Human Penile Erectile Tissue Research Articles

(231) Endogenous Vasoactive Peptides in the Control of Human Penile Erectile Tissue: Is There a Significance of the Neuropeptide Y (NPY)?

Abstract Introduction Aside from the neurotransmitters of the sympathetic adrenergic system, vasoconstrictor peptides may also play a role in mediating the constant tone of the erectile tissue during penile flaccidity and in returning the erect penis to the flaccid state. Neuropeptide Y (NPY) is present in high concentrations in the male genital tract. The peptide has been shown to induce contraction of isolated human penile tissue (corpus cavernosum, penile arteries) and potentiate its response to noradrenaline. Objective The purpose of our study was to measure in the cavernous and systemic blood of healthy male volunteers the course of NPY through different stages of sexual arousal. Methods Whole blood was drawn from the corpus cavernosum and the cubital vein of 15 healthy male volunteers during penile flaccidity (Fl), tumescence (Tu), rigidity (Ri) and detumescence (Det). Penile tumescence and erection were induced by applying audiovisual and tactile stimulation. Plasma levels of NPY (given in pmol/L) were determined by means of an enzyme-linked immunoassay (ELISA, IBL GmbH, Hamburg, Germany). Results NPY significantly decreased in the cavernous blood with the beginning of sexual arousal, when the flaccid penis became tumescent and finally rigid (Fl: 88.8 ± 35.8, Tu: 62.4 ± 22.7, Ri: 62.3 ± 19.7). In the phase of detumescence, only a slight increase was noted (64.8 ± 23). In the systemic circulation, no pronounced alterations in the concentration of NPY were registered through the different penile stages (Fl: 64.4 ± 27, Tu: 65.8 ± 19, Ri: 59.6-25, Det: 67.6 ± 29.3). Conclusions Our findings are in favor of the hypothesis that NPY could contribute to the maintenance of the resting state of cavernous smooth muscle. It remains to be elucidated whether the peptide may play a role in the pathophysiology of erectile dysfunction. Disclosure No

312 Endogenous Vasoactive Peptides in the Control of Penile Erectile Tissue: Is there a Role of Arginine-Vasopressin (AVP)?

The role of the adrenergic system in mediating the constant tone of corpus cavernosum (CC) smooth musculature during penile flaccidity and in returning the erect penis into the flaccid state is well established. However, it is not yet known whether additional non-adrenergic, non-cholinergic (NANC) transmitters are involved in this process. Arginine-Vasopressin (AVP, ADH), a pituitary peptide hormone with vasoconstrictor properties, has been assumed to be an important mediator contributing to such a control. The present study was conducted in order to determine whether there is a role of AVP in controlling CC smooth muscle tension. Plasma levels of AVP (ng/L) were determined in the systemic and cavernous blood of 25 healthy adult male volunteers who were exposed to visual and tactile erotic stimuli in order to elicit penile tumescence and erection. Whole blood was aspirated from the CC and a cubital vein. Following the separation of plasma volumes, AVP was quantified by means of radioimmunometric methods (RIA). The effects of AVP (0.1 nM - 100 nM) on isolated human penile erectile tissue at basal tension were examined using the tissue bath technique.

Is β-endorphin significant in the control of the male sexual response?

It has been assumed that β-endorphin, belonging to the family of opiodergic neuropeptides, might facilitate the inhibition of the male sexual response; however, its role in the control of the penile erectile tissue remains to be elucidated. This study aimed to evaluate in healthy men the course of β-endorphin in the systemic and cavernous blood through different stages of sexual arousal. Thirty-four (34) men were exposed to erotic stimuli to induce penile tumescence and rigidity. Blood was aspirated from the corpus cavernosum and a cubital vein during the penile conditions flaccidity, tumescence, rigidity and detumescence. Plasma levels of β-endorphin were determined by means of radioimmunometric methods. The effects of β-endorphin on isolated human penile erectile tissue were investigated in vitro. β-endorphin did not induce a contractile response of the cavernous tissue or reverse the contraction induced by noradrenaline. β-endorphin decreased in the systemic blood when the penis became tumescent and rigid and increased during detumescence. In the cavernous blood, no alterations in β-endorphin concentrations were observed. The drop in β-endorphin observed during tumescence and rigidity seems likely to reflect the inhibition of the opioidergic input with the beginning of sexual arousal.

