Response Of Corpus Cavernosum Research Articles

MP45-05 ACTIVATION OF NRF2 IMPROVES ENDOTHELIAL FUNCTION IN CORPUS CAVERNOSUM FROM AGED RATS AND IN CORPUS CAVERNOSUM AND PENILE ARTERIES FROM ED PATIENTS

You have accessJournal of UrologySexual Function/Dysfunction: Basic Research & Pathophysiology I1 Apr 2017MP45-05 ACTIVATION OF NRF2 IMPROVES ENDOTHELIAL FUNCTION IN CORPUS CAVERNOSUM FROM AGED RATS AND IN CORPUS CAVERNOSUM AND PENILE ARTERIES FROM ED PATIENTS Juan Ignacio Martínez-Salamanca, Mariam El Assar, Argentina Fernández, Alberto Sánchez-Ferrer, Agustín Fraile, Leocadio Rodríguez-Mañas, Joaquín Carballido, and Javier Angulo Juan Ignacio Martínez-SalamancaJuan Ignacio Martínez-Salamanca More articles by this author , Mariam El AssarMariam El Assar More articles by this author , Argentina FernándezArgentina Fernández More articles by this author , Alberto Sánchez-FerrerAlberto Sánchez-Ferrer More articles by this author , Agustín FraileAgustín Fraile More articles by this author , Leocadio Rodríguez-MañasLeocadio Rodríguez-Mañas More articles by this author , Joaquín CarballidoJoaquín Carballido More articles by this author , and Javier AnguloJavier Angulo More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2017.02.1423AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Adequate antioxidant response is essential for tissue homeostasis and function. However, systems responsible for antioxidant response are down-regulated in some pathological situations and aging. This is the case for Nrf2 that orchestrates cellular response to oxidative stress. The aim was to evaluate pharmacological activation of Nrf2 on the impairment of endothelial relaxation and reactive oxygen species-induced responses in corpus cavernosum (CC) from aged rats and in CC and penile arteries from patients with erectile dysfunction (ED). METHODS Endothelium-dependent relaxations to carbachol and responses to H2O2 were evaluated in CC from 3-months (young) and 20-months (aged) old rats in the absence or the presence of the Nrf2-activators, sulforaphane (10 microM) and oltipraz (30 microM). Upregulation of Nrf2 was assessed by ELISA. The effects of these Nrf2-activators were also evaluated on endothelial relaxation and H2O2-induced responses in human corpus cavernosum (HCC) and penile resistance arteries (HPRA) obtained from patients undergoing penile prosthesis implantation. RESULTS Aged rats CC displayed ED and impaired endothelium-dependent and H2O2-induced relaxation. Ex vivo exposure to either sulforaphane or oltipraz improved endothelial and H2O2-induced relaxation of CC from aged rats. HCC and HPRA were obtained from 19 patients (age: 60.7+/-2.0 years, hypertension: 8, dyslipidemia: 7, diabetes: 6, CVD: 4, obesity: 2). Treatment with sulforaphane improved endothelium-dependent (pD2 for acetylcholine: 5.18+/-0.28 vs 6.34+/-0.37∗) as well as neurogenic relaxation (Emax: 45.7+/-6.4% vs 60.9+/-3.0%∗) in HCC. Sulforaphane also improved endothelial (pD2 for acetylcholine: 5.82+/-0.38 vs 7.21+/-0.32∗) and H2O2-induced vasodilation in HPRA (pD2 for H2O2: 4.13+/-0.13 vs 5.07+/-0.17∗). Positive effects of Nrf2-activation were confirmed by the improvement of endothelial vasodilation driven by oltipraz in HPRA. CONCLUSIONS Pharmacological activation of Nrf2 improves cavernosal function in aged animals with ED. These effects were confirmed in human tissue, including penile arteries, from patients with ED, suggesting that Nrf2 activation could be a reasonable target for the management of ED. © 2017FiguresReferencesRelatedDetails Volume 197Issue 4SApril 2017Page: e613 Advertisement Copyright & Permissions© 2017MetricsAuthor Information Juan Ignacio Martínez-Salamanca More articles by this author Mariam El Assar More articles by this author Argentina Fernández More articles by this author Alberto Sánchez-Ferrer More articles by this author Agustín Fraile More articles by this author Leocadio Rodríguez-Mañas More articles by this author Joaquín Carballido More articles by this author Javier Angulo More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Ginsenoside Re Enriched Fraction (GS-F3K1) from Ginseng Berries Ameliorates Ethanol-Induced Erectile DysfunctionviaNitric Oxide-cGMP Pathway

