RESUMO
Fabry disease is a glycosphingolipidosis caused by deficient activity of α-galactosidase A; it is one of a few diseases that are associated with priapism, an abnormal prolonged erection of the penis. The goal of this study was to investigate the pathogenesis of Fabry disease-associated priapism in a mouse model of the disease. We found that Fabry mice develop late-onset priapism. Neuronal nitric oxide synthase (nNOS), which was predominantly present as the 120-kDa N-terminus-truncated form, was significantly upregulated in the penis of 18-month-old Fabry mice compared to wild type controls (~fivefold). Endothelial NOS (eNOS) was also upregulated (~twofold). NO level in penile tissues of Fabry mice was significantly higher than wild type controls at 18 months. Gene transfer-mediated enzyme replacement therapy reversed abnormal nNOS expression in the Fabry mouse penis. The penile nNOS level was restored by antiandrogen treatment, suggesting that hyperactive androgen receptor signaling in Fabry mice may contribute to nNOS upregulation. However, the phosphodiesterase-5A expression level and the adenosine content in the penis, which are known to play roles in the development of priapism in other etiologies, were unchanged in Fabry mice. In conclusion, these data suggested that increased nNOS (and probably eNOS) content and the consequential elevated NO production and high arterial blood flow in the penis may be the underlying mechanism of priapism in Fabry mice. Furthermore, in combination with previous findings, this study suggested that regulation of NOS expression is susceptible to α-galactosidase A deficiency, and this may represent a general pathogenic mechanism of Fabry vasculopathy.
Assuntos
Doença de Fabry/complicações , Óxido Nítrico Sintase Tipo III/metabolismo , Óxido Nítrico Sintase Tipo I/metabolismo , Ereção Peniana , Pênis/enzimologia , Priapismo/etiologia , Animais , Modelos Animais de Doenças , Terapia de Reposição de Enzimas/métodos , Doença de Fabry/enzimologia , Doença de Fabry/fisiopatologia , Doença de Fabry/terapia , Terapia Genética/métodos , Masculino , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Óxido Nítrico/metabolismo , Pênis/fisiopatologia , Priapismo/enzimologia , Priapismo/fisiopatologia , Priapismo/terapia , Fluxo Sanguíneo Regional , Transdução de Sinais , Regulação para Cima , alfa-Galactosidase/biossíntese , alfa-Galactosidase/genéticaRESUMO
Summary Objective: The pathogenesis of recurrent priapism is currently being investigated based on the regulation of the phosphodiesterase 5 (PDE5) enzyme. We explored the daily use of PDE5 inhibitors to treat and prevent priapism recurrences. Method: We administered PDE5 inhibitors using a long-term therapeutic regimen in seven men with recurrent priapism, with a mean age of 29.2 years (range 21 to 35 years). Six men (85.7%) had idiopathic priapism recurrences and one man (24.3%) had sickle cell disease-associated priapism recurrences. Tadalafil 5 mg was administered daily. The mean follow-up was 6.6 months (range 3 to 12 months). Results: Daily long-term oral PDE5 inhibitor therapy alleviated priapism recurrences in all patients. Five (71.4%) had no episodes of priapism and two (28.6%) referred decrease in their episodes of priapism. All patients referred improvement in erectile function. Conclusion: These findings suggest the hypothesis that PDE5 dysregulation exerts a pathogenic role for both sickle cell disease-associated priapism and for idiopathic priapism, and that it offers a molecular target for the therapeutic management of priapism. These preliminary observations suggest that continuous long-term oral PDE5 inhibitor therapy may treat and prevent recurrent priapism.
Resumo Objetivo: Uma das teorias propostas para explicar a etiologia do priapismo recorrente está baseada no mecanismo de regulação da fosfodiesterase tipo 5. Estudamos o uso diário dos inibidores de fosfodiesterase tipo 5 no tratamento e na prevenção do priapismo recorrente. Método: Sete homens com diagnóstico de priapismo recorrente, com idade média de 29,5 anos (21 a 35 anos), utilizaram inibidor de fosfodiesterase tipo 5 em dose diária (tadalafila 5 mg/dia) por período prolongado. Seis homens (85,7%) apresentavam priapismo recorrente de etiologia idiopática, e um homem (24,3%), de etiologia associada à anemia falciforme. O seguimento médio foi de 6,6 meses (3 a 12 meses). Resultados: Todos os pacientes se beneficiaram com a utilização de inibidores de fosfodiesterase tipo 5. Cinco (71,4%) não apresentaram nenhum episódio de priapismo e dois (28,6%) relataram diminuição dos episódios. Todos os pacientes relataram melhora da função erétil. Conclusão: Estes achados sugerem que a hipótese do mecanismo de regulação da fosfodiesterase tipo 5 exerce papel importante na patogenia do priapismo recorrente. O uso contínuo e diário de inibidores da fosfodiesterase tipo 5 pode ser uma opção no tratamento do priapismo recorrente.
