Publications by authors named "Selim Cellek"

37 Publications

Associations Between Mobile Health Technology use and Self-rated Quality of Life: A Cross-sectional Study on Older Adults with Cognitive Impairment.

Gerontol Geriatr Med 2021 Jan-Dec;7:23337214211018924. Epub 2021 May 25.

Blekinge Institute of Technology, Karlskrona, Sweden.

Quality of life (QoL) is affected even at early stages in older adults with cognitive impairment. The use of mobile health (mHealth) technology can offer support in daily life and improve the physical and mental health of older adults. However, a clarification of how mHealth technology can be used to support the QoL of older adults with cognitive impairment is needed. To investigate factors affecting mHealth technology use in relation to self-rated QoL among older adults with cognitive impairment. A cross-sectional research design was used to analyse mHealth technology use and QoL in 1,082 older participants. Baseline data were used from a multi-centered randomized controlled trial including QoL, measured by the Quality of Life in Alzheimer's Disease (QoL-AD) Scale, as the outcome variable. Data were analyzed using logistic regression models. Having moderately or high technical skills in using mHealth technology and using the internet via mHealth technology on a daily or weekly basis was associated with good to excellent QoL in older adults with cognitive impairment. The variation in technical skills and internet use among the participants can be interpreted as an obstacle for mHealth technology to support QoL.
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http://dx.doi.org/10.1177/23337214211018924DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8155754PMC
May 2021

Single-cell Transcriptomics Uncover a Novel Role of Myeloid Cells and T-lymphocytes in the Fibrotic Microenvironment in Peyronie's Disease.

Eur Urol Focus 2021 May 4. Epub 2021 May 4.

Laboratory of Experimental Urology, Department of Development and Regeneration, KU Leuven, Leuven, Belgium; Department of Urology, University Hospitals Leuven, Leuven, Belgium.

Background: Peyronie's disease (PD) is an acquired fibrotic disease affecting the penile tunica albuginea that can lead to curvature and deformities, shortening, and erectile dysfunction. Although immunological mechanisms have been suggested for the pathophysiology of PD, these have not been investigated using single-cell transcriptomics.

Objective: To investigate the immunological signature of plaques from PD patients using immunohistochemistry (IHC) and single-cell RNA sequencing (scRNA-Seq).

Design, Setting, And Participants: Tunica albuginea biopsy was performed in patients undergoing penile surgery for either PD (n = 12) or plication or penile cancer (control, n = 6). The inclusion criteria for PD patients were stable chronic disease (≥12 mo in duration) and no previous penile surgery or intralesional injection therapy.

Outcome Measurements And Statistical Analysis: IHC was performed on surgical samples from ten patients with PD and five control subjects. An additional two PD and one control sample were used for scRNA-Seq (droplet-based; 10X Genomics). Cell clusters were visualised using heatmaps and t-distributed stochastic neighbour embedding plots (BioTuring v2.7.5).

Results And Limitations: IHC revealed the presence of myeloid dendritic cells (DCs; CD68, TLR4, CD206), cytotoxic T lymphocytes (CTLs; CD3, CD8), and B lymphocytes (CD20) in PD plaques, which were absent in controls. scRNA-Seq yielded results for 3312 PD and 5658 control cells. Cell clusters contained fibroblasts (COL1A2), myofibroblasts (COL1A2, ACTA2), smooth muscle cells (ACTA2, DES), endothelial cells (VWF), myeloid cells (CD14), T lymphocytes (CD3D), and neutrophils (ALPL). Myeloid cell subclustering showed infiltration of monocyte-derived cells; control tissue contained classical DCs and resident macrophages. Lymphocyte subclustering revealed mucosal-associated invariant T (MAIT) cells and CTLs in PD. Differential gene expression suggests an increase in inflammatory and immune responses in chronic PD. The study is limited by the small scRNA-seq sample size (n = 3) for IHC, mitigated by a larger cohort of historic paraffin-embedded samples (n = 15), which showed largely parallel findings. Owing to tissue stiffness and extracellular matrix adhesion, our single-cell yield was lower for PD than for the control sample.

Conclusions: Our data suggest that even in the chronic PD stage (painless and stable curvature) there is a sustained inflammatory reaction. While vascularisation and collagen production are elevated, the inflammation is driven by specialised monocyte-derived CTL and MAIT cells. These findings could uncover new avenues for medical treatment of PD.

Patient Summary: We looked at the role of the immune system in patients suffering from Peyronie's disease, a condition causing shortening and curvature of the penis. We found that even in a stable, chronic stage of the disease, there is activation of the immune system. Our results suggest that there is potential for novel treatments for this condition.
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http://dx.doi.org/10.1016/j.euf.2021.04.012DOI Listing
May 2021

Feasibility-Usability Study of a Tablet App Adapted Specifically for Persons with Cognitive Impairment-SMART4MD (Support Monitoring and Reminder Technology for Mild Dementia).

Int J Environ Res Public Health 2020 09 18;17(18). Epub 2020 Sep 18.

Brain, Cognition and Behavior: Clinical Research, Consorci Sanitari de Terrassa, 08227 Terrasa, Spain.

Population ageing within Europe has major social and economic consequences. One of the most devastating conditions that predominantly affects older people is dementia. The SMART4MD (Support Monitoring and Reminder Technology for Mild Dementia) project aims to develop and test a health application specifically designed for people with mild dementia. The aim of this feasibility study was to evaluate the design of the SMART4MD protocol, including recruitment, screening, baseline examination and data management, and to test the SMART4MD application for functionality and usability before utilization in a full-scale study. The feasibility study tested the protocol and the app in Spain and Sweden. A total of nineteen persons with cognitive impairment, and their informal caregivers, individually performed a task-based usability test of the SMART4MD app model in a clinical environment, followed by four-week testing of the app in the home environment. By employing a user-centered design approach, the SMART4MD application proved to be an adequate and feasible interface for an eHealth intervention. In the final usability test, a score of 81% satisfied users was obtained. The possibility to test the application in all the procedures included in the study generated important information on how to present the technology to the users and how to improve these procedures.
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http://dx.doi.org/10.3390/ijerph17186816DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7557766PMC
September 2020

Phosphodiesterase Type 5 Inhibitors and Selective Estrogen Receptor Modulators Can Prevent But Not Reverse Myofibroblast Transformation in Peyronie's Disease.

J Sex Med 2020 10 5;17(10):1848-1864. Epub 2020 Aug 5.

Medical Technology Research Centre, Anglia Ruskin University, Chelmsford, Essex, UK.

