RESUMEN
Low-intensity extracorporeal shockwave therapy (LI-ESWT) to the penis has recently emerged as novel therapeutic option in the treatment of erectile dysfunction (ED). Randomized-controlled studies investigating the effect of this new treatment modality revealed promising results in men with vasculogenic ED. However, the efficacy of LI-ESWT in men who develop ED following radical prostatectomy (RP) remains obscure due to the exclusion of this group in nearly all clinical trials. In this review, the authors synthesize the findings from available preclinical and clinical studies that examine the potential utility of LI-ESWT in men with post-RP ED.
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Disfunción Eréctil/terapia , Complicaciones Posoperatorias/terapia , Terapia por Ultrasonido , Animales , Modelos Animales de Enfermedad , Disfunción Eréctil/etiología , Humanos , Masculino , Complicaciones Posoperatorias/etiología , Prostatectomía/efectos adversosRESUMEN
PURPOSE: Azoospermia is one of the major causes of male infertility and is basically classified into obstructive (OA) and non-obstructive azoospermia (NOA). The molecular background of NOA still largely remains elusive. It has been shown that the poly(A)-binding proteins (PABPs) essentially play critical roles in stabilization and translational control of the mRNAs during spermatogenesis. METHODS: In the present study, we aim to evaluate expression levels of the PABP genes, EPAB, PABPC1, and PABPC3, in the testicular biopsy samples and in the isolated spermatocyte (SC) and round spermatid (RS) fractions obtained from men with various types of NOA including hypospermatogenesis (hyposperm), RS arrest, SC arrest, and Sertoli cell-only syndrome (SCO). RESULTS: In the testicular biopsy samples, both PABPC1 and PABPC3 mRNA expressions were gradually decreased from hyposperm to SCO groups (P < 0.05), whereas there was no remarkable difference for the EPAB expression among groups. The expression levels of cytoplasmically localized PABPC1 and PABPC3 proteins dramatically reduced from hyposperm to SCO groups (P < 0.05). In the isolated SC and RS fractions, the EPAB, PABPC1, and PABPC3 mRNA expressions were gradually decreased from hyposperm to SC arrest groups (P < 0.05). Similarly, both PABPC1 and PABPC3 proteins were expressed at higher levels in the SC and RS fractions from hyposperm group when compared to the SC and RS fractions from either RS arrest or SC arrest group (P < 0.05). CONCLUSION: Our findings suggest that observed significant alterations in the PABPs expression may have an implication for development of different NOA forms.
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Azoospermia/genética , Proteína I de Unión a Poli(A)/genética , Proteínas de Unión a Poli(A)/genética , Testículo/fisiología , Adulto , Anciano , Biopsia , Regulación de la Expresión Génica , Humanos , Masculino , Persona de Mediana Edad , Oligospermia/genética , Oligospermia/patología , Proteína I de Unión a Poli(A)/metabolismo , Proteínas de Unión a Poli(A)/metabolismo , Síndrome de Sólo Células de Sertoli/genética , Síndrome de Sólo Células de Sertoli/patología , Testículo/fisiopatologíaRESUMEN
The relationship between erectile dysfunction (ED) and chronic renal failure (CRF) has been reported in several studies. This study aimed to investigate whether the chronic use of sildenafil could enhance the erectile capacity in CRF-induced rats. In addition, we assessed the effect of that treatment on certain molecules, which have been suggested to play crucial roles in erectile physiology and CRF-related ED as well. Three groups of animals were utilized: (1) age-matched control rats, (2) CRF-induced rats, (3) CRF-induced rats treated with chronic administration of sildenafil (5 mg kg-1 p.o. for 6 weeks [treatment started after 6 weeks of CRF induction]). At 3 months, all animals underwent cavernosal nerve stimulation (CNS) to assess erectile function. Penile tissue advanced glycation end products (AGE's)/5-hydroxymethyl-2-furaldehyde, malondialdehyde (MDA), cGMP (ELISA), inducible nitric oxide synthase (iNOS) and neuronal NOS (nNOS) (Western blot) analyses were performed in all rat groups. CRF-induced rats had a significant decrease in erectile function when compared to control rats (P < 0.05). The increase in both intracavernosal pressure (ICP) and area under the curve of CRF-induced rats treated with sildenafil (Group 3) was greater than CRF-induced rats (Group 2). Additionally, sildenafil treatment decreased AGE, MDA and iNOS levels, while it preserved nNOS and cGMP contents in CRF-induced penile tissue. Decreased AGE, MDA, iNOS and increased nNOS, cGMP levels at the sildenafil-treated group increased both ICP and Total ICP to CNS, which led to improve erectile function in CRF-induced rats. The results of the present study revealed the therapeutic effect of chronic sildenafil administration on erectile function in CRF-induced rats.
