Pereira Dalila Andrade, Calmasini Fabiano Beraldi, Costa Fernando Ferreira, Burnett Arthur L, Silva Fábio Henrique
Laboratory of Pharmacology, São Francisco University Medical School, Bragança Paulista, SP, Brazil (D.A.P., F.H.S.); Universidade Federal de São Paulo, Escola Paulista de Medicina, Department of Pharmacology, São Paulo, SP, Brazil (F.B.C.); Hematology and Hemotherapy Center, University of Campinas, Campinas, SP, Brazil (F.F.C.); and The James Buchanan Brady Urological Institute and Department of Urology, The Johns Hopkins School of Medicine, Baltimore, Maryland (A.L.B.).
Laboratory of Pharmacology, São Francisco University Medical School, Bragança Paulista, SP, Brazil (D.A.P., F.H.S.); Universidade Federal de São Paulo, Escola Paulista de Medicina, Department of Pharmacology, São Paulo, SP, Brazil (F.B.C.); Hematology and Hemotherapy Center, University of Campinas, Campinas, SP, Brazil (F.F.C.); and The James Buchanan Brady Urological Institute and Department of Urology, The Johns Hopkins School of Medicine, Baltimore, Maryland (A.L.B.)
J Pharmacol Exp Ther. 2024 Jul 18;390(2):203-212. doi: 10.1124/jpet.123.001962.
Patients with sickle cell disease (SCD) display priapism, a prolonged penile erection in the absence of sexual arousal. The current pharmacological treatments for SCD-associated priapism are limited and focused on acute interventions rather than prevention. Thus, there is an urgent need for new drug targets and preventive pharmacological therapies for this condition. This review focuses on the molecular mechanisms linked to the dysfunction of the NO-cyclic guanosine monophosphate (cGMP)-phosphodiesterase type 5 (PDE5) pathway implicated in SCD-associated priapism. In murine models of SCD, reduced nitric oxide (NO)-cGMP bioavailability in the corpus cavernosum is associated with elevated plasma hemoglobin levels, increased reactive oxygen species levels that inactive NO, and testosterone deficiency that leads to endothelial nitric oxide synthase downregulation. We discuss the consequences of the reduced cGMP-dependent PDE5 activity in response to these molecular changes, highlighting it as the primary pathophysiological mechanism leading to excessive corpus cavernosum relaxation, culminating in priapism. We also further discuss the impact of intravascular hemolysis on therapeutic approaches, present current pharmacological strategies targeting the NO-cGMP-PDE5 pathway in the penis, and identify potential pharmacological targets for future priapism therapies. In men with SCD and priapism, PDE5 inhibitor therapy and testosterone replacement have shown promising results. Recent preclinical research reported the beneficial effect of treatment with haptoglobin and NO donors. SIGNIFICANCE STATEMENT: This review discusses the molecular changes that reduce NO-cGMP bioavailability in the penis in SCD and highlights pharmacological targets and therapeutic strategies for the treatment of priapism, including PDE5 inhibitors, hormonal modulators, NO donors, hydroxyurea, soluble guanylate cyclase stimulators, haptoglobin, hemopexin, and antioxidants.
镰状细胞病（SCD）患者会出现阴茎异常勃起，即在无性唤起的情况下阴茎长时间勃起。目前针对SCD相关性阴茎异常勃起的药物治疗有限，且侧重于急性干预而非预防。因此，迫切需要针对这种情况的新药物靶点和预防性药物治疗。本综述重点关注与SCD相关性阴茎异常勃起所涉及的一氧化氮（NO）-环磷酸鸟苷（cGMP）-5型磷酸二酯酶（PDE5）途径功能障碍相关的分子机制。在SCD小鼠模型中，海绵体内一氧化氮（NO）-cGMP生物利用度降低与血浆血红蛋白水平升高、使NO失活的活性氧水平增加以及导致内皮型一氧化氮合酶下调的睾酮缺乏有关。我们讨论了cGMP依赖性PDE5活性降低对这些分子变化的反应所产生的后果，强调其作为导致海绵体过度松弛并最终导致阴茎异常勃起的主要病理生理机制。我们还进一步讨论了血管内溶血对治疗方法的影响，介绍了目前针对阴茎中NO-cGMP-PDE5途径的药物策略，并确定了未来阴茎异常勃起治疗的潜在药物靶点。在患有SCD和阴茎异常勃起的男性中，PDE5抑制剂治疗和睾酮替代疗法已显示出有希望的结果。最近的临床前研究报道了触珠蛋白和NO供体治疗的有益效果。意义声明：本综述讨论了SCD中降低阴茎内NO-cGMP生物利用度的分子变化，并强调了治疗阴茎异常勃起的药物靶点和治疗策略，包括PDE5抑制剂、激素调节剂、NO供体、羟基脲、可溶性鸟苷酸环化酶刺激剂、触珠蛋白、血红素结合蛋白和抗氧化剂。
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