Background: Myofibroblast transformation is a key step in the pathogenesis of Peyronie's disease (PD). Phosphodiesterase type 5 inhibitors (PDE5is) and selective estrogen receptor modulators (SERMs) can prevent the formation of fibrosis in in vitro and in vivo models of PD. However, it is unknown whether these drugs can also reverse established fibrosis.

Aim: To investigate whether PDE5is and SERMs can reverse transforming growth factor beta 1 (TGF-β1)-induced myofibroblast transformation and determine the point of no return.

Methods: In-Cell enzyme-linked immunosorbent assay was used to quantify TGF-β1-induced myofibroblast transformation of human primary fibroblasts isolated from tunica albuginea (TA) of patients undergoing surgery for treatment of PD. Extracellular matrix production and collagen contraction assays were used as secondary assays. Reverse transcription-quantitative polymerase chain reaction and In-Cell enzyme-linked immunosorbent assay were used to measure drug target expression. PDE5i (vardenafil) and SERM (tamoxifen) were applied at various time points after TGF-β1.

Outcomes: Reversibility of myofibroblast transformation and drug target expression were investigated in a time-dependent manner in TA-derived fibroblasts.

Results: Vardenafil or tamoxifen could not reverse the myofibroblast traits of alpha-smooth muscle actin expression and extracellular matrix production, whereas only tamoxifen affected collagen contraction after 72 hours of TGF-β1 treatment. Phosphodiesterase 5A and estrogen receptor (ER)-β were downregulated after 72 hours, and estrogen receptor -α protein could not be quantified. Tamoxifen could prevent myofibroblast transformation until 36 hours after TGF-β1 treatment, whereas vardenafil could prevent only 24 hours after TGF-β1 treatment. This was mirrored by downregulation of drug targets on mRNA and protein level. Furthermore, antifibrotic signaling pathways, peroxisome proliferator-activated receptor gamma and betaglycan (TGFB receptor III), were significantly downregulated after 36 hours of TGF-β1 exposure, as opposed to upregulation of profibrotic thrombospondin-1 at the same time point.

Clinical Translation: This study suggests that using PDE5is and SERMs might only help for early-phase PD and further highlights the need to test drugs at the appropriate stage of the disease based on their mechanism of action.

Strengths & Limitations: The study uses primary human TA-derived fibroblasts that enhances translatability of the results. Limitations include that only 1 example of PDE5i- and SERM-type drug was tested. Time course experiments were only performed for marker expression experiments and not for functional assays.

Conclusion: This is the first study to demonstrate that timing for administration of drugs affecting myofibroblast transformation appears to be vital in in vitro models of PD, where 36 hours of TGF-β1 treatment can be suggested as a "point of no return" for myofibroblast transformation. Ilg MM, Stafford SJ, Mateus M, et al. Phosphodiesterase Type 5 Inhibitors and Selective Estrogen Receptor Modulators Can Prevent But Not Reverse Myofibroblast Transformation in Peyronie's Disease. J Sex Med 2020;17:1848-1864.
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http://dx.doi.org/10.1016/j.jsxm.2020.06.022DOI Listing
October 2020

Unwinding Fibrosis in Peyronie's Disease.

J Sex Med 2020 05 20;17(5):838-840. Epub 2020 Mar 20.

Medical Technology Research Centre, Anglia Ruskin University, Chelmsford, Essex, UK. Electronic address:

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http://dx.doi.org/10.1016/j.jsxm.2020.02.021DOI Listing
May 2020

Pathophysiology and Future Therapeutic Perspectives for Resolving Fibrosis in Peyronie's Disease.

Sex Med Rev 2019 10 5;7(4):679-689. Epub 2019 Apr 5.

Laboratory of Experimental Urology, Department of Development and Regeneration, University of Leuven, Leuven, Belgium; Department of Urology, University Hospitals of Leuven, Leuven, Belgium. Electronic address:

Introduction: Peyronie's disease (PD) is a debilitating affliction for the male population, causing severe curvatures to the erect penis and erectile dysfunction in about 50% of men. This deviation of the penis significantly impairs sexual intercourse and causes depression and strains in the relationship. As of today, medical treatment options are few and far between, with surgery remaining as the sole reliable treatment.

Aim: To give a general overview regarding fibrosis and the specific role of extracellular matrix, macrophages, and myofibroblasts in PD. Additionally, we will provide an overview of past and present research and how this has shaped our vision concerning the pathophysiology of PD.

Methods: We performed a non-systematic literature review using the search terms "fibrosis," "pathophysiology," "myofibroblast," "extracellular matrix," "Peyronie's disease," and "drug discovery."

Main Outcome Measure: We assessed current knowledge regarding fibrosis in PD and the possibility to use this knowledge for new treatment options.

Results: Interpreting findings from the most recent next-generation sequencing, in vitro and in vivo PD research, we provide novel insights for the pathophysiology of PD. Using this knowledge, we will attempt to provide future directions for PD research and drug discovery, which is urgently needed, because its treatment has essentially been stagnating for about 30 years.

Conclusion: Historically, PD has not been studied as widely as kidney, lung, or hepatic fibrosis, and our knowledge of its pathophysiology still remains relatively obscure. Nonetheless, recent breakthroughs using stem cells, next-generation sequencing, and phenotypical screening assays bring us several steps closer to filling the gaps in our knowledge. In the near future, clinical trials will prove essential to translate this plethora of preclinical data into usable tools that can improve the lives of many of our patients. Milenkovic U, Ilg MM, Cellek S, et al. Pathophysiology and Future Therapeutic Perspectives for Resolving Fibrosis in Peyronie's Disease. Sex Med Rev 2019;7:679-689.
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http://dx.doi.org/10.1016/j.sxmr.2019.02.004DOI Listing
October 2019

Antifibrotic Synergy Between Phosphodiesterase Type 5 Inhibitors and Selective Oestrogen Receptor Modulators in Peyronie's Disease Models.

Eur Urol 2019 02 19;75(2):329-340. Epub 2018 Oct 19.

Anglia Ruskin University, Chelmsford, UK. Electronic address:

Background: Peyronie's disease (PD) is a fibrotic disorder of the penile tunica albuginea, characterised by the formation of a localised fibrous plaque that can lead to deformity and erectile dysfunction. Nonsurgical therapeutic options for PD are limited in efficacy and safety. Myofibroblasts are key cells in the pathogenesis of PD, and inhibition of myofibroblast transformation has been suggested as a therapeutic option.

Objective: To identify potential drugs using a novel phenotypic assay and then to test them using in vitro and in vivo models of PD.