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Disfunción Eréctil/tratamiento farmacológico , Fallo Renal Crónico/fisiopatología , Erección Peniana/efectos de los fármacos , Citrato de Sildenafil/farmacología , Agentes Urológicos/farmacología , Animales , GMP Cíclico/metabolismo , Modelos Animales de Enfermedad , Disfunción Eréctil/etiología , Disfunción Eréctil/metabolismo , Disfunción Eréctil/fisiopatología , Productos Finales de Glicación Avanzada/metabolismo , Fallo Renal Crónico/complicaciones , Fallo Renal Crónico/metabolismo , Masculino , Malondialdehído/metabolismo , Óxido Nítrico Sintasa de Tipo I/metabolismo , Óxido Nítrico Sintasa de Tipo II/metabolismo , Pene/efectos de los fármacos , Pene/metabolismo , Ratas , Citrato de Sildenafil/uso terapéutico , Agentes Urológicos/uso terapéuticoRESUMEN
INTRODUCTION: In addition to the previously defined "lifelong" and "acquired" premature ejaculation (PE), the existence of two more subtypes of PE, namely "natural variable PE" and "premature-like ejaculatory dysfunction," has been proposed. AIMS: To evaluate the diagnostic value of the Premature Ejaculation Diagnostic Tool (PEDT) and Arabic Index of Premature Ejaculation (AIPE) in a population-based study, in relation to their sensitivity across these four different PE syndromes and to assess the Premature Ejaculation Profile (PEP) scores of patients with lifelong, acquired, natural variable PE and premature-like ejaculatory dysfunction. METHODS: Between June 2009 and December 2009, couples were randomly selected from 17 provinces of Turkey. Subjects with the complaint of ejaculating prematurely were classified as lifelong, acquired, natural variable PE, and premature-like ejaculatory dysfunction according to the medical and sexual history they described. PE status was also assessed with PEDT, AIPE and PEP. The sensitivity, specificity, positive predictive value and negative predictive value were calculated for PEDT and AIPE in the study population whereas detection rates of these two questionnaires were also compared among the four PE syndromes. Moreover, PEP scores of patients with lifelong, acquired, natural variable PE and premature-like ejaculatory dysfunction were compared. Significance level was considered as P < 0.05. MAIN OUTCOME MEASURES: Scores obtained from PEDT, AIPE, and PEP questionnaires. RESULTS: A total of 2,593 couples were enrolled where 512 (20.0%) male subjects reported PE. PEDT, AIPE, and PEP measures of the PE patients indicated worse sexual function (P < 0.001 each). Mean scores obtained from questionnaires were significantly better in patients with premature-like ejaculatory dysfunction and they were the worst in patients with acquired PE (P < 0.001 each). The sensitivity values of PEDT and AIPE were 89.3 and 89.5, whereas their specificity values were 50.5 and 39.1, respectively. There were statistically significant differences in detection rates of PEDT and AIPE among the four PE syndromes (P = 0.006 and P < 0.001). They were higher in acquired and lifelong PE and lower in premature-like ejaculatory dysfunction. CONCLUSION: PEDT and AIPE can diagnose PE with high sensitivity, especially in patients with lifelong and acquired PE. The complaint of patients with acquired PE seems to be more severe than those complaining of lifelong, natural variable PE and premature-like ejaculatory dysfunction patients.
