Relaxation Of Corpus Cavernosum Smooth Muscle Research Articles

6-Nitrodopamine is an endogenous mediator of the rabbit corpus cavernosum relaxation.

6-Nitrodopamine (6-ND) is a novel endogenous catecholamine that has a potent relaxant action on vascular smooth muscle in vitro. To evaluate the basal release of 6-ND and noradrenaline from rabbit-isolated corpus cavernosum (RbCC) and its relaxing action on this tissue. Rabbit corpus cavernosa were dissected and suspended in a 5-mL organ bath containing oxygenated Krebs-Henseleit's solution. 6-ND and noradrenaline release was quantified by liquid chromatography coupled to tandem mass spectrometry. The relaxant activity of 6-ND was assessed in RbCC strips pre-contracted with endothelin-1 (10nM). Rabbit corpus cavernosum presented basal release of both 6-ND (2.9±0.8ng/mL, n=12) and noradrenaline (1.7±1.3ng/mL, n=12). The 6-ND release was reduced by pre-treatment with Nω-nitro-l-arginine methyl ester (l-NAME) (100 µM), whereas that of noradrenaline was unaffected. Tetrodotoxin (TTX, 1 µM) abolished the noradrenaline release but had no effect on 6-ND release, indicating a non-neurogenic origin for 6-ND. 6-ND and the selective dopamine D2-agonist L-741,626 caused concentration-dependent RbCC relaxations (pEC50 of 11±0.15 and 11.15±0.28, respectively). Pre-treatment with either l-NAME or the soluble guanylate cyclase inhibitor 1H-[1,2,4] oxadiazolo[4,3-a]quinoxalin-1-on (ODQ) (100 µM) caused a rightward shift of the concentration-response curve to 6-ND, without affecting the L-741,626 responses. In TTX (100nM)-pre-treated preparations, neither l-NAME nor ODQ shifted the 6-ND concentration-response curve. Dopamine, noradrenaline, and adrenaline caused concentration-dependent RbCC contractions. Pre-incubation with 6-ND concentration-dependently inhibited the dopamine-induced contractions, without affecting those induced by either noradrenaline or adrenaline. 6-Nitrodopamine is the most potent endogenous relaxant agent in RbCC ever described and represents a novel mechanism by which NO causes corpus cavernosum smooth muscle relaxation. The finding that 6-ND acts as a truly selective dopamine D2-receptor antagonist indicates that the balance of dopamine and 6-ND release/synthesis may be the main mechanism that modulates corpus cavernosum smooth muscle tonus in vivo.

Intravascular hemolysis leads to exaggerated corpus cavernosum relaxation: Implication for priapism in sickle cell disease

Patients with sickle cell disease (SCD) display priapism. Clinical studies have shown a strong positive correlation between priapism and high levels of intravascular hemolysis in men with SCD. However, there are no experimental studies that show that intravascular hemolysis promotes alterations in erectile function. Therefore, we aimed to evaluate the corpus cavernosum smooth muscle relaxant function in a murine model that displays intravascular hemolysis induced by phenylhydrazine (PHZ), as well as the role of intravascular hemolysis in increasing the stress oxidative in the penis. Corpus cavernosum strips were dissected free and placed in organ baths. Acetylcholine and electrical field stimulation (EFS)-induced corpus cavernosum relaxations in vitro were obtained. Increased corpus cavernosum relaxant responses to acetylcholine and EFS were observed in the PHZ group. Protein expression of heme oxygenase-1 increased in the corpus cavernosum of the PHZ group, but PDE5 protein expression was not modified. Preincubation with the heme oxygenase inhibitor 1J completely reversed the increased relaxant responses to acetylcholine and EFS in PHZ mice. Protein expression of NADPH oxidase subunit gp91phox, 3-nitrotyrosine, and 4-hydroxynonenal increased in the corpus cavernosum of the PHZ group, suggesting a state of oxidative stress. Basal cGMP production was lower in the PHZ group. Our results show that intravascular hemolysis promotes increased corpus cavernosum smooth muscle relaxation associated with increased HO-1 expression, as well as increased oxidative stress associated with upregulation of gp91phox expression. Moreover, our study supports clinical studies that point to a strong positive correlation between priapism and high levels of intravascular hemolysis in men with SCD.

Galanin Administration Partially Restores Erectile Function After Cavernous Nerve Injury and Mediates Endogenous Nitrergic Nerve Outgrowth In Vitro