Design, Setting, And Participants: We have developed and validated a phenotypic screening assay that measures myofibroblast transformation, by which we tested 21 compounds that were suggested to be efficacious in treating PD. The successful hits from this assay were further tested using in vitro and in vivo models of PD.

Results And Limitations: The new assay was able to detect transforming growth factor-β1-induced myofibroblast transformation. Using this assay, phosphodiesterase type 5 inhibitors (PDE5i) and selective oestrogen receptor modulators (SERMs) were identified to significantly inhibit myofibroblast transformation. A PDE5i (vardenafil) and an SERM (tamoxifen) inhibited myofibroblast transformation, collagen gel contraction, and extracellular matrix production in a synergistic fashion. In a rat model of PD, the antifibrotic effect of the combination of vardenafil and tamoxifen was greater than that of each drug alone. This study is limited by not providing a molecular mechanism for the proposed synergy.

Conclusions: This is the first demonstration of a synergistic activity between a PDE5i and an SERM discovered through a phenotypic screening approach. Future clinical trials using a combination of these drugs should be considered during the active phase of PD, given the early evidence of benefit in both in vitro and in vivo models.

Patient Summary: This report suggests that the combination of a phosphodiesterase type 5 inhibitor and a selective oestrogen receptor modulator may be efficacious in treating Peyronie's disease in its active phase.
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http://dx.doi.org/10.1016/j.eururo.2018.10.014DOI Listing
February 2019

Understanding the Role of Adenosine Receptors in the Myofibroblast Transformation in Peyronie's Disease.

J Sex Med 2018 07 8;15(7):947-957. Epub 2018 Jun 8.

Anglia Ruskin University, Faculty of Medical Science, Chelmsford, United Kingdom. Electronic address:

Background: Peyronie's disease (PD) is a chronic fibrotic disease of the penis affecting a significant number of men worldwide without effective medical treatments. Myofibroblasts are pivotal in the pathogenesis of PD. Adenosine and adenosine receptors have been suggested to be involved in the pathophysiology of fibrosis.

Aim: To understand the role of adenosine receptors in myofibroblast transformation in PD.

Methods: Fibroblasts were isolated from the non-PD tunica albuginea (TA) tissue and PD plaque tissue and were transformed into myofibroblasts using transforming growth factor (TGF)-β1. Quantification of α-smooth muscle actin and adenosine receptors (adenosine receptor A1 [ADORA1], adenosine receptor A2A, adenosine receptor A2B [ADORA2B], and adenosine receptor A3) was performed using immuno-cytochemistry, in-cell enzyme-linked immuno-sorbent assay (ICE), and real-time reverse transcription quantitative polymerase chain reaction. The effect of various adenosine receptor agonists or antagonists on TGF-β1-induced myofibroblast transformation was measured using ICE.

Outcomes: Expression of adenosine receptors in myofibroblasts obtained from human TA and the effect of adenosine receptor ligands on myofibroblast transformation were investigated.

Results: The experiments showed that the protein and messenger RNA levels of α-smooth muscle actin in non-PD TA cells and PD plaque-derived cells were significantly higher in cells exposed to TGF-β1 than those not treated with TGF-β1. 2 of 4 adenosine receptors (ADORA1 and ADORA2B) were found to be expressed in both cell populations. Among various adenosine receptor agonists/antagonist investigated, only ADORA2B agonist, BAY 60-6583, significantly inhibited myofibroblast transformation in a concentration-dependent manner when applied simultaneously with TGF-β1 (IC = 30 μmol/L).

Clinical Translation: ADORA2B agonists may be clinically efficacious in early-stage PD. STRENGTHS & LIMITATIONS: The strength of this study is the use of primary fibroblasts from human TA. Limitation of the study is the high concentrations of the ligands used.

Conclusion: The effect of an ADORA2B agonist on TGF-β1-induced myofibroblast transformation shows a novel potential therapeutic target for PD if applied during early, non-stable phase of PD. Mateus M, Ilg MM, Stebbeds WJ, et al. Understanding the Role of Adenosine Receptors in the Myofibroblast Transformation in Peyronie's Disease. J Sex Med 2018;15:947-957.
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http://dx.doi.org/10.1016/j.jsxm.2018.05.003DOI Listing
July 2018

Early Effect of Bariatric Surgery on Urogenital Function in Morbidly Obese Men.

J Sex Med 2017 02 10;14(2):205-214. Epub 2017 Jan 10.

Anglia Ruskin University, Chelmsford, Essex, UK. Electronic address:

Introduction: Obesity is an independent risk factor for erectile dysfunction (ED) and lower urinary tract symptoms (LUTS). Bariatric surgery has been shown to improve erectile function and urinary symptoms in medium- to long-term studies (3- to 12-month postoperative follow-up).

Aim: To investigate the early effect (1 month postoperatively) of bariatric surgery on ED and LUTS, which has not previously been investigated.

Methods: Morbidly obese men (body mass index > 35 kg/m) undergoing bariatric surgery were asked to complete the International Index of Erectile Function (IIEF) and International Prostate Symptom Score (IPSS) questionnaires before surgery and 1, 3, and 6 months after surgery.

Main Outcome Measure: The influence of bariatric surgery on urogenital function, body mass index, fasting blood glucose, and glycated hemoglobin were analyzed using parametric and non-parametric tests for paired samples.

Results: Of 30 patients who completed the study, 18 reported ED (IIEF score < 25) and 14 reported moderate or severe LUTS (IPSS ≥ 8) before the operation. Twelve patients had ED and moderate or severe LUTS. IIEF score, IPSS, body mass index, percentage of weight loss, fasting blood glucose, and glycated hemoglobin showed significant and rapid improvement after bariatric surgery starting at the 1-month postoperative time point and improvement continued throughout the study in all patients with ED or moderate to severe LUTS.

Conclusion: This is the first study showing improvement in erectile and urinary function within 1 month after bariatric surgery, an effect that was parallel to glycemic improvement and weight loss.
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http://dx.doi.org/10.1016/j.jsxm.2016.12.004DOI Listing
February 2017

Histone deacetylase inhibition: a new target for Peyronie's disease?

BJU Int 2014 Dec;114(6):796

Centre for Biomedical Engineering, Cranfield University, Cranfield, London, UK.

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http://dx.doi.org/10.1111/bju.12835DOI Listing
December 2014

The role of intrinsic pathway in apoptosis activation and progression in Peyronie's disease.

Biomed Res Int 2014 13;2014:616149. Epub 2014 Aug 13.

Department of Urology, School of Medicine Tor Vergata University of Rome, 00133 Rome, Italy.