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Eyaculación , Salud del Hombre , Conducta Sexual , Disfunciones Sexuales Fisiológicas/diagnóstico , Disfunciones Sexuales Psicológicas/diagnóstico , Adulto , Anciano , Andrología , Estudios Transversales , Femenino , Indicadores de Salud , Encuestas Epidemiológicas , Humanos , Masculino , Persona de Mediana Edad , Factores de Riesgo , Sensibilidad y Especificidad , Disfunciones Sexuales Fisiológicas/clasificación , Disfunciones Sexuales Psicológicas/clasificación , Estadísticas no Paramétricas , Encuestas y Cuestionarios , TurquíaRESUMEN
INTRODUCTION: In addition to the previously known lifelong and acquired premature ejaculation (PE) syndromes, the existence of two more PE syndromes has been suggested: natural variable PE and premature-like ejaculatory dysfunction. However, epidemiological studies investigating the prevalence of these four PE syndromes have yet to be conducted. AIM: To determine the prevalence of the complaint of ejaculating prematurely across the four PE syndromes. METHODS: This study, conducted between June 2009 and December 2009, was designed as a non-interventional, observational cross-sectional field survey. Participating couples were randomly selected from 17 provinces of Turkey. All participants were asked to complete a questionnaire including data regarding demographics, socioeconomic status, social and cultural factors, medical and sexual history, current medications, and ejaculation time. Subjects with a complaint of ejaculating prematurely were classified as lifelong, acquired, and natural variable PE, or premature-like ejaculatory dysfunction. MAIN OUTCOME MEASURES: The main outcome measures were prevalence of complaint of ejaculating prematurely in the general population and across the four PE syndromes. RESULTS: A total of 2,593 couples (mean age, 41.9±12.7 years for males and 38.2±12.1 years for females) were enrolled. Five-hundred twelve subjects (20.0%) complained of ejaculating prematurely. Fifty-eight (2.3%), 100 (3.9%), 215 (8.5%), and 131 (5.1%) subjects were classified as lifelong, acquired, and natural variable PE, and premature-like ejaculatory dysfunction, respectively. CONCLUSIONS: The prevalence of the complaint of ejaculating prematurely among Turkish men was 20.0%, with the highest PE syndrome being natural variable PE (8.5%) and premature-like ejaculatory dysfunction (5.1%).
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Eyaculación , Disfunciones Sexuales Psicológicas/epidemiología , Adulto , Anciano , Distribución de Chi-Cuadrado , Comorbilidad , Estudios Transversales , Femenino , Encuestas Epidemiológicas , Humanos , Masculino , Persona de Mediana Edad , Método de Montecarlo , Prevalencia , Estadísticas no Paramétricas , Síndrome , Turquía/epidemiología , Adulto JovenAsunto(s)
Apoptosis/efectos de los fármacos , Complicaciones de la Diabetes/tratamiento farmacológico , Disfunción Eréctil/tratamiento farmacológico , Músculo Liso/efectos de los fármacos , Pene/efectos de los fármacos , Inhibidores de Fosfodiesterasa 5 , Inhibidores de Fosfodiesterasa/farmacología , Proteínas Proto-Oncogénicas c-akt/efectos de los fármacos , Proteínas Proto-Oncogénicas c-akt/fisiología , Pirimidinonas/farmacología , Sulfonas/farmacología , Animales , Modelos Animales de Enfermedad , Disfunción Eréctil/etiología , Masculino , Ratas , Ratas Sprague-Dawley , Transducción de SeñalAsunto(s)
Fibroblastos/efectos de los fármacos , Interferón gamma/farmacología , Induración Peniana/tratamiento farmacológico , Biopsia , Western Blotting , Proteína Morfogenética Ósea 2 , Proteínas Morfogenéticas Óseas/metabolismo , Proteínas Morfogenéticas Óseas/farmacología , Células Cultivadas , Humanos , Técnicas para Inmunoenzimas , Interferón gamma/metabolismo , Masculino , Fosforilación , Transducción de Señal , Proteínas Smad/metabolismo , Factor de Crecimiento Transformador beta/metabolismo , Factor de Crecimiento Transformador beta/farmacologíaRESUMEN
The aim of the study was to determine the immunolocalisation of glial cell-derived neurotrophic factor (GDNF) and its receptor (GFRalpha1) in testicular dysfunction induced by experimental left varicocele. Male Wistar rats were divided randomly into two groups: a varicocele-induced group and a sham-operated group for 9, 11 and 13 weeks (each group n=6). After orchiectomy, part of the left testis from each animal was fixed, processed and embedded in paraffin wax for immunohistochemistry and the other part was fixed for ultrastructural investigations. GDNF immunoreactivity was localized in the interstitial space in Leydig cell cytoplasm and there was no significant difference (P=0.5) between the varicocele-induced groups at the various time points. GFRalpha1 localization was perinuclear in spermatids and cytoplasmic in Leydig cells. The decrease of GFRalpha1 immunoreactivity was significant (P=0.001) in varicocele-induced testis at 13 weeks when compared with the age-matched sham group. This is the first study to describe the immunolocalization patterns of GDNF and GFRalpha1 in a rat model of varicocele. Although there was no change in GDNF labelling at the different time points after varicocele, GFRalpha1 was significantly decreased in the 13-week group. Distribution of GDNF and its receptor GFRalpha1 in normal and varicocele-induced rat testes suggests both autocrine and paracrine regulation of spermatogenesis.