Endopeptidase inhibition attenuates the contraction induced by big endothelin-1 of isolated human penile erectile tissue.

Peptides, such as C-type natriuretic peptide (CNP), vasoactive intestinal polypeptide (VIP) and endothelin 1 (ET-1), are involved in the control of penile erectile tissue (corpus cavernosum=CC). Inhibiting the degradation of CNP and VIP or conversion of Big ET-1 into ET-1 by endopeptidase enzymes should result in an enhancement of CC smooth muscle relaxation. Using the tissue bath technique, responses of isolated CC, challenged by noradrenaline (NA, 1μm), to increasing concentrations of the endopeptidase inhibitor KC 12615 (1nm - 10μm), CNP and VIP (0.1nm - 1μm), were investigated. Effects of CNP, VIP and Big ET-1 (0.1nm - 100nm) on the tissue tension were also evaluated following pre-exposure to 10μm of KC 12615. Big ET-1 induced contraction of the CC amounting to a force generation of 1,200mg. The contraction was attenuated in the presence of KC 12615 by 35% and 50%, respectively. The tension induced by NA was reversed by VIP and CNP to 38.7%±15.8% and 61%±13%, respectively, of the initial force. The findings might be of significance with regard to future pharmacological treatment options for male ED, where an endothelial dysfunction exists.

Expression and distribution of the transient receptor potential cationic channel A1 (TRPA1) in the human clitoris-comparison to male penile erectile tissue.

The transient receptor potential cationic channel ankyrin 1 (TRPA1) is a channel protein assumed to act in various human tissues as mechano- and pain sensor and play a role in neurotransmission. The expression of TRPA has already been investigated in the human prostate and urethra, however, only very few studies have addressed the expression and distribution in the male and female genital tract. The present study aimed to investigate by means of immunohistochemistry (double-labeling technique, laser fluorescence microscopy) in the human clitoris and penile erectile tissue the localization of TRPA1 in relation to nNOS, the vasoactive intestinal polypeptide (VIP) and vesicular acetylcholine transporter (VAChT). In the clitoral tissue, TRPA1 was observed in basal epithelial cells and slender nNOS-positive nerve fibers transversing the subepithelial space. To a certain degree, in the clitoral epithelial cells, TRPA1 was found co-localized with vimentin. In human corpus cavernosum, immunoreactivity for TRPA1 was seen in nerves transversing the cavernous sinusoidal space and running alongside small arteries, these nerves also displayed expression of the vesicular acetylcholine transporter protein (VAChT). Varicose nerves containing nNOS or VIP were not immunoreactive for TRPA1. It seems likely that TRPA1 is involved in nitric oxide-mediated afferent sensory transmission in the clitoris while, in penile erectile tissue, a role for TRPA1 in cholinergic signaling might be assumed.

PS-04-010 Expression and distribution of carboanhydrase (CA) in human penile erectile tissue

PS-04-010 Expression and distribution of carboanhydrase (CA) in human penile erectile tissue

Effects of endopeptidase inhibition on the relaxation response of isolated human penile erectile tissue to vasoactive peptides.