Assuntos
Humanos , Masculino , Adulto , Adulto Jovem , Priapismo/prevenção & controle , Inibidores da Fosfodiesterase 5/administração & dosagem , Tadalafila/administração & dosagem , Priapismo/enzimologia , Recidiva , Estudos Prospectivos , Seguimentos , Nucleotídeo Cíclico Fosfodiesterase do Tipo 5/metabolismo , Prevenção SecundáriaRESUMO
Patients with sickle cell disease (SCD) display priapism, and dysregulated nitric oxide (NO) pathway may contribute to this condition. However, current therapies offered for the prevention of priapism in SCD are few. The 3-(1,3-dioxoisoindolin-2-yl)benzyl nitrate (compound 4C) was synthesized through molecular hybridization of hydroxyurea and thalidomide, which displays an NO-donor property. This study aimed to evaluate the effects of compound 4C on functional and molecular alterations of erectile function in murine models that display low NO bioavailability, SCD transgenic mice, and endothelial NO synthase and neuronal NO synthase double gene-deficient (dNOS-/) mice, focusing on the dysregulated NO-cGMP- phosphodiesterase type 5 (PDE5) pathway and oxidative stress in erectile tissue. Wild-type, SCD, and dNOS-/- mice were treated with compound 4C (100 µmol/kg/d, 3 weeks). Intracavernosal pressure in anesthetized mice was evaluated. Corpus cavernosum tissue was dissected free and mounted in organ baths. SCD and dNOS-/- mice displayed a priapism phenotype, which was reversed by compound 4C treatment. Increased corpus cavernosum relaxant responses to acetylcholine and electrical-field stimulation were reduced by 4C in SCD mice. Likewise, increased sodium nitroprusside-induced relaxant responses were reduced by 4C in cavernosal tissue from SCD and dNOS-/- mice. Compound 4C reversed PDE5 protein expression and reduced protein expressions of reactive oxygen species markers, NADPH oxidase subunit gp91phox, and 3-nitrotyrosine in penises from SCD and dNOS-/- mice. In conclusion, 3-week therapy with the NO donor 4C reversed the priapism in murine models that display lower NO bioavailability. NO donor compounds may constitute an additional strategy to prevent priapism in SCD.
Assuntos
Nucleotídeo Cíclico Fosfodiesterase do Tipo 5/metabolismo , Isoindóis/farmacologia , NADPH Oxidases/metabolismo , Nitratos/farmacologia , Doadores de Óxido Nítrico/farmacologia , Pênis/efeitos dos fármacos , Ftalimidas/farmacologia , Priapismo/tratamento farmacológico , Espécies Reativas de Nitrogênio/metabolismo , Acetilcolina/farmacologia , Anemia Falciforme/complicações , Animais , Moléculas de Adesão Celular/metabolismo , Relação Dose-Resposta a Droga , Estimulação Elétrica , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Humanos , Isoindóis/uso terapêutico , Masculino , Glicoproteínas de Membrana/metabolismo , Camundongos , Proteínas dos Microfilamentos/metabolismo , NADPH Oxidase 2 , Nitratos/uso terapêutico , Doadores de Óxido Nítrico/uso terapêutico , Nitroprussiato/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Pênis/metabolismo , Fosfoproteínas/metabolismo , Fosforilação/efeitos dos fármacos , Ftalimidas/uso terapêutico , Priapismo/complicações , Priapismo/enzimologia , Priapismo/metabolismo , Fatores de Tempo , Tirosina/análogos & derivados , Tirosina/metabolismoRESUMO
INTRODUCTION: Priapism featured with painful prolonged penile erection is dangerous and commonly seen in sickle cell disease (SCD). The preventive approaches or effective treatment options for the disorder are limited because of poor understanding of its pathogenesis. Recent studies have revealed a novel role of excess adenosine in priapism caused by heightened cavernosal relaxation, and therefore present an intriguing mechanism-based therapeutic possibility. AIM: The aim of this study was to determine the therapeutic effects of adenosine deaminase (ADA) enzyme therapy to lower adenosine in priapism. METHODS: Both ADA-deficient mice and SCD transgenic (Tg) mice display priapism caused by excessive adenosine. Thus, we used these two distinct lines of mouse models of priapism as our investigative tools. Specifically, we treated both of these mice with different dosages of polyethylene glycol-modified ADA (PEG-ADA) to reduce adenosine levels in vivo. At the end points of the experiments, we evaluated the therapeutic effects of PEG-ADA treatment by measuring adenosine levels and monitoring the cavernosal relaxation. MAIN OUTCOME MEASURES: Adenosine levels in penile tissues were measured by high-performance liquid chromatography, and cavernosal relaxation was quantified by electrical field stimulation (EFS)-induced corporal cavernosal strip (CCS) assays. RESULTS: We found that lowering adenosine levels in penile tissues by PEG-ADA treatment from birth in ADA-deficient mice prevented the increased EFS-induced CCS relaxation associated with priapism. Intriguingly, in both ADA-deficient mice and SCD Tg mice with established priapism, we found that normalization of adenosine levels in penile tissues by PEG-ADA treatment relieved the heightened EFS-induced cavernosal relaxation in priapism. CONCLUSIONS: Our studies have identified that PEG-ADA is a novel, safe, and mechanism-based drug to prevent and correct excess adenosine-mediated increased cavernosal relaxation seen in two independent priapic animal models, and suggested its therapeutic possibility in men suffering from priapism.