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Receptores del Factor Neurotrófico Derivado de la Línea Celular Glial/análisis , Factores Neurotróficos Derivados de la Línea Celular Glial/análisis , Testículo/metabolismo , Varicocele/metabolismo , Animales , Inmunohistoquímica/métodos , Masculino , Microscopía Electrónica de Transmisión , Ratas , Ratas Wistar , Espermátides/metabolismo , Espermátides/ultraestructura , Espermatogénesis , Testículo/fisiopatología , Testículo/ultraestructura , Factores de TiempoRESUMEN
Mesenchymal stem cells (MSCs) can be used in adult stem cell-based gene therapy for vascular diseases. To test the hypothesis that MSCs alone or endothelial nitric oxide synthase (eNOS)-modified MSCs can be used for treatment of erectile dysfunction (ED), syngeneic rat MSCs (rMSCs) were isolated, ex vivo expanded, transduced with adenovirus containing eNOS, and injected into the penis of aged rats. Histological analysis demonstrated that rMSCs survived for at least 21 days in corporal tissue after intracavernous injection, and an inflammatory response was not induced. Intracavernous administration of eNOS-modified rMSCs improved the erectile response in aged rats at 7 and 21 days after injection. The increase in erectile function was associated with increased eNOS protein, NOS activity, and cGMP levels. rMSCs alone increased erectile function of aged rats at day 21, but not at day 7, with the transplanted cells exhibiting positive immunostaining for several endothelial and smooth muscle cell markers. This change in rMSC phenotype was accompanied by upregulation of penile eNOS protein expression/activity and elevated cGMP levels. These findings demonstrate that an adenovirus can be used to transduce ex vivo expanded rMSCs to express eNOS and that eNOS-modified rMSCs improve erectile function in the aged rat. Intracavernous injection of unmodified wildtype rMSCs improved erectile function 21 days after injection through mechanisms involving improved endothelium-derived NO/cGMP signaling and rMSC differentiation into penile cells expressing endothelial and smooth muscle markers. These data highlight the potential clinical use of adult stem cell-based therapy for the treatment of ED.
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Disfunción Eréctil/terapia , Trasplante de Células Madre Mesenquimatosas , Células Madre Mesenquimatosas/enzimología , Óxido Nítrico Sintasa de Tipo III/genética , Envejecimiento , Animales , Masculino , Ratas , Ratas Endogámicas BNRESUMEN
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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Diabetes Mellitus Experimental/complicaciones , Angiopatías Diabéticas/complicaciones , Productos Finales de Glicación Avanzada/metabolismo , Guanidinas/administración & dosificación , Impotencia Vasculogénica/tratamiento farmacológico , Tiazoles/administración & dosificación , Animales , Angiopatías Diabéticas/inducido químicamente , Relación Dosis-Respuesta a Droga , Inmunohistoquímica , Impotencia Vasculogénica/etiología , Impotencia Vasculogénica/prevención & control , Masculino , Ratas , Ratas Sprague-Dawley , EstreptozocinaRESUMEN
Basic science research on erectile physiology has been devoted to investigating the pathogenesis of erectile dysfunction (ED) and has led to the conclusion that ED is predominately a disease of vascular origin. It is well recognized that the incidence of ED dramatically increases in men who suffer from diabetes mellitus, hypercholesterolemia, and cardiovascular disease. Endothelial nitric oxide synthase (eNOS) is an important factor in cardiovascular homeostasis, angiogenesis, and erectile function. Given the impact of endothelial-derived nitric oxide (NO) in vascular biology, a great deal of research over the past decade has focused on the role of NO synthesis from the endothelium in normal erectile physiology as well as in disease states. Loss of the functional integrity of the endothelium and subsequent endothelial dysfunction plays an integral role in the occurrence of ED. Therefore, a likely target of gene therapy for the treatment of ED is eNOS. This communication reviews the role of eNOS in erectile physiology and discusses the alterations in eNOS expression in various vascular diseases of the penis. Putative gene therapy interventions to restore eNOS expression and subsequent endothelial function may represent an exciting new therapeutic strategy for the future treatment of ED.