Peptides, such as CNP, CGRP and VIP, are involved in the function of male penile erectile tissue. Tissue levels of said peptides are controlled by the endopeptidase enzymes. Theoretically, the inhibition of the degradation of CNP, CGRP and/or VIP should result in an enhancement in penile smooth muscle relaxation. The effects were investigated of CNP or VIP (0.1nm-1μm), without and following pre-exposure of the tissue to a threshold concentration of the endopeptidase inhibitor KC 12615 (10μm, for 20min), on the reversion of tension induced by means of electrical field stimulation. Drug effects on the production of cyclic AMP/GMP were also evaluated. Neither KC 12615, CNP and VIP nor the combination of CNP plus KC 12615 or VIP plus KC 12615 increased the response of the tissue to EFS. While no effects were observed of a pre-exposure of the tissue to KC 12615 on the production of cyclic AMP in the presence of VIP, an enhancement was registered in the accumulation of cyclic AMP in the presence of CNP plus KC 12615. Further studies are indicated to investigate whether endopeptidase inhibitors might tend to be more effective in tissues affected by a decreased local production of vasoactive peptides.

MP52-17 EXPRESSION AND DISTRIBUTION OF THE TRANSIENT RECEPTOR POTENTIAL CATIONIC CHANNEL A1 (TRPA1) IN HUMAN PENILE ERECTILE TISSUE AND THE SEMINAL VESICLES

You have accessJournal of UrologySexual Function/Dysfunction/Andrology: Basic Research I1 Apr 2015MP52-17 EXPRESSION AND DISTRIBUTION OF THE TRANSIENT RECEPTOR POTENTIAL CATIONIC CHANNEL A1 (TRPA1) IN HUMAN PENILE ERECTILE TISSUE AND THE SEMINAL VESICLES Stefan Ückert, Andreas Bannowsky, Markus Kuczyk, and Petter Hedlund Stefan ÜckertStefan Ückert More articles by this author , Andreas BannowskyAndreas Bannowsky More articles by this author , Markus KuczykMarkus Kuczyk More articles by this author , and Petter HedlundPetter Hedlund More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2015.02.1734AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES The transient receptor potential cationic channel A1 (TRPA1) has been suggested to be involved in mechano-afferent/efferent signaling in the bladder, prostate, and urethra. Up until today, no study has addressed the expression of this receptor in male genital and reproductive tissues. Thus, it was the aim of the present study to evaluate in human penile erectile tissue (corpus cavernosum penis) and the seminal vesicles (SV) by means of molecular biology and immunohistochemistry the expression and localization of TRPA/TRPA1. METHODS Human penile erectile tissue was obtained from 5 subjects who underwent reassignment surgery. SV tissue was excised from 5 male patients during pelvic surgery due to malignancies of the prostate or urinary bladder. Using immunohistochemical methods (double-labelling technique, laser fluorescence microscopy), the distribution of TRPA1 in relation to neuronal nitric oxide synthase (nNOS), the neuropeptide vasoactive intestinal polypeptide (VIP), and vesicular acetylcholine transporter protein (VAChT) was examined in sections of the CC, while, in sections of the SV, the distribution of TRPA1 was investigated in relation to eNOS, nNOS, VIP and CGRP. RESULTS In the CC, immunoreactivity for TRPA1 was located in nerves transversing the cavernous sinusoidal space. These nerves also displayed the expression of VAChT. Signals specific for TRPA1 were also observed in meshworks of nerve fibers running alongside the walls of cavernous arteries. Varicose nerves containing nNOS or VIP were not immunoreactive for TRPA1. In the SV, TRPA1 was seen expressed in nerves running through the smooth muscle portion. Here, the protein was in part colocalized with nNOS and CGRP, whereas no colocalization with VIP was observed. Dot-like signals specific for TRPA1 were observed in the cytoplasm of epithelial cells lining the lacunar lumen of glandular spaces. The epithelial layer also presented staining for eNOS. Both the vascular and non-vascular smooth muscle of CC and SV appeared free of immunosignals related to TRPA1. CONCLUSIONS The distribution of TRPA1 and VAChT receptors in penile erectile tissue suggests a role for TRPA1 in the mechanism of cholinergic signaling in the human penis while, in the SV, TRPA1 might be involved in the control of secretory function (mediated by cyclic GMP). © 2015 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 193Issue 4SApril 2015Page: e633 Advertisement Copyright & Permissions© 2015 by American Urological Association Education and Research, Inc.MetricsAuthor Information Stefan Ückert More articles by this author Andreas Bannowsky More articles by this author Markus Kuczyk More articles by this author Petter Hedlund More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Guanylin peptide family: history, interactions with ANP, and new pharmacological perspectives