Erectile dysfunction (ED) is a highly prevalent disorder that affects millions of men and considered to be an early symptom of atherosclerosis and a precursor of various systemic vascular disorders. The aim of the present study was to prepare ginsenoside Re enriched fraction (GS-F3K1, ginsenoside Re 10%, w/w) from ginseng berries flesh and to investigate the enhanced activities of GS-F3K1 on alcohol-induced ED. GS-F3K1 was prepared by the continuous liquid and solid separating centrifugation and circulatory ultrafiltration from ginseng berries flesh. GS-F3K1 was administered for 5 weeks in ethanol-induced ED rat by oral administration of 20% ethanol. To investigate the effects of GS-F3K1 on ED model, the levels of nitrite expression, cyclic guanosine monophosphate (cGMP) and erectile response of the penile corpus cavernosum of rat were measured. The erectile response of the corpus cavernosum was restored after GS-F3K1 administration, to a level similar to the normal group. The level of nitrite and cGMP expression in the corpus cavernosum of GS-F3K1-administered male rats was increased significantly compared to positive control group. GS-F3K1 from ginseng berries should effectively restore ethanol-induced ED in male rats and could be developed as a new functional food for the elderly men.

Lipopolysaccharide increases agonist‐induced contractile responses in Sprague Dawley rat corpus cavernosum

Chronic inflammatory conditions are frequent co‐morbidities of erectile dysfunction (ED) and elevated lipopolysaccharide (LPS) levels may increase inflammation via Toll‐like receptor 4 (TLR4) activation. An imbalance between vascular dilatation and contraction underlies ED. We hypothesized that LPS increases the agonist‐induced contractile response in corpus cavernosum (CC). The CC tissues were isolated, incubated for 6 hours in tissue culture media with 1 ug/mL LPS or vehicle, before being mounted in a muscle strip myograph for studies of isometric force generation. Contraction to 120 mM KCl did not differ between LPS and vehicle treated CC. KCl‐induced contraction data were used to normalize contraction data from the serotonin concentration response curve (30 nM‐100 uM). The CC tissue exposed to LPS exhibited enhanced contraction to serotonin (as % of KCl contraction) compared to control values. At 30 uM concentration: 67.34±5.15 vs. 43.34±6.67% (p<0.05), and at 100 uM: 77.61±5.4 vs. 56.61±6.98% (p<0.05). These results show that treatment with the TLR4 ligand LPS increased the contractile response to serotonin in rat corpus cavernosum. Thus, TLR4 activation may play a role in the etiology of ED which is a condition that has been shown to predict cardiovascular disease.Support: NIH and SMSNA.

Enhancement effects of nicotine on neurogenic relaxation responses in the corpus cavernosum in rabbits: The role of nicotinic acetylcholine receptor subtypes

Nicotine acts as an agonist of nicotinic acetylcholine receptors, which belong to a superfamily of neurotransmitter-gated ion channels. We previously demonstrated that nicotine increases the electrical field stimulation (EFS)-evoked nitrergic relaxation responses via activation of nicotinic acetylcholine receptors. The aim of the present study is to investigate the subtypes of nicotinic acetylcholine receptors in rabbit corpus cavernosum. EFS-evoked relaxation responses were recorded from corpus cavernosum strips obtained from rabbits with an isometric force displacement transducers. Effects of nicotine on EFS-evoked relaxations were examined in pre-contracted tissues. Then the effect of nicotine on the EFS-evoked relaxations was examined in the presence of hexamethonium, dihydro-β-erythroidine, mecamylamine or α-bungarotoxin. In our study, nicotine (3 × 10 − 5 , 10 − 4 ) transiently increased nitrergic relaxations induced by EFS in the rabbit isolated corpus cavernosum. While hexamethonium and mecamylamine near totally inhibited or abolished the neurorelaxation response to nicotine (3 × 10 − 5 ) on EFS, dihydro-β-erythroidine and α-bungarotoxin partially inhibited these responses. These findings demonstrated that the alpha3–beta4, alpha4–beta2 and alpha7 subunits of nicotinic acetylcholine receptors play role on the nicotine-induced augmentation in EFS-evoked relaxation responses in rabbit corpus cavernosum.