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Disfunción Eréctil/terapia , Terapia Genética/métodos , Óxido Nítrico Sintasa de Tipo III/genética , Óxido Nítrico Sintasa de Tipo III/metabolismo , Disfunción Eréctil/etiología , Disfunción Eréctil/fisiopatología , Humanos , Masculino , Óxido Nítrico Sintasa de Tipo III/uso terapéuticoRESUMEN
PURPOSE: We investigated the involvement of poly(adenosine diphosphate-ribose) (PAR) polymerase (PARP) activation in the development of erectile dysfunction and the therapeutic benefit of the potent PARP inhibitor INO-1001 (Inotek Pharmaceuticals Corp., Beverly, Massachusetts) in a bilateral cavernous nerve crush injury (BCNCI) model in rats. MATERIALS AND METHODS: Sprague-Dawley rats were divided into 3 groups, namely sham treated, BCNCI plus vehicle and BCNCI plus the PARP inhibitor INO-1001. One week after surgical intervention all groups underwent in vivo cavernous nerve stimulation. PAR activation, nitrotyrosine and inducible nitric oxide synthase were evaluated by immunohistochemistry and serum levels of INO-1001 were measured by high performance liquid chromatography. Penile tissues were analyzed for levels of malondialdehyde and myeloperoxidase. Data sets were statistically compared in all groups. RESULTS: Neurogenic mediated erectile responses were evaluated. Mean intracavernous pressure (ICP), the ICP-to-blood-pressure ratio and total ICP were significantly decreased in BCNCI plus vehicle rats. These values were not statistically different between the sham and PARP inhibitor treated groups. There was a marked decrease in PAR staining in the treatment group. There was a substantial increase in malondialdehyde tissue levels but not myeloperoxidase in response to BCNCI, which was unchanged with PARP inhibitor treatment. There was a marked increase in tyrosine nitration in the treatment group. Up-regulation of nitric oxide synthase and increased tyrosine nitration were not observed in the penile tissues of the treatment group. CONCLUSIONS: These data demonstrate that BCNCI in a rat model causes increased PARP activation, resulting in severe erectile dysfunction. Treatment with the PARP inhibitor INO-1001 decreases the degree of nitrosative stress, prevents PARP activation and provides significant cavernous neuroprotection, which in turn preserves erectile function.
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Adenosina Difosfato Ribosa/metabolismo , Disfunción Eréctil/tratamiento farmacológico , Disfunción Eréctil/enzimología , Indoles/farmacología , Poli(ADP-Ribosa) Polimerasas/efectos de los fármacos , Análisis de Varianza , Animales , Biopsia con Aguja , Modelos Animales de Enfermedad , Disfunción Eréctil/patología , Inmunohistoquímica , Masculino , Óxido Nítrico Sintasa/análisis , Óxido Nítrico Sintasa/metabolismo , Pene/lesiones , Pene/inervación , Peroxidasa/análisis , Peroxidasa/metabolismo , Poli(ADP-Ribosa) Polimerasas/metabolismo , Probabilidad , Ratas , Ratas Sprague-Dawley , Valores de Referencia , Sensibilidad y EspecificidadRESUMEN
We report a case of 41-year-old man with idiopathic prostatic giant calculi presenting with voiding difficulty. To our knowledge this is the youngest case with idiopathic prostatic giant calculi reported in the literature. The etiopathogenesis of prostatic calculi are also discussed.