The guanylin family of peptides has 3 subclasses of peptides containing either 3 intramolecular disulfide bonds found in bacterial heat-stable enterotoxins (ST), or 2 disulfides observed in guanylin and uroguanylin, or a single disulfide exemplified by lymphoguanylin. These peptides bind to and activate cell-surface receptors that have intrinsic guanylate cyclase (GC) activity. These hormones are synthesized in the intestine and released both luminally and into the circulation, and are also produced within the kidney. Stimulation of renal target cells by guanylin peptides in vivo or ex vivo elicits a long-lived diuresis, natriuresis, and kaliuresis by both cGMP-dependent and independent mechanisms. Uroguanylin may act as a hormone in a novel endocrine axis linking the digestive system and kidney as well as a paracrine system intrarenally to increase sodium excretion in the postprandial period. This highly integrated and redundant mechanism allows the organism to maintain sodium balance by eliminating excess sodium in the urine. In addition, small concentrations of the atrial natriuretic peptide (ANP) can synergize with low concentrations of both guanylin or uroguanylin, which do not induce natriuresis per se, to promote significant natriuresis. Interestingly, the activation of the particulate guanylate cyclase receptors by natriuretic peptides can promote relaxation of animal and human penile erectile tissue and increase intracavernosal pressure to induce penile erection. These peptides can be prototypes for new drugs to treat erectile dysfunction, especially in patients with endothelial and nitrergic dysfunction, such as in diabetes.

Systemic and cavernous plasma levels of neuropeptide Y during sexual arousal in healthy males

Neuropeptide Y (NPY) has been shown to induce contraction of isolated human penile erectile tissue and potentiate the response to noradrenaline. The purpose of our study was to measure in the cavernous and systemic blood of healthy male volunteers the course of NPY through different stages of sexual arousal. Whole blood was drawn simultaneously from the corpus cavernosum and the cubital vein of 16 healthy male volunteers during penile flaccidity, tumescence, rigidity and detumescence. Tumescence and erection were induced by applying audiovisual and tactile stimulation. Plasma levels of NPY (given in pmol l(-1)) were determined by means of an enzyme-linked immunoassay. NPY significantly decreased in the cavernous blood on sexual arousal, when the flaccid penis became tumescent and, finally, rigid (F: 88.8 ± 35.8, T: 62.4 ± 22.7, R: 62.3 ± 19.7), and only slightly rose in the phase of detumescence (64.8 ± 23). In the systemic circulation, no pronounced alterations in the concentration of NPY were registered (F: 64.4 ± 27, T: 65.8 ± 19, R: 59.6 ± 25, D: 67.6 ± 29.3). Our findings are in favour of the hypothesis that NPY could contribute to the maintenance of the resting state of cavernous smooth muscle.

Potential Mechanism of Action of Human Growth Hormone on Isolated Human Penile Erectile Tissue

Potential Mechanism of Action of Human Growth Hormone on Isolated Human Penile Erectile Tissue

Potential mechanism of action of human growth hormone on isolated human penile erectile tissue

Potential mechanism of action of human growth hormone on isolated human penile erectile tissue

Potential Mechanism of Action of Human Growth Hormone on Isolated Human Penile Erectile Tissue