Assuntos
Adenosina Desaminase/farmacologia , Relaxamento Muscular/efeitos dos fármacos , Priapismo/tratamento farmacológico , Priapismo/enzimologia , Adenosina Desaminase/deficiência , Adenosina Desaminase/metabolismo , Animais , Cromatografia Líquida de Alta Pressão , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Estimulação Elétrica , Masculino , Camundongos , Camundongos Knockout , Músculo Liso/efeitos dos fármacos , Pênis/enzimologia , Pênis/inervação , PolietilenoglicóisRESUMO
INTRODUCTION: Priapism is defined as abnormal prolonged penile erection lasting at least for 4 hours occurring without sexual interest. Forty percent of sickle cell disease (SCD) patients display priapism. The disorder is dangerous and urgent given its association with ischemia-mediated erectile tissue damage and subsequent erectile dysfunction. Current strategies to manage the disorder are poor due to lack of fundamental understanding of the molecular mechanisms of priapism. Adenosine is a signaling nucleoside that elicits many pathophysiological effects by engaging membrane receptors. Recent evidence shows that adenosine may play an important role in priapism via adenosine receptor. AIM: To summarize the recent findings on the importance of adenosine signaling in the pathogenesis of priapism. MAIN OUTCOME MEASURES: Evidence in the literature on the association between adenosine signaling and the development of priapism. METHODS: This article reviews the literature that relates to the contributory role of adenosine signaling in priapism in multiple animal models and humans. RESULTS: Excessive adenosine accumulation in the penis, coupled with increased A(2B)R signaling, contributes to priapism in two independent lines of mutant mice. One is adenosine deaminase (ADA)-deficient mice, the only animal displaying spontaneously prolonged penile erection, and the other is SCD transgenic mice, a well-accepted priapic animal model. Both polyethylene glycol-modified ADA (PEG-ADA) enzyme therapy and A(2B)R antagonists are capable of inhibiting potent corpus cavernosal vascular relaxation associated with priapic-like activity seen in both ADA-deficient mice and SCD transgenic mice, indicating that PEG-ADA enzyme therapy is likely to be a novel therapy for such a dangerous urological disorder. CONCLUSION: Overall, the research reviewed here raises the intriguing possibility that elevated adenosine signaling contributes to priapism in general and that this signaling pathway represents a potentially important therapeutic target for the treatment of priapism.
Assuntos
Adenosina Desaminase/metabolismo , Adenosina/fisiologia , Inibidores de Fosfodiesterase/uso terapêutico , Priapismo , Transdução de Sinais/fisiologia , Adenosina/metabolismo , Animais , Endotélio Vascular/enzimologia , Endotélio Vascular/patologia , Endotélio Vascular/fisiopatologia , Fibrose/patologia , Fibrose/fisiopatologia , Masculino , Camundongos , Músculo Liso/metabolismo , Músculo Liso/patologia , Músculo Liso/fisiopatologia , Pênis/patologia , Pênis/fisiopatologia , Inibidores da Fosfodiesterase 5 , Priapismo/tratamento farmacológico , Priapismo/enzimologia , Priapismo/fisiopatologiaRESUMO
Phosphodiesterase 5 (PDE5) has been identified in many species. The three isoforms, PDE5A1, PDE5A2, and PDE5A3, differ only in their N-terminal sequence. PDE5A1 and PDE5A2 are ubiquitous, but PDE5A3 is specific to smooth muscle. The initial three exons (A1-A3-A2) of PDE5A, located on chromosome 4q26, are alternative first exons encoding the isoform-specific sequences. The PDE5A promoter overlaps with the A1-specific exon, while the PDE5A2 promoter is located between the A3- and A2-specific exons. Both respond to cyclic guanosine monophosphate (cGMP) or cyclic adenosine monophosphate (cAMP) stimulation. The PDE5A2 promoter contains an Sp1-binding sequence critical for basal and cGMP/cAMP-inducible promoter activities. PDE5A is induced by adjacent sequences (enhancers) containing Sp1-binding sites. The potential role of PDE5A promoters in the tachyphylaxis effect of PDE5 inhibitors is currently being investigated. Preliminary data suggest that hypoxia might down-regulate PDE5A promoters, implying an involvement of PDE5 in stuttering priapism.