BackgroundPreviously, we found that the neuropeptide galanin was strongly upregulated soon after bilateral cavernous nerve injury (BCNI) and that galanin and its receptors were expressed in nitrergic erectile innervation. Galanin has been observed to exert neuroregenerative effects in dorsal root ganglion neurons, but evidence for these effects in the major pelvic ganglion (MPG) after BCNI is lacking. AimTo evaluate the neurotropic effects of galanin receptor agonists and antagonists in vitro in nitrergic neurons and MPG and in vivo in rats after BCNI. MethodsMale Sprague-Dawley rats underwent BCNI and sham surgery. Organ culture and single-cell neuron culture of the MPG were performed. Osmotic pump treatment with the galanin agonist in vivo and measurement of erectile response to electrostimulation after BCNI, immunohistochemical localization of galanin and receptors in the human neurovascular bundle, and myographic analysis of rat corpus cavernosum smooth muscle relaxation to galanin receptor agonists were investigated. OutcomesNeurite outgrowth in vitro and erectile response to electrostimulation after BCNI in vivo, immunohistochemical localization of galanin and receptors, and penile muscle relaxation in vitro. ResultsGalanin showed neurotrophic action in vitro and inhibition of endogenous galanin significantly impaired neurite outgrowth in nitrergic but not in sympathetic MPG neurons. In vivo administration of a selective galanin receptor-2 agonist, M1145, resulted in partial recovery of erectile function (EF) after BCNI. Galanin did not act as a direct vasodilator on corpus cavernosum muscle strips. Clinical TranslationEndogenous neurotrophins such as galanin could be used as a strategy to improve EF for patients after BCNI from radical prostatectomy. Strengths and LimitationsWe evaluated the effect of galanin on nerve regeneration and EF recovery in vivo and in vitro. Limitations include the lack of washout period for the in vivo experiment and absence of differences in the expression of neuronal markers between treatment groups. ConclusionsWe identified galanin as a potential endogenous mechanism for nerve regeneration after BCNI, which could play a physiologic role in EF recovery after radical prostatectomy. In vivo treatment with exogenous galanin was beneficial in enhancing EF recovery after BCNI, but further research is necessary to understand the underlying mechanisms.Weyne E, Hannan JL, Gevaert T, et al. Galanin Administration Partially Restores Erectile Function After Cavernous Nerve Injury and Mediates Endogenous Nitrergic Nerve Outgrowth In Vitro. J Sex Med 2018;15:480–491.

In vitro and in vivo aphrodisiac properties of the seed extract from Allium tuberosum on corpus cavernosum smooth muscle relaxation and sexual behavior parameters in male Wistar rats

BackgroundAllium tuberosum is a well-known spice as well as a herb in traditional Chinese medicine, used for increasing libido and treating erectile dysfunction. However, not many studies have been done to evaluate the sexual enhancing properties of A. tuberosum. The aim of this study was to evaluate the aphrodisiac and vasorelaxant properties of A. tuberosum on corpus cavernosum smooth muscle (CCSM) as well as checking the effect on enhancing male rat sexual behavior, libido, potency as well as its spermatogenic properties.MethodThe seeds were powdered and sequentially extracted with hexane, ethyl acetate and butanol. Male Wistar rats were administered with graded doses of the n-BuOH extracts (ATB) of A. tuberosum (50, 100, 200 and 400 mg/kg) and Viagra was used as the positive control drug. The extract/drug was administered by gastric probe once daily for 45 days and the sexual behavior was analyzed by exposing the male rats to female rats in the estrus period.ResultsATB relaxed corpus cavernosum smooth muscle (68.9%) at a concentration of 200 μg/ml. The results obtained from the animal studies indicated that ATB significantly increased mount frequency (MF), intromission frequency (IF), ejaculation frequency (EF), ejaculation latency (EL) and markedly reduced post ejaculatory interval (PEI), mount latency (ML), and intromission latency (IL). Furthermore, a remarkable increase in the test for potency was observed as witnessed by marked increase in erections, quick flips, long flips and total reflex. In addition, ATB significantly improved the sperm viability and count as well as increased the concentrations of testosterone, follicle stimulating hormone (FSH), and phosphatases in the treated animals.ConclusionThus our results suggest that A. tuberosum could stimulate sexual arousal and enhance sexual execution in male rats, thus providing valuable experimental evidence that A. tuberosum possesses sexual enhancing properties.

Light-controlled relaxation of the rat penile corpus cavernosum using NOBL-1, a novel nitric oxide releaser.

PurposeTo investigate whether relaxation of the rat penile corpus cavernosum could be controlled with NOBL-1, a novel, light-controllable nitric oxide (NO) releaser.Materials and MethodsFifteen-week-old male Wistar-ST rats were used. The penile corpus cavernosum was prepared and used in an isometric tension study. After noradrenaline (10-5 M) achieved precontraction, the penile corpus cavernosum was irradiated by light (470–500 nm) with and without NOBL-1 (10-6 M). In addition, we noted rats' responses to light with vardenafil (10-6 M), a phosphodiesterase-5 (PDE-5) inhibitor. Next, responses to light in the presence of a guanylate cyclase inhibitor, ODQ (1H-[1,2,4] oxadiazolo[4,3-a]quinoxalin-1-one) (10-5 M), were measured. All measurements were performed in pretreated L-NAME (10-4 M) conditions to inhibit endogenous NO production.ResultsCorpus cavernosal smooth muscle, precontracted with noradrenaline, was unchanged by light irradiation in the absence of NOBL-1. However, in the presence of NOBL-1, corpus cavernosal smooth muscle, precontracted with noradrenaline, relaxed in response to light irradiation. After blue light irradiation ceased, tension returned. In addition, the light response was obviously enhanced in the presence of a PDE-5 inhibitor.ConclusionsThis study showed that rat corpus cavernosal smooth muscle relaxation can be light-controlled using NOBL-1, a novel, light sensitive NO releaser. Though further in vivo studies are needed to investigate possible usefulness, NOBL-1 may be prove to be a useful tool for erectile dysfunction therapy, specifically in the field of penile rehabilitation.