To evaluate the mechanisms of growth hormone (GH) action on isolated human penile erectile tissue. Human GH (hGH) has been suggested to play a role in male reproductive function, including penile erection. Nevertheless, it still remains unclear which intracellular pathways mediate the physiological effects of GH on the human corpus cavernosum (HCC). Using the organ bath technique, the effects of GH were investigated on electrical field stimulation (EFS)-induced relaxation of isolated HCC in the absence and presence of the guanylyl cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) and nitric oxide synthase (NOS) inhibitor N(G)-nitro-l-arginine (l-NOARG, 10 microm). Effects of GH on the production of tissue cyclic guanosine monophosphate (cGMP) in the absence and presence of ODQ and l-NOARG were also elucidated using radioimmunoassay. ODQ and l-NOARG abolished the relaxation of the tissue induced by EFS, whereas amplitudes were increased by physiological concentrations of GH (1-100 nm). The attenuation of EFS-induced amplitudes by l-NOARG but not ODQ was, in part, reversed by GH. The production of cGMP (pmol cGMP/mg protein) induced by 10 nm GH was abolished in the presence of 10 microm ODQ. In contrast, the combination of GH (10 nm) and l-NOARG (10 microm) maintained cGMP production significantly greater than baseline (0.68 +/- 0.36 vs 1.07 +/- 0.48 pmol cGMP/mg protein). Our data provide evidence that GH may act on human HCC by an NO-independent effect on guanylyl cyclase activity and may thus explain how growth factors, such as hGH, regulate male erectile function.

Effects of arginase inhibitors on the contractile and relaxant responses of isolated human penile erectile tissue

An impairment in the local availability of nitric oxide (NO) may impair male erectile function. The activity of l-arginine-degrading arginase enzymes may attenuate the relaxation of cavernous smooth muscle by reducing local NO production. Arginase enzymes compete with the nitric oxide synthases for the common substrate, the amino acid l-arginine. Very little data are available regarding the significance of arginase enzymes in the control of human penile erectile tissue. The aim of the present study was to elucidate the effects of drugs known to inhibit arginase activity on the relaxation of isolated human corpus cavernosum (HCC) and the production of cyclic GMP. Using the organ bath technique, the effects of the arginase inhibitors DFMO, H-Orn-OH·HCl, H-lle-OH and nor-NOHA (10 nM–10 μM) on the tension induced by NE (1 μM) and the relaxation induced by electrical field stimulation (EFS) of HCC were investigated. HCC strips were also exposed to increasing concentrations of the compounds, and the production of cGMP was determined by means of a radioimmunoassay. Only marginal effects of the arginase inhibitors were registered on the tension induced by NE and the relaxation exerted by EFS. Mean reversion of tension ranged from 18 to 8%. Only DFMO and nor-NOHA amplified the EFS-induced relaxation by 11 and 29%, respectively. These effects were not paralleled by an increase in tissue levels of cGMP. Arginase inhibitors appeared to be ineffective in reversing the adrenergic tension and increasing the electrically induced relaxation of isolated HCC.

Expression and Distribution of Cyclic GMP-Dependent Protein Kinase-1 Isoforms in Human Penile Erectile Tissue

Besides the bioavailability of nitric oxide (NO), downstream guanine monophosphate (cGMP) effector proteins are also considered to play a significant role in penile vascular disease. In animal studies, a downregulation of the cGMP-dependent protein kinase-1 (cGKI) alpha isoform has been linked to erectile dysfunction and diabetes mellitus. So far, the expression of cGKI alpha and beta isoforms has not been evaluated in human penile erectile tissue. To evaluate the expression of cGKI alpha and beta isoforms in relation to smooth muscle alpha-actin, cGMP, and endothelial NO synthase (eNOS) in human cavernous arteries (HCAs) and human corpus cavernosum (HCC). Cryostat sections of HCA and HCC were incubated with primary antibodies directed against alpha-actin, cGMP, eNOS, cGKI, cGKI alpha, and cGKI beta. Visualization of double-labeled immunofluorescent stainings was achieved by laser microscopy. Western blot analysis was performed in order to confirm the expression of cGKI isoforms. Expression of cGKI alpha and beta isoforms in relation to smooth muscle alpha-actin, cGMP, and eNOS in human penile erectile tissue. Immunoreactivities specific for cGKI, cGKI alpha, and cGKI beta were observed within the smooth musculature and the endothelium of cavernous arteries and sinusoids. Double stainings revealed the colocalization of alpha-actin, cGMP, eNOS, and cGKI isoforms. The expression of cGKI isoforms was confirmed by Western blot analysis. Our results demonstrate, for the first time, the expression of both cGKI alpha and beta isoforms in the smooth musculature of HCA and HCC. Corresponding to recent findings from animal studies, the presence of cGKI alpha and beta provides further evidence for a significant role of these enzymes in the control of smooth muscle function in human penile erectile tissue.