Peyronie's disease (PD) is characterized with formation of fibrous plaques which result in penile deformity, pain, and erectile dysfunction. The aim of this study was to investigate the activation of the intrinsic apoptotic pathway in plaques from PD patients. Tunica albuginea from either PD or control patients was assessed for the expression of bax, bcl-2 and caspases 9 and 3 using immunohistochemistry and by measurement of apoptotic cells using TUNEL assay. Bax overexpression was observed in metaplastic bone tissue, in fibroblasts, and in myofibroblast of plaques from PD patients. Little or no bcl-2 immunostaining was detected in samples from either patients or controls. Caspase 3 immunostaining was very strong in fibrous tissue, in metaplasic bone osteocytes, and in primary ossification center osteoblasts. Moderate caspase 9 immunostaining was seen in fibrous cells plaques and in osteocytes and osteoblasts of primary ossification centers from PD patients. Control samples were negative for caspase 9 immunostaining. In PD patients the TUNEL immunoassay showed intense immunostaining of fibroblasts and myofibroblasts, the absence of apoptotic cells in metaplasic bone tissue and on the border between fibrous and metaplastic bone tissue. Apoptosis occurs in stabilized PD plaques and is partly induced by the intrinsic pathway.
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http://dx.doi.org/10.1155/2014/616149DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4147380PMC
June 2015

Sexual enhancement products for sale online: raising awareness of the psychoactive effects of yohimbine, maca, horny goat weed, and Ginkgo biloba.

Biomed Res Int 2014 15;2014:841798. Epub 2014 Jun 15.

Cranfield University, Bedfordshire MK43 0AL, UK.

Introduction: The use of unlicensed food and herbal supplements to enhance sexual functions is drastically increasing. This phenomenon, combined with the availability of these products over the Internet, represents a challenge from a clinical and a public health perspective.

Methods: A comprehensive multilingual assessment of websites, drug fora, and other online resources was carried out between February and July 2013 with exploratory qualitative searches including 203 websites. Additional searches were conducted using the Global Public Health Intelligence Network (GPHIN). Once the active constitutes of the products were identified, a comprehensive literature search was carried out using PsycInfo and PubMed.

Results: The most common sexual enhancement products available on the Internet were identified. Their active ingredients included yohimbine, maca, horny goat weed and Ginkgo biloba. These four substances were reported with the occurrence of adverse events and the induction of psychological symptoms, such as mood changes, anxiety, and hallucinations as well as addictive behaviours.

Conclusions: Uncontrolled availability of sexual enhancement products that contain potentially harmful substances is a major public health concern. The possible impact on population health, particularly among subjects with psychiatric disorders, usually at risk for sexual dysfunction, may be significant. This new trend needs to be extensively studied and monitored.
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http://dx.doi.org/10.1155/2014/841798DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4082836PMC
March 2015

Microvascular dysfunction and efficacy of PDE5 inhibitors in BPH-LUTS.

Nat Rev Urol 2014 04 11;11(4):231-41. Epub 2014 Mar 11.

Lilly UK, Lilly House, Priestley Road, Basingstoke, Hampshire RG24 9NL, UK.

Benign prostatic hyperplasia (BPH)-related lower urinary tract symptoms (LUTS) and erectile dysfunction commonly coexist, and both respond to phosphodiesterase (PDE) 5 inhibitors, suggesting a shared pathophysiological mechanism. We propose that both BPH-LUTS and erectile dysfunction are caused by microvascular dysfunction within the pelvic organs, and we present an overview of preclinical and clinical studies supporting the hypothesis that, within both the penis and the lower urinary tract, a combination of endothelial and neural dysfunction leads to a vicious cycle of hypoxia, vasoconstriction, altered smooth muscle contractility, and degeneration of autonomic neurons and ganglia. This hypothesis explains much of the preclinical and clinical research relating to these two conditions, and provides a rationale for further investigation into the effects of PDE5 inhibitors on the pathophysiology and symptoms of BPH-LUTS.
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http://dx.doi.org/10.1038/nrurol.2014.53DOI Listing
April 2014

Vasa nervorum in rat major pelvic ganglion are innervated by nitrergic nerve fibers.

J Sex Med 2013 Dec 12;10(12):2967-74. Epub 2013 Sep 12.

Cranfield Health, Cranfield University, Cranfield, Bedfordshire, UK.

Introduction: The vasa nervorum comprises a network of small diameter blood vessels that provide blood supply to nerves and ganglia. The cell bodies of autonomic nerves innervating the urogenital organs are housed in the major pelvic ganglia (MPG) in rats. The vasa nervorum of rat MPG have not been characterized previously, and it is not known whether these blood vessels are innervated by neuronal nitric oxide synthase (nNOS) containing nitrergic nerves.

Aim: To characterize the blood vessels in and around the rat MPG and to assess their nitrergic innervation.

Main Outcome Measures: Characterization of small blood vessels in and around the rat MPG and expression of nNOS in nerve fibers around those blood vessels.

Methods: MPG were obtained from healthy Sprague Dawley rats, fixed in paraformaldehyde, frozen and sectioned using a cryostat. The blood vessels and their nitrergic innervation were assessed with immunohistochemistry using antibodies against alpha-smooth muscle actin (smooth muscle marker), CD31 (endothelial marker), collagen IV (basal membrane marker) and nNOS. The immunofluorescence was imaged using a laser scanning confocal microscope.

Results: The neuronal cell bodies were contained within a capsule in the MPG. Blood vessels were observed within the capsule of the MPG as well as outside the capsule. The blood vessels inside the capsule were CD31-positive capillaries with no smooth muscle staining. Outside the capsule capillaries, arterioles and venules were observed. The extra-capsular arterioles and venules, but not the capillaries were innervated by nNOS-positive nerve fibers.

Conclusions: This study, to our knowledge, is the first to demonstrate the blood vessel distribution pattern and their nitrergic innervation in the rat MPG. While similar studies in human pelvic plexus are warranted, these results suggest that the blood flow in the MPG may be regulated by nitrergic nerve fibers and reveal a reciprocal relationship between nerves and blood vessels.
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http://dx.doi.org/10.1111/jsm.12313DOI Listing
December 2013

Common pitfalls in some of the experimental studies in erectile function and dysfunction: a consensus article.

J Sex Med 2012 Nov 13;9(11):2770-84. Epub 2012 Sep 13.

Cranfield Health, Cranfield University, Bedfordshire, UK.