S3.4 Impaired corpus cavernosum responses to cavernous nerve stimulation in diabetic rats: Effects of treatment with erythropoietin-delta

S3.4 Impaired corpus cavernosum responses to cavernous nerve stimulation in diabetic rats: Effects of treatment with erythropoietin-delta

Improvement in relaxation response in corpus cavernosum from trained rats

Objectives To evaluate the contractile and relaxing responses in rat corpus cavernosum (RCC) from rats after 8 weeks of run training, because erectile function is highly dependent on nitric oxide (NO) from nitrergic fibers or endothelium. Physical activity enhances NO production and improves endothelial function, with beneficial effects on cardiovascular disease. Methods The training program consisted of 8 weeks of run training, 5 days/wk, and each session lasted 60 minutes. The RCC was isolated, and concentration-response curves to NO, acetylcholine, sodium nitroprusside, phenylephrine, and endothelin were obtained. The excitatory and inhibitory effects of electrical field stimulation (2 to 32 Hz) were also evaluated. Results NO (0.1 to 100 μM) and sodium nitroprusside (0.01 to 1000 μM) produced a relaxing effect in RCC in a dose-dependent manner, with the maximal responses to NO (control 62% ± 4%, trained 88% ± 3%) and sodium nitroprusside (control 83% ± 3%, trained 95% ± 2%) significantly enhanced after 8 weeks of run training. However, acetylcholine-induced relaxations were not affected by exercise. Similarly, electrical field stimulation-induced relaxations were significantly increased in RCC from trained rats at 2 Hz (control 2.4% ± 0.3%, trained 4.2% ± 0.5%) and 4 Hz (control 5.3% ± 1.2%, trained 12.5% ± 1.7%). The contractile sensitivity of RCC to phenylephrine (0.01 to 100 μM) and endothelin (0.01 to 100 nM) was not modified by training exercise. Conclusions Our findings suggest that run training enhances functional responses in rat RCC that involves increases in the NO-cyclic guanosine monophosphate signaling pathway by endothelium-independent mechanisms that is not accompanied by changes in contractile sensitivity.

Relaxation effects of adrenomedullin in isolated rabbit corpus cavernosum smooth muscle.

To clarify the pharmacological effects of adrenomedullin, a potent vasodilator and hypotensive peptide isolated from human phaeochromocytoma cells, on corpus cavernosal smooth muscle in vitro, as the intracavernosal injection of adrenomedullin induces penile erection in the anaesthetized cat. The effects of adrenomedullin were investigated in isolated muscle strips from New Zealand rabbit corpus cavernosum smooth muscle pre-contracted with phenylephrine alone, in the presence of indomethacin (cyclooxygenase inhibitor), Nomega-nitro l-arginine methyl ester (L-NAME, a nitric oxide synthase inhibitor), and K+-channel blockers. Adrenomedullin caused relaxation of isolated pre-contracted rabbit corpus cavernosum strips in a concentration-dependent manner. The response of corpus cavernosum was unaffected L-NAME, indomethacin and K+-channel blockers. The relaxation exerted by adrenomedullin in rabbit corporal tissue may arise from the effect of the drug on its specific receptors and/or calcitonin gene-related peptide-1 receptors. The relaxant effect of adrenomedullin might lead to novel clinical applications for erectile dysfunction.

Corpus cavernosum dysfunction in diabetic rats: effects of combined alpha-lipoic acid and gamma-linolenic acid treatment.