Expression of Messenger Ribonucleic Acid Encoding for Phosphodiesterase Isoenzymes in Human Female Genital Tissues

The use of inhibitors of phosphodiesterase 5 (PDE5) has been suggested to treat symptoms of female sexual dysfunction (FSD). Nonetheless, there has been a relatively low success rate of PDE5 inhibitors in FSD in comparison with male erectile dysfunction. The elevated expression of PDE5 in the human penile erectile tissue is considered the reason for the high clinical efficacy of PDE5 inhibitors in the pharmacotherapy of male erectile dysfunction. To evaluate by means of molecular biology the expression of messenger ribonucleic acid expression (mRNA) encoding for cyclic AMP and cyclic GMP PDE isoenzymes in female genital tissues. The amount of mRNA transcripts specifically encoding for cyclic AMP- and/or cyclic GMP-degrading PDE isoenzymes was determined. Human clitoral, labial, and vaginal tissue was obtained from four female cadavers (age at death: 18-42 years). The expression of mRNA specifically encoding for PDE1A, 1B, 1C, 2A, 4A, 5A, 10A, and 11A was elucidated by means of real-time polymerase chain reaction (PCR) analysis (TaqMan). Human penile erectile tissue (corpus cavernosum [HCC]) was used as a reference tissue. mRNA encoding for all PDE isoforms mentioned above is expressed in the female genital tissues. Different magnitudes of mRNA expression were observed: a predominant expression of mRNA encoding for PDE1A but only insignificant amounts of PDE1B, 1C, 4A, 10, and 11A mRNA were registered. With PDE1A being the only exception, the mRNA expression was always higher in the HCC than in the female genital tissues. Especially, the expression of mRNA encoding for PDE5 was several-fold higher in the HCC. On the mRNA level, various PDE isoforms are expressed in the clitoris, labia, and vagina. It remains to be established as to whether the low expression of PDE5 in female genital tissue might be a negative predictor for the success of PDE5 inhibitors in the treatment of FSD.

MP-12.05: Mechanisms of action of human growth hormone on isolated human penile erectile tissue

MP-12.05: Mechanisms of action of human growth hormone on isolated human penile erectile tissue

678: Expression of Cyclic AMP-Dependent Protein Kinase-1 Isoforms in Human Penile Erectile Tissue: Relation to Vasoactive Intestinal Polypeptide-Containing Nerves and PDE4

678: Expression of Cyclic AMP-Dependent Protein Kinase-1 Isoforms in Human Penile Erectile Tissue: Relation to Vasoactive Intestinal Polypeptide-Containing Nerves and PDE4

1072: Mechanisms of Action of Human Growth Hormone(GH) on Isolated Human Penile Erectile Tissue

1072: Mechanisms of Action of Human Growth Hormone(GH) on Isolated Human Penile Erectile Tissue

Non-synergistic relaxant effects of vasoactive intestinal polypeptide and SIN-1 in human isolated cavernous artery and corpus cavernosum

Since vasoactive intestinal peptide (VIP) and nitric oxide (NO) are considered to be non-adrenergic, non-cholinergic (NANC) inhibitory mediators in human penile erectile tissue, the goal of this study was to discover possible synergistic effects of exogeneous VIP and the NO donor 3-morpholino-sydnonimine (SIN-1) in human isolated cavernous arteries and cavernosal smooth muscle. In contrast to VIP, SIN-1 elicited complete and reproducible relaxant actions. Combined administration of VIP and SIN-1 revealed non-synergistic, independent relaxant effects in both investigated tissues. The results do not favour a combined administration of VIP and SIN-1 as a new therapeutic approach in the treatment of erectile dysfunction.