Effects of insulin-like growth factor-1 on the relaxation responses of the cavernous smooth muscle from aged rats

Objective. The aim of this study was determine whether intracavernosal injection (ICI) of insulin-like growth factor-1 (IGF-1) protein can improve corpus cavernosal smooth muscle relaxation in aging rats. Materials and methods. Ten young (4-month-old) and 30 old (24-month-old) Sprague–Dawley male rats were enrolled in the study. The old rats were divided into three groups: vehicle-only (n = 10), IGF-1 1 µg/kg (n = 10) and IGF-1 10 µg/kg treatment groups (n = 10). After 4 weeks of single IGF-1 injection treatment, strips of corporal tissue were precontracted with phenylephrine, and dose–response curves were generated to evaluate endothelial-dependent [acetylcholine (ACh)], endothelial-independent [sodium nitroprusside (SNP)] and electrical field stimulation (EFS) vasoreactivity. The changes in percentage of cavernosal smooth muscle and the concentration of nitric oxide (NO) in penile tissue were also evaluated. Results. After IGF-1 treatment, the vasoreactivity was significantly improved in both the 1 µg/kg and the 10 µg/kg treatment groups compared with the vehicle-only group at 4 weeks in response to ACh, SNP and EFS (all p < 0.05). The percentage of cavernosal smooth muscle was increased in the IGF-1 treatment groups. The NO concentrations were increased after IGF-1 treatment. Conclusions. These data demonstrate that ICI of IGF-1 can improve vasoreactivity via endothelium-dependent and endothelial-independent mechanisms in the corpus cavernosum of the aging rat.

Long-term testosterone supplementation is useful for ED with testosterone deficiency

Long-term testosterone supplementation is useful for ED with testosterone deficiency

Angiotensin II Increases Corpus Cavernosal Contractility and Oxidative Stress in Partial Bladder Outlet Obstructed Rabbits: Relevance to Erectile Dysfunction

We investigated the effect angiotensin II (Ang II), a corpus cavernosal smooth muscle (CCSM) constrictor peptide, has on tissue taken from rabbits following chronic partial bladder outlet obstruction (PBOO), as this model is characterized by an increase in corpus cavernosal collagen deposition and a marked reduction and impaired relaxation of CCSM cells. To determine the interaction between Ang II and nitric oxide (NO) and the development of oxidative stress (OS) in a rabbit model of chronic PBOO. Corpus cavernosal tissue was obtained from 12 sham-operated and 20 PBOO rabbits. Organ bath studies determined Ang II/NO interaction on CCSM function using losartan (AT1 receptor antagonist), sodium nitroprusside (SNP, NO donor), electrical field stimulation (EFS), and vardenafil (phosphodiesterase type 5 inhibitor). The role of OS in the Ang II response was also determined using diphenylene iodonium chloride (DPI), the nicotinamide adenine dinucleotide phosphate oxidase inhibitor, which inhibits superoxide production and superoxide dismutase (SOD, the enzyme that accelerates the breakdown of superoxide). Action of Ang II and AT1 receptor antagonist, as well as SOD and DPI on CCSM function. Ang II caused a dose-dependent contraction of CCSM strips that was enhanced in PBOO rabbits and inhibited by losartan, DPI, and SOD. CCSM relaxation induced by SNP/EFS was impaired in this model and improved by vardenafil and losartan. These findings imply that the increased Ang II contractile response is a pathological consequence of PBOO and that AT1 receptor inhibition may be a therapeutic approach to treat ED associated with PBOO.

In vitro and in vivo aphrodisiac properties of Corchorus depressus Linn. on rabbit corpus cavernosum smooth muscle relaxation and sexual behavior of normal male rats

Ethnopharmacological relevanceCorchorus depressus Linn. has been used as an aphrodisiac in traditional Indian medicine to treat male sexual dysfunction and impotency. Aim of the studyThe petroleum ether, chloroform, ethyl acetate, n-butanol and aqueous fractions of 95% methanol extract of Corchorus depressus were screened initially for their in vitro aphrodisiac activity on rabbit corpus cavernosum smooth muscle. The chloroform fraction (CDC) was found to be the most active and therefore investigated further on general mating behavior, libido and potency of normal male Wistar albino rats in comparison with the standard drug, Sildenafil citrate. Materials and methodsAnimals were divided into the following groups: Control, SC CDC 100, CDC 200, and CDC 400, who received saline, Sildenafil citrate or the chloroform fraction of Corchorus depressus at doses of 100, 200 or 400mg/kg b.wt., respectively. The route of administration for all the groups was oral dosing, which was once in a day for 45 days. To analyze the mating behavior, female rats with estrus phase were used. ResultsThe chloroform fraction of methanolic extract of Corchorus depressus significantly reduced ML, IL, PEI and III. There was a significant increase in the MF, IF and EL and serum testosterone levels throughout the study period. The potency test significantly increased erections, quick flips, long flips and total reflex. In vitro aphrodisiac activity was significantly higher in chloroform fraction at a concentration of 25.0mg/ml, which induced 71.4% relaxation. The combined results of the above mentioned models indicate that the chloroform fraction of Corchorus depressus produces a significant increase in sexual activity as exhibited by 25mg/ml in vitro and 400mg/kg in vivo. In comparison with the control, all the drug-treated groups have shown drug-induced effects for a few parameters. ConclusionsIn vitro and in vivo studies provide valuable experimental evidence that the chloroform fraction of methanolic extract of Corchorus depressus possesses aphrodisiac property. This study further substantiates the ethnopharmacological claims of Corchorus depressus as a sexual stimulating agent and offers a significant potential for studying the effect on male sexual response and its dysfunctions.