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Cálculos/patología , Enfermedades de la Próstata/patología , Adulto , Humanos , MasculinoRESUMEN
OBJECTIVE: To evaluate the factors influencing the results of endoureterotomy using cold-knife and cutting balloon dilatation, and permanent ureteral wall stents in patients with benign ureteral strictures after different operations affecting the ureter. MATERIALS AND METHODS: Over a 4-year period, in 18 patients, endoscopic cold-knife and Acucise endoureterotomies were performed in 13 and 7 renal units, respectively. Eight Memoterm permanent ureteral wall stents were inserted into 7 patients when endoureterotomy failed. Successful outcome was defined by the absence of re-stricture assessed both clinically and radiologically. RESULTS: The strictures were secondary to ureterolithotomy in 6, ureteroscopy in 3, gynecological procedures in 4, abdominal surgeries in 2, transplantation in 2 and continent urinary diversion in 1. The right and left ureters were unilaterally affected in 5 and 11 patients, respectively (5 of them had a solitary kidney), while the remaining 2 patients had bilateral ureteral strictures. We achieved total ureteral patency of 3 (43%) and 7 (54%) renal units with Acucise and cold-knife incision, respectively. Obstructive uropathy was resolved in 6 renal units (75%) of 8 using ureteral wall stents. CONCLUSION: Endoureterotomy with cold-knife or Acucise cutting balloon dilatation is effective in the treatment of iatrogenic ureteral strictures, but only in a selected group. Based on our results, the favorable prognostic criteria for endoureterotomy are the length (< or =1.5 cm), the nonischemic nature of the stricture and adequate renal function. As a salvage approach, permanent self-expanding ureteral wall stents with a 75% success rate may provide a satisfactory outcome for decompression of an obstructed system.
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Criocirugía , Stents , Obstrucción Ureteral/cirugía , Ureteroscopía , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Terapia RecuperativaRESUMEN
INTRODUCTION: Penile duplex Doppler ultrasound (PDDU) is currently the preferred method for the functional evaluation of penile hemodynamics. PDDU may be used to monitor objectively changes in penile vascular parameters in men who undergo treatment for Peyronie's disease (PD), including intralesional interferon alpha-2b (IFN alpha-2b). AIM: To investigate the impact of intralesional IFN alpha-2b therapy for PD on penile hemodynamics by using PDDU and to assess the objective role of PDDU in monitoring treatment outcomes. MATERIALS AND METHODS: Thirty-nine patients (20 in the placebo and 19 in the IFN alpha-2b treatment arm) were enrolled in this prospective, placebo-controlled, parallel study. Patients received either 10 mL saline or 5 x 10(6) units of IFN alpha-2b intralesional injections every other week for a total of six injections. Patients in each group were evaluated at baseline and after completion of treatment regarding changes in penile hemodynamic parameters, penile curvature, plaque size and density, pain on erection, and erectile function. Specific published criteria were used for PDDU measurements. Outcomes were statistically compared between each group by using Mann-Whitney U and chi-square tests. RESULTS: The mean age of the patients and the duration of PD were similar in both groups. The improvement in penile blood flow was significantly greater in IFN alpha-2b-treated patients than those in the placebo group. The number with the nonvascular classification increased significantly in the IFN alpha-2b arm from 31.5% to 57.8%. Additionally, improvements in penile curvature, plaque size and density, and pain on erection were better in the IFN alpha-2b group compared with the control. No significant improvement was observed in the erectile function domain in either group. CONCLUSION: This study reveals that intralesional IFN alpha-2b injections have a significant benefit on penile hemodynamic parameters. Moreover, intralesional IFN alpha-2b is an effective, minimally invasive treatment for PD, and PDDU is a useful adjunct to monitor objectively changes in penile vascular parameters. interferon alpha-2b injection therapy on penile hemodynamics in men with Peyronie's disease.
