs in diabetes-related ED and the effect of an AGE cross-link breaker alagebrium/ALT-711+sildenafil therapy on some critical molecules related to AGE-related ED pathways.

The Effects of Chronic 5‐Alpha‐Reductase Inhibitor (Dutasteride) Treatment on Rat Erectile Function

Numerous clinical series have reported an association between 5-alpha-reductase inhibitors (5ARIs) and sexual dysfunction, but there are limited preclinical data available. To further investigate the mechanisms of erectile dysfunction (ED) related to 5ARI therapy using a rat model. Outcome measures include serum dihydrotestosterone (DHT), relaxant and contractile properties of cavernosal muscle, and nitric oxide synthase expression. Twenty adult male Sprague-Dawley rats were randomized into control (N = 10) and dutasteride (0.5 mg/rat/day, in drinking water, N = 10) groups. Serum samples were obtained at baseline, from which DHT was measured after 30 days of treatment via radioimmunoassay (Beckman Coulter, Fullerton, CA, USA). Before the terminal blood draw, erectile response was measured using cavernosal nerve stimulation. The relaxant and contractile properties of cavernosal muscle strips were evaluated in tissue baths, and immunohistochemical (IHC) staining for nitric oxide synthase (NOS) and collagen deposition was performed. Mean serum DHT was suppressed by 86.5% (range 64.2-94.8%) after 30 days of 5ARI treatment and was statistically significant (P = 0.0024). In vivo erectile response in the dutasteride treated group decreased significantly compared with control (P < 0.001). While electrical field stimulation (EFS)-induced and acetylcholine-induced relaxation was decreased, EFS-induced and phenlyephrine-induced adrenergic contraction was significantly enhanced in the dutasteride group (P < 0.01). IHC studies demonstrated increased collagen deposition in the treatment arm as well as altered expression of neuronal NOS (nNOS) and inducible NOS (iNOS). The 5ARIs, as demonstrated in these rat cavernosal smooth muscle studies, have a detrimental effect on erectile function. Enhanced iNOS expression may protect penile smooth muscle from fibrosis. The effect of 5ARIs on human sexual function warrants further investigation.

764 EFFECT OF THE ETHANOL ON THE ERECTILE FUNCTION IN THE RAT

You have accessJournal of UrologySexual Function/Dysfunction/Andrology: Basic Research1 Apr 2011764 EFFECT OF THE ETHANOL ON THE ERECTILE FUNCTION IN THE RAT Sung Chul Kam, Jeong Seok Hwa, and Jae Seog Hyun Sung Chul KamSung Chul Kam Jinju, Korea, Republic of More articles by this author , Jeong Seok HwaJeong Seok Hwa Jinju, Korea, Republic of More articles by this author , and Jae Seog HyunJae Seog Hyun Jinju, Korea, Republic of More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2011.02.1789AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Alcohol consumption is associated with the erectile function. However, the effect of ethanol (ETOH) on penile tissue is not fully understood. We investigated the acute and chronic effects of ETOH on corporal tissue in the rat. METHODS To examine the acute effect of ETOH, the rats were divided into a control group and four experimental groups (1 hour, 2 hours, 4 hours and 6 hours after injected the ETOH). The intracavernosal pressure/ blood pressure (ICP/BP) response to cavernosal nerve stimulation was assessed after intraperitoneal injection of normal saline in control group and ETOH (15%, 3g/Kg) in the experimental groups. Each the control group and experimental group (the highest ICP/BP), the concentration of released cGMP and cAMP were measured. To examine the chronic effect of ETOH, the rats were divided into a control group (oral intake normal saline, 3g/Kg, 4 weeks) and experimental groups (oral intake 15% ETOH, 3g/kg, 4 weeks). The ICP/BP response to cavernosal nerve stimulation was assessed. And the concentration of released cGMP and cAMP were measured. RESULTS In acute ETOH study, the percentage of ICP/BP of the normal control group was 71.6±4.8 (N=7), the four experimental groups (1 hour, 2 hours, 4 hours and 6 hours after injected the ETOH) were 79.3±8.3 (N=7), 86.6±7.6 (N=7), 74.6±7.3 (N=7), 75.1±5.2 (N=7). The percentage of ICP/BP of experimental group (2 hours) only was statistically higher than the control group (P<0.05). The concentration of cAMP of experimental group (2 hours) was statistically higher than the control group (control group N=6, 4.56±1.14 pmol/ml Vs. 2 hours 13.30±4.92 pmol/ml) (P<0.05). In chronic ETOH study, the percentage of ICP/BP of the normal control group was 84.0±4.0 (N=6), the experimental group was 88.5±6.5 (N=6) (P>0.05). The concentration of cAMP and cGMP were not statistically higher than the control group (P>0.05). CONCLUSIONS Acute effect of ETOH was improved the percentage of ICP/BP, and increased cAMP concentration in the corpus cavernosum of the rat. It can be one of the mechanisms for erectile function after alcohol drinking. © 2011 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 185Issue 4SApril 2011Page: e307 Advertisement Copyright & Permissions© 2011 by American Urological Association Education and Research, Inc.MetricsAuthor Information Sung Chul Kam Jinju, Korea, Republic of More articles by this author Jeong Seok Hwa Jinju, Korea, Republic of More articles by this author Jae Seog Hyun Jinju, Korea, Republic of More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

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

Diabetes 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. Goto-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. Wistar 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. GK diabetic rats display ED associated with decreased cavernosal expression of eNOS protein. GK 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. Although 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.

A Protein Tyrosine Kinase Inhibitor, Imatinib Mesylate (Gleevec), Improves Erectile and Vascular Function Secondary to a Reduction of Hyperglycemia in Diabetic Rats

Erectile dysfunction (ED) afflicts 50% of diabetic men, many of whom experience poor results with phosphodiesterase type 5 inhibitors. The protein tyrosine kinase (PTK) inhibitor imatinib (Gleevec, Novartis Pharmaceuticals, Basel, Switzerland) has therapeutic potential in diabetic men by maintaining β-cell function. To determine if imatinib has a beneficial effect on erectile and vascular function in diabetic rats. Male Sprague-Dawley rats were divided into six groups: (i) control; (ii) imatinib (50mg/kg, daily gavage)-treated control; (iii) diabetic; (iv) preventive imatinib (8 weeks); (v) reversal imatinib (4 weeks untreated diabetes and 4 weeks of treatment); and (vi) insulin (8 weeks)-treated diabetic rats. After 8 weeks, all groups underwent cavernosal nerve stimulation and measurements of intracavernosal pressure (ICP) and mean arterial pressure (MAP). Contractile and relaxation responses were evaluated using isolated strips of corpus cavernosum smooth muscle (CCSM) and aorta. Diabetic rats exhibited a 32% decrease in weight and fivefold increase in blood glucose levels. Imatinib-treated diabetic rats gained weight and partially improved blood glucose levels. Diabetic rats displayed a decrease in ICP/MAP. While maximum electrical field stimulation- and acetylcholine (ACh)-induced relaxations in CCSM strips from the diabetics were reduced, preventive imatinib or insulin treatment normalized ICP/MAP ratios and improved relaxation responses. ACh responses in diabetic aortas were diminished by 50.1% and restored by imatinib. While contractile responses to phenylephrine in diabetic CCSM were not altered, there was a significant enhancement (59.4 %) in the aortic contractile response in diabetic rats, which was restored by imatinib and insulin treatment. In diabetic rats, prolonged therapy with imatinib improves diabetes-related ED and vascular function, which may involve normalization of high glucose levels and restoration of PTK activation. Future studies are needed to elaborate on the actions of imatinib on diabetic vascular complications.