Bladder outlet obstruction triggers neural plasticity in sensory pathways and contributes to impaired sensitivity in erectile dysfunction

Lower urinary tract symptoms (LUTS) and erectile dysfunction (ED) are common problems in aging males worldwide. The objective of this work was to evaluate the effects of bladder neck nerve damage induced by partial bladder outlet obstruction (PBOO) on sensory innervation of the corpus cavernosum (CC) and CC smooth muscle (CCSM) using a rat model of PBOO induced by a partial ligation of the bladder neck. Retrograde labeling technique was used to label dorsal root ganglion (DRG) neurons that innervate the urinary bladder and CC. Contractility and relaxation of the CCSM was studied in vitro, and expression of nitric oxide synthase (NOS) was evaluated by Western blotting. Concentration of the sensory neuropeptides substance P (SP) and calcitonin gene-related peptide was measured by ELISA. Partial obstruction of the bladder neck caused a significant hypertrophy of the urinary bladders (2.5-fold increase at 2 wk). Analysis of L6-S2 DRG sections determined that sensory ganglia received input from both the urinary bladder and CC with 5-7% of all neurons double labeled from both organs. The contractile responses of CC muscle strips to KCl and phenylephrine were decreased after PBOO, followed by a reduced relaxation response to nitroprusside. A significant decrease in neuronal NOS expression, but not in endothelial NOS or protein kinase G (PKG-1), was detected in the CCSM of the obstructed animals. Additionally, PBOO caused some impairment to sensory nerves as evidenced by a fivefold downregulation of SP in the CC (P ≤ 0.001). Our results provide evidence that PBOO leads to the impairment of bladder neck afferent innervation followed by a decrease in CCSM relaxation, downregulation of nNOS expression, and reduced content of sensory neuropeptides in the CC smooth muscle. These results suggest that nerve damage in PBOO may contribute to LUTS-ED comorbidity and trigger secondary changes in the contraction/relaxation mechanisms of CCSM.

1016 PARTIAL BLADDER OUTLET OBSTRUCTION MODULATES THE RELEASE OF SENSORY NEUROPEPTIDES SUBSTANCE P AND CALCITONIN GENE RELATED PEPTIDE FROM PENILE AFFERENT FIBERS

You have accessJournal of UrologySexual Function/Dysfunction/Andrology: Basic Research (II)1 Apr 20131016 PARTIAL BLADDER OUTLET OBSTRUCTION MODULATES THE RELEASE OF SENSORY NEUROPEPTIDES SUBSTANCE P AND CALCITONIN GENE RELATED PEPTIDE FROM PENILE AFFERENT FIBERS Qi Lei, Xiao-Qing Pan, Shaohua Chang, Ariana Smith, Allen Seftel, and Anna Malykhina Qi LeiQi Lei Glenolden, PA More articles by this author , Xiao-Qing PanXiao-Qing Pan Glenolden, PA More articles by this author , Shaohua ChangShaohua Chang Camden, NJ More articles by this author , Ariana SmithAriana Smith Philadelphia, PA More articles by this author , Allen SeftelAllen Seftel Camden, NJ More articles by this author , and Anna MalykhinaAnna Malykhina Glenolden, PA More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2013.02.601AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Erectile dysfunction (ED) and benign prostatic hyperplasia (BPH) are common problems in aging males worldwide. Despite the epidemiological evidence of the link between BPH and ED, the mechanisms underlying this co-morbidity are still unclear. The objective of this work was to evaluate the effects of partial bladder outlet obstruction (PBOO) on function of sensory terminals innervating the corpus cavernosum (CC), and release of sensory neuropeptides Substance P (SP) and calcitonin gene related peptide (CGRP) in the CC using an animal model of PBOO. METHODS Experiments were conducted on adult male Sprague Dawley rats divided into two groups: sham operated and PBOO surgery. PBOO was surgically induced by a partial ligation of the bladder neck during laparotomy. Concentration of the sensory neuropeptides SP and CGRP was measured by ELISA. Contractility and relaxation of the CCSM was studied in vitro and expression of nitric oxide synthase (NOS) was evaluated by Western blotting. RESULTS The results of neuropeptide analysis established that the release of SP and CGRP in the pelvic viscera is tissue dependent. Concentration of SP in the CC was higher (2.01±0.23 ng/ml, n=10) in comparison to the urinary bladder (0.3±0.05 ng/ml, n=8, p≤0.001) under normal physiological conditions. However, basal concentration of CGRP was significantly elevated in the urinary bladder reaching 120.6±37.2 pg/ml in comparison to 14.5±0.9 pg/ml in the CC (p≤0.01). PBOO caused impairment in SP release from sensory terminals as evidenced by a 5-fold down-regulation of SP in the CC (n=10, p≤0.001) without significant changes in the obstructed bladder. Additionally, concentration of CGRP was down-regulated in the urinary bladder by PBOO without parallel changes in the CC, however, the decrease did not reach the level of statistical significance. The contractile responses of CC muscle strips to KCl and phenylephrine were decreased after PBOO, followed by a reduced relaxation response to nitroprusside. A significant decrease in nNOS expression was also detected in the CC of obstructed animals. CONCLUSIONS Our results provide evidence that PBOO leads to the impairment of bladder neck afferent innervation followed by a decrease in CC smooth muscle relaxation, down-regulation of nNOS expression and reduced release of sensory neuropeptides in the CC smooth muscle. These results suggest that nerve damage in PBOO may contribute to LUTS-ED comorbidity and trigger secondary changes in the contraction/relaxation mechanisms of CCSM. © 2013 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 189Issue 4SApril 2013Page: e416-e417 Advertisement Copyright & Permissions© 2013 by American Urological Association Education and Research, Inc.MetricsAuthor Information Qi Lei Glenolden, PA More articles by this author Xiao-Qing Pan Glenolden, PA More articles by this author Shaohua Chang Camden, NJ More articles by this author Ariana Smith Philadelphia, PA More articles by this author Allen Seftel Camden, NJ More articles by this author Anna Malykhina Glenolden, PA More articles by this author Expand All Advertisement Advertisement PDF DownloadLoading ...