Introduction: Experimental studies investigating physiology of erectile function and pathophysiology erectile dysfunction employ several in vitro and in vivo techniques. As the field of sexual medicine expanding, the proper conduct of such techniques is becoming an even more important necessity than before.

Aim: This review article aims to guide scientists, particularly young researchers and new comers in the field, toward employment of these techniques in an appropriate, timely, and competent fashion.

Methods: The authors reviewed the existing available published articles on the following topics: intracavernosal pressure measurements, cavernous nerve injury models, nitric oxide-cyclic guanosine monophosphate pathway, hypertension- and smoking-induced erectile dysfunction models, and stem cells.

Results: The authors present a consensus on how to best perform these models and techniques and also highlight the pitfalls.

Conclusions: The authors hope that this article will assist and encourage young scientists in the field and that similar articles covering other important models will be also available to them soon.
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http://dx.doi.org/10.1111/j.1743-6109.2012.02916.xDOI Listing
November 2012

Challenges in sexual medicine.

Nat Rev Urol 2012 09 10;9(9):537-42. Epub 2012 Jul 10.

Cranfield Health, Cranfield University, Bedfordshire MK43 0AL, UK.

The sexual medicine field has been in mode of revolution until recently. Like all other fields of biomedical research, the economic situation around the world has had a negative impact on the field's momentum-research funding bodies, regulatory bodies and pharmaceutical companies seem to have placed sexual medicine in their low-priority list. But this is not the only challenge the field is facing. The successful development of phosphodiesterase type 5 (PDE5) inhibitors for treatment of erectile dysfunction (ED) means that research in this area seems to have slowed. However, there remain several unmet medical needs within sexual medicine such as premature ejaculation, severe ED and hypoactive sexual desire disorder, which await novel therapeutic approaches. Despite these challenges, research into finding and developing such therapies is likely to continue in the sexual medicine field, in an effort to improve the lives of our patients, who wait for effective therapies.
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http://dx.doi.org/10.1038/nrurol.2012.134DOI Listing
September 2012

The beta3-adrenoceptor agonist GW427353 (Solabegron) decreases excitability of human enteric neurons via release of somatostatin.

Gastroenterology 2010 Jan 25;138(1):266-74. Epub 2009 Sep 25.

Human Biology, Technische Universität München, Freising, Germany.

Background & Aims: beta3 Adrenoceptor (beta3-AR) is expressed on adipocytes and enteric neurons. GW427353 is a human selective beta3-AR agonist with visceral analgesic effects. Some of its effects may involve release of somatostatin (SST) and actions on enteric neurons. The aim of this study was to investigate the mode of action of GW427353 in human submucous neurons.

Methods: Voltage sensitive dye imaging was used to record from human submucous neurons. SST release from human primary adipocytes was measured with enzyme-linked immunoabsorbent assay. Immunohistochemistry was used to detect adiponectin, beta3-AR, SST, SST2 receptors, tyrosine hydroxylase (TH), and protein gene product 9.5.

Results: Confocal imaging showed cytoplasmic beta3-AR labeling in somata of submucous neurons and nerve varicosities. GW427353 had no direct postsynaptic actions but decreased fast synaptic input to submucous neurons. Tissue perfusion with GW427353 reduced nicotine-evoked neuronal spike frequency, an effect prevented by the beta3-AR antagonist SR-59230 and the SST2-receptor antagonist CYN154806 and mimicked by the SST2 receptor agonist octreotide. Adipocytes expressed adiponectin, beta3-AR, and SST. TH-positive fibers were in close proximity to adipocytes. Submucous neurons expressed SST2 receptors. Human primary adipocytes released SST in response to GW427353 in a concentration-dependent manner, an effect abolished by SR-59230.

Conclusions: Inhibitory action of GW427353 involves release of SST which stimulates inhibitory SST2 receptors on human submucous neurons. Adipocytes are a potential source for SST. beta3-AR activation may be a promising approach to reduce enteric neuron hyperexcitability. The action of GW427353 may be the neurophysiologic correlate of its beneficial effect in patients with irritable bowel syndrome.
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http://dx.doi.org/10.1053/j.gastro.2009.09.046DOI Listing
January 2010

Potentiation by cholinesterase inhibitors of cholinergic activity in rat isolated stomach and colon.

Pharmacol Res 2008 Nov-Dec;58(5-6):297-301. Epub 2008 Sep 9.

Neuroscience Centre of Excellence for Drug Discovery, GlaxoSmithKline, Harlow, Essex, UK.

Acetylcholinesterase (AChE) inhibitors stimulate gastrointestinal (GI) motility and are potential treatments of conditions associated with inadequate GI motility. The ability of itopride to facilitate neuronally (predominantly cholinergic) mediated contractions of rat isolated stomach, evoked by electrical field stimulation (EFS), has been compared with other cholinesterase inhibitors and with tegaserod, a clinically effective prokinetic and non-selective 5-HT(4) receptor agonist which also facilitates GI cholinergic function. Neostigmine greatly increased EFS-evoked contractions over a narrow concentration range (0.01-1 microM; 754+/-337% facilitation at 1 microM); higher concentrations (1, 3 microM) also increased muscle tension. Donepezil increased EFS-evoked contractions gradually over the full range of concentrations (0.01-10 microM; maximum increase 516+/-20% at 10 microM). Itopride increased the contractions even more gradually, rising to 188+/-84% at 10 microM. The butyrylcholinesterase inhibitor iso-OMPA 0.01-10 microM also increased EFS-evoked contractions, to a maximum of 36+/-5.0% at 10 microM, similar to that caused by tegaserod (35+/-5.2% increase at 1 microM). The effects of tegaserod, but not itopride were inhibited by the 5-HT(4) receptor antagonist SB-204070A 0.3 microM. In rat isolated colon, neostigmine was again the most efficacious, causing a defined maximum increase in EFS-evoked contractions (343+/-82% at 10 microM), without changing muscle tension. Maximum increases caused by donepezil and itopride were, respectively, 57.6+/-20 and 43+/-15% at 10 microM. These data indicate that the abilities of different AChE inhibitors to increase GI cholinergic activity differ markedly. Understanding the reasons is essential if AChE inhibitors are to be optimally developed as GI prokinetics.
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http://dx.doi.org/10.1016/j.phrs.2008.09.001DOI Listing
February 2009

The investigation of putative agents, using an in vitro model, to prevent cavernosal smooth muscle dysfunction during low-flow priapism.

BJU Int 2008 Sep 28;102(8):988-92. Epub 2008 Jun 28.

Wolfson Institute for Biomedical Research, University College London, Gower Street, London, UK.