The effects of streptozotocin-induced diabetes on nitric oxide (NO)-mediated relaxation of rat corpus cavernosum smooth muscle to neurogenic and endothelial stimulation was examined. The aim was to assess the effects of treatment with low doses of the antioxidant, alpha-lipoic acid, and the omega-6 essential fatty acid, gamma-linolenic acid, either separately or in combination. Treatment was preventive from diabetes induction or corrective over 4 weeks after 4 weeks of untreated diabetes. Corpus cavernosum responses were examined in vitro. Neither diabetes nor treatment affected contractile responses to transmural electrical field stimulation of noradrenergic nerves. Stimulation of phenylephrine precontracted cavernosa in the presence of guanethidine and atropine caused relaxation via the nitrergic innervation. Maximum relaxation responses were 40% and 46% decreased after 4 and 8 weeks of diabetes, respectively. alpha-Lipoic acid, gamma-linolenic acid combination treatment fully prevented this deficit, and partially (52%) corrected the effect of 4 weeks of untreated diabetes. Neither alpha-lipoic acid nor gamma-linolenic components alone had significant effects, which suggests that there were synergistic interactions between the drugs. Both 4 and 8 weeks of untreated diabetes reduced maximum endothelium-dependent relaxation of phenylephrine precontracted cavernosa to acetylcholine by approximately 40%. While alpha-lipoic acid or gamma-linolenic acid were ineffective, joint treatment fully prevented and corrected this diabetic endothelial deficit. Neither diabetes nor treatment affected endothelium-independent relaxation to the NO donor, sodium nitroprusside. The data show that alpha-lipoic acid and gamma-linolenic acid interact synergistically to improve NO-mediated neurogenic and endothelium-dependent relaxation of corpus cavernosum in experimental diabetes.

Pelvic nerve stimulation-induced pressor responses in corpus cavernosum of anesthetized dogs.

To analyze the mechanism of penile erection and pathogenesis of impotence, pressures in the corpus cavernosum in anesthetized dogs were measured. Pelvic nerve stimulation produced pressor responses in a frequency-dependent manner. Intravenous injections of NG-nitro-L-arginine, a nitric oxide (NO) synthase inhibitor, dose dependently attenuated the response, and the inhibition was reversed by intravenous injection of L-arginine but not of D-arginine. The response was also inhibited by NG-nitro-L-arginine injected into the corpus cavernosum, the potency being approximately 10 times of that applied intravenously. The intracavernous injection of L-arginine restored the response. NG, NG-dimethylarginine, an endogenous NO synthase inhibitor, dose dependently attenuated the stimulation-induced response, which was restored by an intracavernous injection of L-arginine. An intravenous injection of hexamethonium abolished the pressor response to nerve stimulation, whereas phentolamine and atropine did not significantly alter the response. These findings suggest that an increase in intracavernous pressure caused by pelvic nerve stimulation in anesthetized dogs is mediated by NO liberated from postganglionic neurons that originate in the ganglion located in the vicinity of corpus cavernosum.

Chronic treatment with cyclosporine A in New Zealand rabbit: aortic and erectile tissue alterations.

Transplanted patients frequently present erectile impotence. In order to test any interference by cyclosporine A (CsA), which is commonly used in the post-transplantation management, we investigated the in vitro contractile and relaxant responses of corpus cavernosum and aorta from rabbits chronically treated with CsA. Male New Zealand White rabbits 6 months of age were treated with CsA (25 mg/kg per day s.c.) or solvent (corn oil) for 3 weeks. Descending thoracic aorta and erectile tissue were studied in vitro at the end of treatment. Isometric tension was recorded. In thoracic aorta, noradrenaline (0.1-30 mM) induced a concentration-dependent contraction with no difference between the two groups. Acetylcholine (30 nM-3 mM) produced relaxation (52 +/- 4% at 1 mM) that was significantly reduced in comparison to controls (67 +/- 4%, P < 0.05). ATP (3-10 mM) relaxation was not significantly different (maximal 78 +/- 10% and 62 +/- 12% in CsA-treated and controls). The relaxation produced by sodium nitrite was reduced in CsA-treated rabbits (at 10 mM and 0.1 mM concentrations). In erectile tissue, no significant variation in the response of isolated erectile tissue to the above drugs was observed between CsA-treated and control animals. These data indicate that chronic treatment with CsA in rabbits, despite alteration of the in vitro response of thoracic aorta, does not directly influence the function of penile tissue with relaxants.