1017 ADRENOMEDULLIN AND ANGIOPOIETIN-1 HAVE A INTEGRATED RESTIRATION ACTIVITY ON ERECTILE FUNCTION IN DIABETIC RATS: COMPARISON WITH THE COMBINATION THERAPY WITH VASCULAR ENDOTHELIAL GROWTH FACTOR AND ANGIOPOIETIN-1

ity are still unclear. The objective of this work was to evaluate the effects of partial bladder outlet obstruction (PBOO) on function of sensory terminals innervating the corpus cavernosum (CC), and release of sensory neuropeptides Substance P (SP) and calcitonin gene related peptide (CGRP) in the CC using an animal model of PBOO. METHODS: Experiments were conducted on adult male Sprague Dawley rats divided into two groups: sham operated and PBOO surgery. PBOO was surgically induced by a partial ligation of the bladder neck during laparotomy. Concentration of the sensory neuropeptides SP and CGRP was measured by ELISA. Contractility and relaxation of the CCSM was studied in vitro and expression of nitric oxide synthase (NOS) was evaluated by Western blotting. RESULTS: The results of neuropeptide analysis established that the release of SP and CGRP in the pelvic viscera is tissue dependent. Concentration of SP in the CC was higher (2.01 0.23 ng/ml, n 10) in comparison to the urinary bladder (0.3 0.05 ng/ml, n 8, p 0.001) under normal physiological conditions. However, basal concentration of CGRP was significantly elevated in the urinary bladder reaching 120.6 37.2 pg/ml in comparison to 14.5 0.9 pg/ml in the CC (p 0.01). PBOO caused impairment in SP release from sensory terminals as evidenced by a 5-fold down-regulation of SP in the CC (n 10, p 0.001) without significant changes in the obstructed bladder. Additionally, concentration of CGRP was down-regulated in the urinary bladder by PBOO without parallel changes in the CC, however, the decrease did not reach the level of statistical significance. The contractile responses of CC muscle strips to KCl and phenylephrine were decreased after PBOO, followed by a reduced relaxation response to nitroprusside. A significant decrease in nNOS expression was also detected in the CC of obstructed animals. CONCLUSIONS: Our results provide evidence that PBOO leads to the impairment of bladder neck afferent innervation followed by a decrease in CC smooth muscle relaxation, down-regulation of nNOS expression and reduced release of sensory neuropeptides in the CC smooth muscle. These results suggest that nerve damage in PBOO may contribute to LUTS-ED comorbidity and trigger secondary changes in the contraction/relaxation mechanisms of CCSM.

1002 EFFECTS OF COMBINED USE OF PHOSPHODIESTERASE 5 INHIBITOR AND MEDICATIONS FOR HYPERTENSION, LOWER URINARY TRACT SYMPTOMS AND DYSLIPIDEMIA ON TONE OF CORPORAL TISSUE

INTRODUCTION AND OBJECTIVES: To establish theoretical basis of choosing an appropriate medication for ED and concomitant disease, we examined the effects of combination Phosphodiesterase 5 inhibitor (PDE5I) with drug for ED comorbidities (hypertension, lower urinary tract symptoms, and dyslipidemia) on relaxation of rabbit corpus cavernosum (CC). METHODS: Contractility of CC strips was studied in organ baths. Concentration-response curves to mirodenafil were generated on phenylephrine (PE) (10 M)-precontracted strips before and after preincubation of losartan (10, 10 M), amlodipine (10, 10 M), nifedipine (10, 10 M), enalapril (10, 10 M), doxazosin (10, 10 M), tamsulosin (10, 10 M), or simvastatin(10, 10 M). Another organ bath studies were done to determine the losartan/nitric oxide interaction on CC smooth muscle function. We also determined role of potassium channel opening in synergistic effect of mirodenafil and alpha adrenergic blockers. RESULTS: The effect of mirodenafil to relax PE-induced CC tone was significantly enhanced by preincubation of losartan, nifedipine, amlodipine, tamsulosin, and doxazosin. The maximal effect was 35.8 2.0% of inhibition of PE-induced tone for mirodenafil alone vs. 47.2 3.8% for preincubation of 10 M losartan, 57.6 2.6% for 10 M nifedipine, 64.0 3.7% for 10 M amlodipine, 76.1 5.7% for 10 M doxazosin, and 71.7 5.4% for 10 M tamsulosin. But enalapril and simvastatin had no additional effect. Relaxation of CC smooth muscle induced by the nitric oxide donor sodium nitroprusside (SNP) was potentiated by losartan (p 0.05). The maximal responses to SNP alone (39.0 4.0%) were significantly enhanced in the presence of the 10 M losartan (66.0 6.0%). Nonselective K inhibitor tetraethylammonium (1mM) significantly inhibited enhancement effect of tamsulosin or doxazosin on mirodenafil-induced relaxation. CONCLUSIONS: Amlodipine, nifedipine, losartan, doxazosin, and tamsulosin enhancd relaxation effect of mirodenafil in CC. Losartan seems to exert enhancing effect by interaction with nitric oxide. And potassium channel opening effect of PDE5I and alpha adrenergic blocker could be one of action mechanism for enhancing effect. Combination of PDE5I with losartan, nifedipine, amlodipine, doxazosin, or tamsulosin could be a possible pharmacologic strategy to simultaneously treat erectile dysfunction and its comorbidities and to increase response rate to PDE5I.