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Interferón-alfa/uso terapéutico , Induración Peniana , Pene/irrigación sanguínea , Adulto , Anciano , Vías de Administración de Medicamentos , Disfunción Eréctil/diagnóstico , Disfunción Eréctil/tratamiento farmacológico , Disfunción Eréctil/fisiopatología , Hemodinámica/efectos de los fármacos , Humanos , Inyecciones , Interferón alfa-2 , Interferón-alfa/administración & dosificación , Interferón-alfa/farmacología , Masculino , Persona de Mediana Edad , Induración Peniana/diagnóstico por imagen , Induración Peniana/tratamiento farmacológico , Induración Peniana/fisiopatología , Estudios Prospectivos , Proteínas Recombinantes , Ultrasonografía Doppler DúplexRESUMEN
INTRODUCTION: Superoxide anion may contribute to erectile dysfunction (ED) in diabetes mellitus by reducing cavernosal nitric oxide (NO) bioavailability. The purpose of this study was to determine if gene transfer of extracellular superoxide dismutase (EC-SOD) can reduce superoxide anion formation and determine if this reactive oxygen species may contribute to diabetes-related ED in an experimental model of diabetes. METHODS: Three groups of animals were utilized: (1) control; (2) streptozotocin (STZ)-diabetic rats [60 mg/kg intraperitoneally (ip)] intracavernosally injected with AdCMVbetagal (negative control); and (3) STZ-rats intracavernosally injected with AdCMVEC-SOD. Two months after ip injection of STZ, groups 2 and 3 were transfected with the adenoviruses and 2 days after transfection, all animals underwent cavernosal nerve stimulation (CNS) to assess erectile function. Confocal microscopy for superoxide anion and von Willebrand Factor (vWF) was performed in the STZ-diabetic rat. Superoxide anion production, total SOD activity, and cyclic guanosine monophosphate (cGMP) levels were measured in each experimental group of rats. RESULTS: Confocal microscopy demonstrated superoxide in smooth muscle and endothelial cells of the STZ-rat cavernosum and colocalized with vWF in the endothelium. Higher superoxide anion levels and decreased cGMP levels were found in the penis of STZ-rats at a time when erectile function was reduced. Two days after administration of AdCMVEC-SOD, superoxide anion levels were significantly lower in the penis of STZ-rats. Total SOD activity and cavernosal cGMP was increased in the penis of EC-SOD-transfected rats. STZ-rats transfected with AdCMVEC-SOD had a peak intracavernosal pressure (ICP) and total ICP to CNS that was similar to control rats. CONCLUSIONS: These data demonstrate that in vivo adenoviral gene transfer of EC-SOD can reduce corporal superoxide anion levels and raise cavernosal cGMP levels by increasing NO bioavailability thus restoring erectile function in the STZ-diabetic rat.
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Diabetes Mellitus Experimental/metabolismo , Disfunción Eréctil/metabolismo , Terapia Genética , Pene/metabolismo , Superóxido Dismutasa/farmacología , Superóxidos/metabolismo , Adenoviridae/genética , Animales , Modelos Animales de Enfermedad , Estimulación Eléctrica , Endotelio Vascular/metabolismo , Guanosina Monofosfato/metabolismo , Masculino , Microscopía Confocal , Músculo Liso Vascular/metabolismo , Pene/inervación , Ratas , Ratas Sprague-Dawley , Especies Reactivas de Oxígeno/metabolismo , Estreptozocina , Superóxido Dismutasa/genética , TransfecciónRESUMEN
OBJECTIVE: To assess the accumulation of advanced glycation end products (AGEs) in streptozotocin (STZ)-induced diabetic rat cavernosal tissue, and to determine whether the protective effect of aminoguanidine (AG) on erectile function is related to the timing of treatment, as the accumulation of AGEs in the penis may be important in the pathogenesis of diabetes mellitus-induced erectile dysfunction, and prolonged treatment with AG (a selective AGE inhibitor), prevents erectile dysfunction in this situation. MATERIALS AND METHODS: Harlan Sprague-Dawley rats were divided into groups 1-4, i.e. age-matched controls; STZ diabetic rats (60 mg/kg intraperitoneal) given free access to water; STZ diabetic rats treated with AG (1 g/L per day in the drinking water) immediately after inducing diabetes; and STZ-diabetic rats treated with AG 1 month after inducing diabetes, respectively. Two months after inducing diabetes the intracavernosal pressure was measured after cavernosal nerve stimulation, and cavernosal AGE (5-hydroxy methyl furfural, 5-HMF) levels assessed. RESULTS: Cavernosal tissue 5-HMF levels from groups 2 and 4 were significantly higher than in group 1 (control). The expression of 5-HMF in group 3 was similar to that in group 1. Diabetic rats had significantly lower erectile function than controls, while groups 3 and 4 (treated with AG) had normal erectile function, as measured by cavernosal nerve stimulation. CONCLUSIONS: The effect of AG on AGE levels seems to be time-dependent; that the 1-month treatment with AG improved erectile function with no change in AGEs suggests that AG has protective effects on the penile vasculature through alternative pathways.