Objective: To investigate the effect of putative agents for preventing irreversible smooth muscle dysfunction, using an in vitro model of low-flow priapism (a condition conventionally managed using a combination of corporal blood aspiration and instillation of alpha-adrenergic agonists), as failure of detumescence results in a high incidence of erectile dysfunction.

Materials And Methods: We investigated the effects of several agents (N-acetylcysteine, BayK 8644, glutathione, digoxin, calcium and N(omega)-nitro-l-arginine methyl ester) on the recovery of smooth muscle tone after exposure to 4 h of a combination of hypoxia, glucopenia and acidosis in corpus cavernosum isolated from rabbit.

Results: After 4 h of ischaemia, none of the agents were able to prevent irreversible smooth muscle dysfunction.

Conclusion: Prolonged low-flow priapism leads to smooth muscle dysfunction and fibrosis within the corpus cavernosum. When alpha-adrenergic agents fail to reverse the condition, surgical intervention is required. We showed that the administration of novel agents, including antioxidants, does not prevent smooth muscle dysfunction.
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http://dx.doi.org/10.1111/j.1464-410X.2008.07778.xDOI Listing
September 2008

Demonstration of functional neuronal beta3-adrenoceptors within the enteric nervous system.

Gastroenterology 2007 Jul 10;133(1):175-83. Epub 2007 May 10.

Neurology and Gastrointestinal Centre of Excellence in Drug Discovery, GlaxoSmithKline, Harlow, United Kingdom.

Background & Aims: Although the beta(3)-adrenoceptor (AR) has been suggested to be involved in regulation of gut motility and visceral algesia, the precise mechanisms have been unknown. beta(3)-AR has been postulated to have a nonneuronal expression, being initially characterized in adipocytes and subsequently in the smooth muscle. We aimed to investigate the expression of beta(3)-AR in human enteric nervous system and its role in motility and visceral algesia.

Methods: The expression of beta(3)-AR in human colon myenteric and submucosal plexus was investigated using immunohistochemistry. The effects of a beta(3)-AR agonist on nerve-evoked and carbachol-induced contractions as well as somatostatin release were investigated in strips of human colon. The effect of an agonist on diarrhea and visceral pain was investigated in vivo in rat models.

Results: beta(3)-AR is expressed in cholinergic neurons in the myenteric plexus and submucosal plexus of human colon. Activation of beta(3)-AR causes the release of somatostatin from human isolated colon. In a rat model of visceral pain, beta(3)-AR agonist elicits somatostatin-dependent visceral analgesia. beta(3)-AR agonists inhibit cholinergically mediated muscle contraction of the human colon, as well as chemically induced diarrhea in vivo in a rat model.

Conclusions: This is the first demonstration of expression of beta(3)-AR in the enteric nervous system. Activation of these receptors results in inhibition of cholinergic contractions and enhanced release of somatostatin, which may lead to visceral analgesia and inhibition of diarrhea. Therefore, beta(3)-AR could be a novel therapeutic target for functional gastrointestinal disorders.
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http://dx.doi.org/10.1053/j.gastro.2007.05.009DOI Listing
July 2007

The breakdown of preformed advanced glycation end products reverses erectile dysfunction in streptozotocin-induced diabetic rats: preventive versus curative treatment.

J Sex Med 2006 Mar;3(2):242-50; discussion 250-2

Department of Urology, Section of Andrology, Tulane University Health Sciences Center, New Orleans, LA 70112, USA.

Objectives: Accumulation of advanced glycation end products (AGEs) has been linked to many of the complications of diabetes mellitus, including erectile dysfunction (ED). Furthermore, it has been demonstrated that inhibitors of AGE formation, such as aminoguanidine, can prevent ED in diabetic animals. However, it is unknown whether late administration of a putative cross-link breaker, ALT-711, can reverse diabetic ED. We therefore compared ALT-711 and aminoguanidine in their ability to reverse ED in diabetic rats.

Materials And Methods: Male Sprague-Dawley rats were randomly divided into four groups: (i) age-matched controls; (ii) streptozotocin (STZ)-induced diabetic rats (60 mg/kg; intraperitoneal injection); (iii) STZ diabetic rats treated with ALT-711 (3 mg/kg/day, intraperitoneal injection); and (iv) STZ diabetic rats treated with aminoguanidine (1 gm/L in drinking water) during the final 6 weeks of 12 weeks of induced diabetes. At the end of 12 weeks, erectile response to cavernous nerve stimulation (CNS) was determined. Neuronal nitric oxide synthase (nNOS) contents were measured in all penises, and AGE levels were determined both in penile tissues and in serum samples.

Results: Erectile responses to CNS and penile nNOS protein content were significantly reduced, while AGE levels were elevated in the penises and serum of untreated diabetic animals. Treatment with ALT-711, but not with aminoguanidine, reversed ED and nNOS depletion and reduced serum and penile tissue AGE levels.

Conclusions: These results suggest that cross-link breakers, such as ALT-711, are the optimal therapeutic approach, compared with treatment with inhibitors of AGE formation, in the reversal of diabetes-related ED.
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http://dx.doi.org/10.1111/j.1743-6109.2006.00217.xDOI Listing
March 2006

Physiology of erectile function.

J Sex Med 2004 Nov;1(3):254-65

Fundacion para la Investigacion y el Desarrollo en Andrologia, Madrid, Spain.

Introduction: There are numerous investigations concerning the balance and interactions between relaxant and contractile factors regulating penile smooth muscle (arterial and trabecular) tone, the determinant of penile flaccidity or erection. Enhanced knowledge of erectile physiology may improve management of men with erectile dysfunction. Aim. To provide state-of-the-art knowledge on the physiology of erectile function.

Methods: An international consultation in collaboration with the major urology and sexual medicine associations assembled over 200 multidisciplinary experts from 60 countries into 17 committees. Committee members established specific objectives and scopes for various male and female sexual medicine topics. The recommendations concerning state-of-the-art knowledge in the respective sexual medicine topic represent the opinion of experts from five continents developed in a process over a two-year period. Concerning the physiology of erectile function and pathophysiology of erectile dysfunction committee, there were seven experts from five countries.

Main Outcome Measure: Expert opinion was based on the grading of evidence-based medical literature, widespread internal committee discussion, public presentation, and debate.

Results: Key roles in the mechanism determining the tone of penile smooth muscle are played by the rise of the intracellular concentration of free calcium and the sensitivity of the contractile machinery to calcium, endothelial health, endothelium-derived nitric oxide, endothelium-derived hyperpolarizing factor (EDHF), neuronal nitric oxide, cyclic guanosine monophosphate-dependent protein kinase and phosphodiesterase type 5.