The relaxant effect of methanolic extract of yohimbe bark (&amp;lt;i&amp;gt;Pausinystalia yohimbe&amp;lt;/i&amp;gt;) on rabbit corpus cavernosum smooth muscles

Background: Development and maintenance of penile erection requires the relaxation of corpus cavernosum smooth muscle (CCSM) cells and it is essentially mediated by nitric oxide (NO). Pausinystalia yohimbe bark is traditionally used for the treatment of erectile dysfunction (ED). Objectives and Methods: This study aimed to evaluate the effects of the methanolic extract of P. yohimbe bark (10 mg/ml) on isolated rabbit corpus cavernosum smooth muscle (CCSM). Results: Methanolic extract of P. yohimbe bark blocked contractions in CCSM induced by adrenergic agonists, through facilitating NO release from the endothelial cells. Conclusion: The obtained results revealed that, methanolic extract of P. yohimbe bark caused relaxation of CCSM that validates its traditional aphrodisiac property, thus it could be used to initiate and maintain erection in cases of erectile dysfunction.

Amplified NO/cGMP‐mediated relaxation and ryanodine receptor‐to‐BKCa channel signalling in corpus cavernosum smooth muscle from phospholamban knockout mice

Relaxation of corpus cavernosum smooth muscle (CCSM) is induced by NO. NO promotes the formation of cGMP, which activates cGMP-dependent protein kinase I (PKGI). The large conductance calcium-activated potassium (BK(Ca) ) channel is regarded as a major target of NO/cGMP signalling; however, the mechanism of BK(Ca) activation remains unclear. The aim of the present study was to determine whether sarcoplasmic reticulum (SR) Ca(2+) load and Ca(2+) release from the SR via ryanodine receptors (RyRs) is important for BK(Ca) channel activation in response to NO/cGMP. In vitro myography was performed on CCSM strips from wild-type and PLB knockout (PLB(-/-)) mice to evaluate contraction and relaxation in response to pharmacological agents and electrical field stimulation (EFS). In CCSM strips from PLB(-/-) mice, a model of increased SR Ca(2+) load, contractile force in response to EFS or phenylephrine (PE) was increased by nearly 100%. EFS of strips precontracted with PE induced transient relaxation in CCSM, an effect that was significantly larger in PLB(-/-) strips. Likewise, the relaxation of PE-induced contraction in response to SNP and cGMP was greater in PLB(-/-) , as demonstrated by a shift in the concentration-response curve towards lower concentrations. Blocking RyRs and BK(Ca) channels diminished the induced relaxations and eliminated the difference between wild-type and PLB(-/-). NO/cGMP activates BK(Ca) channels through RyR-mediated Ca(2+) release. This signalling pathway is responsible for approximately 40% of the NO/cGMP effects and is amplified by increased SR Ca(2+) concentrations.

Update on Corpus Cavernosum Smooth Muscle Contractile Pathways in Erectile Function: A Role for Testosterone?

Normal erectile function (EF) involves a coordinated relaxation of the arteries that supply the penis and the corpus cavernosum smooth muscle (CCSM), resulting in expansion of the sinusoids and increased intracavernous pressure. But the CCSM spends the majority of its time in the contracted state which is mediated by norepinephrine released from nerve endings and other vasoconstrictors like endothelins released from the endothelium. These agents cause smooth muscle myosin (SMM) phosphorylation by elevating intracellular calcium. When calcium returns to basal levels, the calcium sensitivity increases and prevents myosin dephosphorylation, which involves the RhoA/Rho-kinase (ROK) mechanism, thus maintaining force. Although mounting evidences demonstrate that androgens have a major influence on EF that is not just centrally mediated, this notion remains quite controversial. To summarize the current knowledge on CCSM contractile pathways, the role they play in modulating EF, and the influence of androgens. The article reviews the literature and contains some previously unpublished data on CCSM contraction signaling including the role that androgens are known to play in modulating these pathways. Data from peer-reviewed publications and previously unpublished observations. In addition to downregulation of many pro-erectile molecular mechanisms, decreased testosterone (T) levels upregulate CCSM contractility, including hyperresponsiveness to α-adrenergic agonists, increased SMM phosphorylation, alteration of SMM isoform composition, activation of RhoA/ROK signaling and modulation of sphingosine-1-phosphate regulation of CCSM tone. Decreased T levels upregulate CCSM contractile signaling. Meanwhile, it downregulates CCSM relaxation pathways synergizing to produce erectile dysfunction (ED). Although some urologists and researchers are still skeptical of the influence of androgens on penile erection, understanding these molecular control mechanisms as well as the influence that androgens have on these pathways should provide new evidence supporting the roles of androgens in EF and enhance the discovery of novel targets for drug development to treat ED.