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Diabetes Mellitus Experimental/complicaciones , Inhibidores Enzimáticos/uso terapéutico , Disfunción Eréctil/prevención & control , Productos Finales de Glicación Avanzada/metabolismo , Guanidinas/uso terapéutico , Pene/metabolismo , Animales , Diabetes Mellitus Experimental/metabolismo , Productos Finales de Glicación Avanzada/análisis , Productos Finales de Glicación Avanzada/antagonistas & inhibidores , Masculino , Ratas , Ratas Sprague-Dawley , Factores de TiempoRESUMEN
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.
Asunto(s)
Diabetes Mellitus Experimental/complicaciones , Disfunción Eréctil/enzimología , Óxido Nítrico Sintasa/antagonistas & inhibidores , Pene/enzimología , Proteínas Serina-Treonina Quinasas/fisiología , Adenoviridae/genética , Amidas/farmacología , Animales , Glucemia/metabolismo , Peso Corporal , GMP Cíclico/biosíntesis , Diabetes Mellitus Experimental/sangre , Diabetes Mellitus Experimental/enzimología , Inhibidores Enzimáticos/metabolismo , Disfunción Eréctil/etiología , Expresión Génica , Péptidos y Proteínas de Señalización Intracelular , Masculino , Relajantes Musculares Centrales/farmacología , Fosfatasa de Miosina de Cadena Ligera/biosíntesis , Óxido Nítrico Sintasa/biosíntesis , Óxido Nítrico Sintasa/metabolismo , Óxido Nítrico Sintasa de Tipo I , Óxido Nítrico Sintasa de Tipo III , Pene/efectos de los fármacos , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Proteínas Serina-Treonina Quinasas/biosíntesis , Proteínas Serina-Treonina Quinasas/genética , Piridinas/farmacología , Ratas , Ratas Sprague-Dawley , Transfección , Quinasas Asociadas a rhoRESUMEN
PURPOSE: Erectile dysfunction (ED) occurs in 20% to 54% of men with Peyronie's disease (PD). We investigated the role of vascular status in the pathophysiology of ED in patients with PD. MATERIALS AND METHODS: A total of 509 consecutive men with PD (group 1--impotent 259, 1a, and potent 250, 1b, mean age +/- SD 54.6 +/- 4.4 years) and 507 consecutive men with ED only (group 2--mean age 49.4 +/- 12.4 years) underwent penile duplex ultrasonography (PDU). Detailed sexual and medical history, and focused physical examination were performed in all patients. Patients in the 2, groups were stratified according to age (18 to 80 years) and classified according to PDU results (normal vascular status, arterial insufficiency, veno-occlusive dysfunction [VOD] and mixed vascular pathology). RESULTS: VOD was observed in 23.1% and 42.8% of patients in groups 1 and 2, respectively (p <0.05). Although VOD was significantly more common in group 2 (ED alone) than in group 1a (PD plus ED) in the third decade (p <0.05), overall PDU results showed no statistical difference for VOD between these 2 groups (p >0.05). Of note, mixed vascular pathologies were significantly higher in group 1a than in group 2 in the third through fifth decades (p <0.05), while arterial insufficiency was more common in the seventh decade (p <0.05). CONCLUSIONS: While many groups have investigated the vascular causes of ED, the exact etiology of ED in men with PD remains controversial. A possible relationship between ED and VOD in patients with PD has been previously reported. The current PDU study demonstrates that for all ages except 30 to 39 years the prevalence of VOD in patients with PD plus ED is similar to that of patients with ED alone.