Conclusions: A number of new mechanisms have been identified for the local regulation of penile smooth muscle contractility and therefore penile erection. Molecules participating in these pathways can be considered targets for the development of new treatments to treat erectile dysfunction.
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http://dx.doi.org/10.1111/j.1743-6109.04038.xDOI Listing
November 2004

A nitric oxide-releasing PDE5 inhibitor relaxes human corpus cavernosum in the absence of endogenous nitric oxide.

J Sex Med 2005 Jan;2(1):53-7

The St. Peter's Andrology Centre and Wolfson Institute for Biomedical Research, University College London, UK.

Introduction: In conditions with severe deficiency of endogenous nitric oxide (NO), such as long-term diabetes and cavernosal nerve injury, phosphodiesterase type 5 (PDE5) inhibitors have reduced efficacy in the treatment of erectile dysfunction. NO-releasing PDE5 inhibitors could be an alternative therapeutic approach in such cases.

Aim: We therefore aimed to compare sildenafil and NO-releasing sildenafil (NCX-911) in relaxing human corpus cavernosum in the absence or presence of endogenous NO.

Methods: The two compounds were compared in reducing the phenylephrine-induced tone of human corpus cavernosum in the presence or absence of an inhibitor of NO synthase (L-NAME; 500 microM) or an inhibitor of soluble guanylate cyclase (ODQ, 10 microM).

Results: NCX-911 was as potent as sildenafil in control conditions (EC(50) = 733.1 +/- 94.4 nM and 800.7 +/- 155.8 nM, respectively). The potency of NCX-911 was not altered but that of sildenafil decreased significantly in the presence of L-NAME (EC(50) = 980.4 +/- 106.7 nM and 2446.7 +/- 256.8 nM, respectively; P < 0.001 for sildenafil vs. control). Both compounds below 1 microM failed to induce relaxation in the presence of ODQ (EC(50) = 6,578 +/- 1150 nM and 6,488 +/- 938 nM for NCX-911 and sildenafil, respectively).

Conclusion: These results show that the potency of NCX-911 was maintained unlike sildenafil in the absence of endogenous NO confirming the potential use of NO-releasing PDE5 inhibitors in NO-deficient conditions.
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http://dx.doi.org/10.1111/j.1743-6109.2005.20105.xDOI Listing
January 2005

Pathophysiology of erectile dysfunction.

J Sex Med 2005 Jan;2(1):26-39

Fundación para la Investigación y el Desarrollo en Andrología, Madrid, Spain.

Introduction: Multiple regulatory systems are involved in normal erectile function. Disruption of psychological, neurological, hormonal, vascular, and cavernosal factors, individually, or in combination, can induced erectile dysfunction (ED). The contribution of neurogenic, vascular, and cavernosal factors was thoroughly reviewed by our committee, while psychological and hormonal factors contributing to ED were evaluated by other committees.

Aim: To provide state of the art knowledge on the physiology of ED.

Methods: An international consultation in collaboration with the major urology and sexual medicine associations assembled over 200 multidisciplinary experts from 60 countries into 17 committees. Committee members established specific objectives and scopes for various male and female sexual medicine topics. The recommendations concerning state-of-the-art knowledge in the respective sexual medicine topic represent the opinion of experts from five different continents developed in a process over a 2-year period. Concerning the pathophysiology of ED committee, there were seven experts from five different countries.

Main Outcome Measure: Expert opinion was based on the grading of evidence-based medical literature, widespread internal committee discussion, public presentation, and debate.

Results: The epidemiology and classification of neurogenic ED was reviewed. The evidence for the association between vascular ED and atherosclerosis/hypercholesterolemia, hypertension and diabetes was evaluated. In addition, the pathophysiological mechanisms implicated in vascular ED were defined, including: arterial remodeling, increased vasoconstriction, impaired neurogenic vasodilatation, and impaired endothelium-dependent vasodilatation. The possible mechanisms underlying the association between chronic renal failure and ED were also evaluated as well as the evidence supporting the association of ED with various classes of medications.

Conclusions: A better understanding of how diseases interfere with the physiological mechanisms that regulate penile erection has been achieved over the last few years, which helps establish a strategy for the prevention and treatment of ED.
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http://dx.doi.org/10.1111/j.1743-6109.2005.20103.xDOI Listing
January 2005

Nitrergic neurodegeneration in cerebral arteries of streptozotocin-induced diabetic rats: a new insight into diabetic stroke.

Diabetes 2005 Jan;54(1):212-9

Wolfson Institute for Biomedical Research, University College London, Gower St., Cruciform Building, London WC1E 6BT, UK.

Although autonomic neuropathy is recognized as an independent risk factor for stroke in diabetes, the mechanism by which autonomic nerves are involved in this pathology is unknown. Parasympathetic (cholinergic) nerves of the autonomic nervous system are known to innervate and to cause relaxation of cerebral arteries by releasing nitric oxide (NO); hence, they are called nitrergic nerves. However, the effect of diabetes on nitrergic nerves is unknown. Here, we show that perivascular nitrergic nerves around the cerebral arteries degenerate in two phases in streptozotocin-induced diabetic rats. In the first phase, perivascular nitrergic nerve fibers remain intact while they lose their neuronal NO synthase content. This phase is reversible with insulin treatment. In the second phase, nitrergic cell bodies in the ganglia are lost via apoptosis in an irreversible manner. Throughout the two phases, irreversible thickening of the smooth muscle layer of cerebral arteries is observed. This is the first demonstration of nitrergic degeneration in diabetic cerebral arteries, which could elucidate the link between diabetic autonomic neuropathy and stroke.
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http://dx.doi.org/10.2337/diabetes.54.1.212DOI Listing
January 2005

Morphological, chemical and functional analysis of catuaba preparations.

Planta Med 2004 Oct;70(10):993-1000

Institute of Pharmacognosy, University of Vienna, PharmaCenterVienna, Vienna, Austria.