Ultrastructural features and possible functional role of kit-positive interstitial cells in the guinea pig corpus cavernosum

The objective of the present study was to identify kit-positive interstitial cells (ICs) in guinea pig corpus cavernosum and examine their relationships with adjacent smooth muscle cells (SMCs) and intramural nerves. In addition, we investigated the possible involvement of ICs in nitric oxide (NO)-mediated relaxation of corpus cavernosum smooth muscle (CCSM). ICs were identified by their immunoreactivity to the kit receptor, a cell surface marker encoded by c-kit proto-oncogene and specific for interstitial cells of Cajal. ICs were abundantly distributed in guinea pig corporal tissues. Ultrastructural investigation by conventional transmission electron microscopy revealed the ultrastructural features of ICs and gap junctions located between ICs and adjacent SMCs, furthermore, a close contact between ICs and intramural nerves for the first time. Western blot analysis of purified ICs by fluorescence-activated cell sorting revealed coexpression of soluble guanylate cyclase (sGC)α1, sGCβ1 and kit receptor tyrosine kinase protein in them. These observations imply that ICs express the NO-sensitive sGC molecule and may be involved in the NO-mediated relaxation of CCSM in the guinea pig corpus cavernosum.

Experimental model of human corpus cavernosum smooth muscle relaxation

To describe a technique for en bloc harvesting of the corpus cavernosum, cavernous artery and urethra from transplant organ donors and contraction-relaxation experiments with corpus cavernosum smooth muscle. The corpus cavernosum was dissected to the point of attachment with the crus penis. A 3 cm segment (corpus cavernosum and urethra) was isolated and placed in ice-cold sterile transportation buffer. Under magnification, the cavernous artery was dissected. Thus, 2 cm fragments of cavernous artery and corpus cavernosum were obtained. Strips measuring 3 x 3 x 8 mm(3) were then mounted vertically in an isolated organ bath device. Contractions were measured isometrically with a Narco-Biosystems force displacement transducer (model F-60, Narco-Biosystems, Houston, TX, USA) and recorded on a 4-channel Narco-Biosystems desk model polygraph. Phenylephrine (1 microM) was used to induce tonic contractions in the corpus cavernosum (3-5 g tension) and cavernous artery (0.5-1 g tension) until reaching a plateau. After precontraction, smooth muscle relaxants were used to produce relaxation-response curves (10(-12) M to 10(-4) M). Sodium nitroprusside was used as a relaxation control. The harvesting technique and the smooth muscle contraction-relaxation model described in this study were shown to be useful instruments in the search for new drugs for the treatment of human erectile dysfunction.

875 RESVERATROL, A POLYPHENOLIC SIRT1 ACTIVATOR, IMPROVES ERECTILE FUNCTION IN STREPTOZOTOCIN INDUCED DIABETIC RATS

You have accessJournal of UrologySexual Function/Dysfunction/Andrology: Basic Research II1 Apr 2010875 RESVERATROL, A POLYPHENOLIC SIRT1 ACTIVATOR, IMPROVES ERECTILE FUNCTION IN STREPTOZOTOCIN INDUCED DIABETIC RATS Shinichiro Fukuhara, Hidenobu Okuda, Keisuke Yamamoto, Jiro Nakayama, Tetsuya Takao, Yasushi Miyagawa, Akira Tsujimura, Norio Nonomura, and Akihiko Okuyama Shinichiro FukuharaShinichiro Fukuhara More articles by this author , Hidenobu OkudaHidenobu Okuda More articles by this author , Keisuke YamamotoKeisuke Yamamoto More articles by this author , Jiro NakayamaJiro Nakayama More articles by this author , Tetsuya TakaoTetsuya Takao More articles by this author , Yasushi MiyagawaYasushi Miyagawa More articles by this author , Akira TsujimuraAkira Tsujimura More articles by this author , Norio NonomuraNorio Nonomura More articles by this author , and Akihiko OkuyamaAkihiko Okuyama More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2010.02.1631AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES SIRT1 is an important enzyme for many cellular processes including cell cycle regulation, fatty acid metabolism, and life span extension. Recently, it has been reported that SIRT1 promotes endothelium-dependent vascular relaxation by activating endothelial nitric oxide synthase (eNOS) in endothelial cells, however its effect on corpus cavernosal smooth muscle relaxation remain poorly defined. Resveratrol is a polyphenolic compound, and has been reported to be an activator of SIRT1. Therefore, we investigated the effects of resveratrol on NO/cGMP pathway in human corpus cavernosal smooth muscle cells (CCSMCs) which were shown to express eNOS and synthesize NO in our previous report, and its therapeutic potential for erectile dysfunction in diabetic rats. We also examined the hypothesis that a combination of SIRT1 activation and phosphodiesterase 5 (PDE5) inhibition has synergistic effect in vitro and vivo. METHODS We measured intraceller cGMP concentration after incubation of human CCSMCs with resveratrol, PDE5 inhibitor (vardenafil), and both. In addition, to eliminate possible nonspecific effects, the cells were also incubated with sirtinol which inhibit SIRT1. Then, to investigate erectile function, four weeks after establishment of diabetes due to streptozotocin injection (50mg/kg i.p), rats treated with either only vehicle, PDE5 inhibitor (vardenafil 0.5m/kg/day p.o), resveratrol (5mg/kg/day p.o) or resveratrol plus PDE5 inhibitor. After four weeks treatment, the intracavernosal pressure (ICP) with electrical stimulation to the cavernous nerve and mean arterial pressure (MAP) were measured. RESULTS The levels of cGMP in human CCSMCs were significantly increased either by administration of PDE5 inhibitor or resveratrol compare with those of controls. A drastic synergistic increase in cGMP was observed when treated with both PDE5 inhibitor and resveratorol simultaneously. Furthermore, the effects of resveratrol on cGMP synthesis were reversed by sirtinol a specific SIRT1 inhibitor. In vivo experiments, while the ICP/MAP was significantly lower in treated with only vehicle rats, ICP/MAP in treated with resveratrol rats showed significantly higher. And more, The ICP/MAP in treated with both agents was higher than all other groups. CONCLUSIONS Resveratorol leads to enhancement of cGMP synthesis in human CCSMSs and improves erectile function in storeptozotocin induced diabetic rats, particularly with PDE5 inhibitor. Our data indicate that resveratrol has therapeutic potential for diabetic erectile dysfunction. Suita, Japan© 2010 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 183Issue 4SApril 2010Page: e342 Advertisement Copyright & Permissions© 2010 by American Urological Association Education and Research, Inc.MetricsAuthor Information Shinichiro Fukuhara More articles by this author Hidenobu Okuda More articles by this author Keisuke Yamamoto More articles by this author Jiro Nakayama More articles by this author Tetsuya Takao More articles by this author Yasushi Miyagawa More articles by this author Akira Tsujimura More articles by this author Norio Nonomura More articles by this author Akihiko Okuyama More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