Fourteen commercial samples of the popular Brazilian aphrodisiac Catuaba specified as bark drugs of Anemopaegma, Erythroxylum and Trichilia species were examined for identity and purity. Only a minority of the examined Catuaba samples contained the crude drugs claimed on the labels. More than half of the products were adulterated with different crude drugs. The majority of the samples contained a bark originating from Trichilia catigua. The TLC fingerprints confirmed the heterogeneity, in 50% of the samples tropane alkaloids of various concentrations were detected. TLC and HPLC methods for separation and identification of the tropane alkaloids were developed and their analytical data (RF values, retention times, ESI-MS) given. The structure elucidation of the two main alkaloids, catuabine D and its hydroxymethyl derivative, is presented. The 1H- and 13C-NMR assignments of these alkaloids are discussed with regard to literature data. Neither aqueous nor methanolic extracts of the Trichilia catigua reference material nor alkaloid-enriched fractions of commercial samples showed any effect on the rabbit corpus cavernosum in an in vitro test.
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http://dx.doi.org/10.1055/s-2004-832627DOI Listing
October 2004

RhoA/Rho-kinase suppresses endothelial nitric oxide synthase in the penis: a mechanism for diabetes-associated erectile dysfunction.

Proc Natl Acad Sci U S A 2004 Jun 7;101(24):9121-6. Epub 2004 Jun 7.

Department of Urology, Tulane Health Sciences Center, New Orleans, LA 70112, USA.

Significant impairment in endothelial-derived nitric oxide is present in the diabetic corpus cavernosum. RhoA/Rho-kinase may suppress endothelial nitric oxide synthase (eNOS). Here, we tested the hypothesis that RhoA/Rho-kinase contributes to diabetes-related erectile dysfunction and down-regulation of eNOS in the streptozotocin (STZ)-diabetic rat penis. Colocalization of Rho-kinase and eNOS protein was present in the endothelium of the corpus cavernosum. RhoA/Rho-kinase protein abundance and MYPT-1 phosphorylation at Thr-696 were elevated in the STZ-diabetic rat penis. In addition, eNOS protein expression, cavernosal constitutive NOS activity, and cGMP levels were reduced in the STZ-diabetic penis. To assess the functional role of RhoA/Rho-kinase in the penis, we evaluated the effects of an adeno-associated virus encoding the dominant-negative RhoA mutant (AAVTCMV19NRhoA) on RhoA/Rho-kinase and eNOS and erectile function in vivo in the STZ-diabetic rat. STZ-diabetic rats transfected with AAVCMVT19NRhoA had a reduction in RhoA/Rho-kinase and MYPT-1 phosphorylation at a time when cavernosal eNOS protein, constitutive NOS activity, and cGMP levels were restored to levels found in the control rats. There was a significant decrease in erectile response to cavernosal nerve stimulation in the STZ-diabetic rat. AAVT19NRhoA gene transfer improved erectile responses in the STZ-diabetic rat to values similar to control. These data demonstrate a previously undescribed mechanism for the down-regulation of penile eNOS in diabetes mediated by activation of the RhoA/Rho-kinase pathway. Importantly, these data imply that inhibition of RhoA/Rho-kinase improves eNOS protein content and activity thus restoring erectile function in diabetes.
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http://dx.doi.org/10.1073/pnas.0400520101DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC428483PMC
June 2004

A comparative study of sildenafil, NCX-911 and BAY41-2272 on the anococcygeus muscle of diabetic rats.

Int J Impot Res 2004 Dec;16(6):479-85

Wolfson Institute for Biomedical Research, University College London, Gower Street, Cruciform Building, London, UK.

We compared the effects of a nitric oxide (NO)-releasing sildenafil (NCX-911), NO-independent soluble guanylate cyclase activator (BAY41-2272) and sildenafil on the anococcygeus muscle from streptozotocin-induced 16-weeks diabetic rats. NCX-911, BAY41-2272 and sildenafil reduced the phenylephrine-induced tone in the control group (EC50=1088.8+/-165.0, 151.6+/-9.3 and 827.1+/-167.3 nM, respectively). The potencies of NCX-911 and BAY41-2272 were not altered, but that of sildenafil was significantly reduced in the diabetic group. EC50 values for NCX-911, BAY41-2272 and sildenafil in the diabetic group were 1765.9+/-303.5, 209.7+/-27.3 and 2842.2+/-640.3 nM, respectively (P<0.05 for sildenafil). Nitrergic relaxation responses were significantly decreased in the diabetic group. The remaining nitrergic relaxation responses were potentiated by BAY41-2272 but not by sildenafil or NCX-911. These results confirm that endogenous NO derived from nitrergic nerves is significantly decreased in diabetes, and suggest that NO-releasing PDE5 inhibitors and NO-independent soluble guanylate cyclase activators could be more useful than PDE5 inhibitors in the treatment of ED in long-term diabetes.
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http://dx.doi.org/10.1038/sj.ijir.3901224DOI Listing
December 2004

Y-27632, a Rho-kinase inhibitor, inhibits proliferation and adrenergic contraction of prostatic smooth muscle cells.

J Urol 2003 Dec;170(6 Pt 1):2517-22

Wolfson Institute for Biomedical Research, University College London, United Kingdom.

Purpose: Benign prostatic hyperplasia (BPH) causes mechanical urinary flow obstruction by 2 components, namely an enlarged prostate (static component) and elevated smooth muscle tone (dynamic component). Currently available treatments for BPH aim to inhibit the proliferation of prostatic cells or decrease the elevated tone. To our knowledge no single agent that can achieve these 2 ends has yet been identified. A specific inhibitor of Rho-kinase, Y-27632 ((+)-(R)-trans-4-(1-aminoethyl)-N-(4-pyridyl)cyclohexanecarboxamide dihydrochloride), has been demonstrated to cause smooth muscle relaxation and inhibit smooth muscle cell proliferation. Therefore, we investigated the effect of Y-27632 on prostatic smooth muscle proliferation and tone.

Materials And Methods: Rho-kinase expression was investigated by immunocytochemistry and immunoblotting in smooth muscle cells obtained from rat and human prostates. The effect of Y-27632 was examined on the proliferation of these cells and on the contractions elicited by electrical field stimulation and exogenous phenylephrine in rat prostatic strips.

Results: Immunoblot and immunofluorescence analysis showed that Rho-kinase is present in the cytosol and located in the perinuclear region in human and rat prostatic smooth muscle cells. Y-27632 decreased the proliferation of human and rat prostatic smooth muscle cells, and inhibited noradrenergic contractions elicited by electrical field stimulation and exogenous phenylephrine in rat prostatic strips (EC50 17.8 +/- 4.8 and 7.8 +/- 2.1 microM, respectively).

Conclusions: To our knowledge we report the first demonstration of the presence of Rho-kinase in prostatic smooth muscle cells, and of the relaxant and antiproliferative effect of a Rho-kinase inhibitor. We suggest a novel use for Rho-kinase inhibitors in the treatment of BPH as a single agent with dual action.
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http://dx.doi.org/10.1097/01.ju.0000085024.47406.6cDOI Listing
December 2003