874 THE REGULATION OF ANGIOTENSIN II-INDUCED CONTRACTION AND NON ADRENERGIC-NON CHOLINERGIC NEUROTRANSMISSION IN HUMAN CORPUS CAVERNOSAL TISSUE: A ROLE FOR LOSARTAN

You have accessJournal of UrologySexual Function/Dysfunction/Andrology: Basic Research II1 Apr 2010874 THE REGULATION OF ANGIOTENSIN II-INDUCED CONTRACTION AND NON ADRENERGIC-NON CHOLINERGIC NEUROTRANSMISSION IN HUMAN CORPUS CAVERNOSAL TISSUE: A ROLE FOR LOSARTAN Hani Ertemi, Faiz Mumtaz, James Bellringer, Philip Thomas, Dimitri Mikhailidis, and Cecil Thompson Hani ErtemiHani Ertemi More articles by this author , Faiz MumtazFaiz Mumtaz More articles by this author , James BellringerJames Bellringer More articles by this author , Philip ThomasPhilip Thomas More articles by this author , Dimitri MikhailidisDimitri Mikhailidis More articles by this author , and Cecil ThompsonCecil Thompson More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2010.02.1630AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Angiotensin II (Ang II), a vasoactive peptide, induces smooth muscle contraction and is an important regulator of systemic blood pressure. However, its influence on human corpus cavernosal smooth muscle (CCSM) function has barely been assessed. We have studied the effect Ang II has on human CCSM contractility and the influence of losartan the AT1 receptor antagonist. In addition, the interaction between Ang II and NO in modulating non adrenergic-non cholinergic neurotransmission following electrical field stimulation (EFS) was also assessed with losartan METHODS Experiments were carried out on corpus cavernosal tissue obtained from patients undergoing gender reassignment surgery, using organ baths. CCSM response to Ang II (10-8 – 10-5 M), in the absence and presence of losartan (10-5 M; AT1 receptor antagonist) were determined; together with the effect of losartan on sodium nitroprusside (SNP; NO donor)-mediated CCSM relaxation. In other experiments EFS-induce relaxation were obtained following the addition of cholinergic and cyclooxygenase inhibitors; the effect of losartan on this response was also determined RESULTS The results were expressed as a percentage of the phenylephrine 10-4 M response and showed that Ang II caused a dose dependent contraction of human CCSM strips. The Ang II contractile response was inhibited by losartan (e.g. Ang II; 10-5 M & 10-6 M were reduced by 65% & 78%; p<0.006, respectively). In addition, losartan potentiated the SNP-induced relaxation of CCSM tissue by 9% and 35% at 3x10-7M & 10-7M; p<0.04, respectively. EFS-induced relaxation of CCSM tissue at 8 Hz was also potentiated by losartan (p<0.027) CONCLUSIONS Ang II caused a profound contraction of human CCSM tissue via the activation of AT1 receptor. It is likely that Ang II and NO interact to modulate human cavernosal function, since losartan potentiated SNP- and EFS-mediated CCSM relaxation. These findings further strengthen the argument for the role of Ang II in the regulation of human penile smooth muscle tone, moreover, AT1 receptor inhibition, at least in part, may be a therapeutic approach to treat erectile dysfunction. London, United Kingdom© 2010 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetailsCited byErtemi H, Mumtaz F, Howie A, Mikhailidis D and Thompson C (2018) Effect of Angiotensin II and its Receptor Antagonists on Human Corpus Cavernous Contractility and Oxidative Stress: Modulation of Nitric Oxide Mediated RelaxationJournal of Urology, VOL. 185, NO. 6, (2414-2420), Online publication date: 1-Jun-2011. Volume 183Issue 4SApril 2010Page: e342 Advertisement Copyright & Permissions© 2010 by American Urological Association Education and Research, Inc.MetricsAuthor Information Hani Ertemi More articles by this author Faiz Mumtaz More articles by this author James Bellringer More articles by this author Philip Thomas More articles by this author Dimitri Mikhailidis More articles by this author Cecil Thompson More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...