Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.4.1 (phosphodiesterase)
 18,767 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Introduction: Priapism is prolonged penile erection in the absence of sexual arousal or desire and is a devastating condition affecting millions of patients with sickle cell disease (SCD) globally. Available drug treatments for SCD-related priapism remain limited and have been primarily reactive rather than preventive. Hence, there is an unmet need for new drug targets and pharmacologic therapies.Areas covered: We examine the molecular mechanisms underlying SCD-associated priapism evaluated mostly in animal models. In mouse models of SCD, molecular defects of priapism operating at the cavernous tissue level include reduced tonic NO/cGMP signaling, elevated oxidative/nitrosative stress, vascular adhesion molecule derangements, excessive adenosine and opiorphin signaling, dysregulated vasoconstrictive RhoA/ROCK signaling, and testosterone deficiency. We discuss the consequences of downregulated cGMP-dependent phosphodiesterase type 5 (PDE5) activity in response to these molecular signaling derangements, as the main effector mechanism causing unrestrained cavernous tissue relaxation that results in priapism.Expert opinion: Basic science studies are crucial for understanding the underlying pathophysiology of SCD-associated priapism. Understanding the molecular mechanisms could unearth new therapeutic targets for this condition based on these mechanisms. Treatment options should aim to improve deranged erection physiology regulatory signaling to prevent priapism and potentially restore or preserve erectile function.
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PMID:Mechanisms underlying priapism in sickle cell disease: targeting and key innovations on the preclinical landscape. 3219 46

Erectile dysfunction (ED) is defined as the persistent inability to achieve and/or maintain an erection for a satisfactory sexual activity. It is secondary to several organic, psychogenic, and combined causes, and represents a serious health dilemma affecting both men and their partners. The diagnostic approach to erectile dysfunction has significantly changed in the last years with the advent of phosphodiesterase-5 (PDE5) inhibitors, and with the recognition that surgical treatment of both arterial insufficiency and penile venous leak have poor long-term clinical outcomes. Although imaging modalities have diminished in importance, differentiating among causes of erectile dysfunction remains mandatory in good medical practice, and ultrasound (US) still remains the cornerstone of the diagnostic workup. US provides an objective, minimally invasive evaluation of penile hemodynamics. Moreover, it provides an excellent depiction of the penile anatomy and of its changes in pathological conditions such as in patients with Peyronie's disease, priapism, and posttraumatic erectile dysfunction.
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PMID:Sonography of the penis/erectile dysfunction. 3228 81

Priapism, a prolonged penile erection in the absence of sexual arousal, is common among patients with sickle cell disease (SCD). Hypogonadism is also common in patients with SCD. While the administration of exogenous testosterone reverses hypogonadism, it is contraceptive. We hypothesized that the stimulation of endogenous testosterone production decreases priapism by normalizing molecular signaling involved in penile erection without decreasing intratesticular testosterone production, which would affect fertility. Treatment of SCD mice with FGIN-1-27, a ligand for translocator protein (TSPO) that mobilizes cholesterol to the inner mitochondrial membrane, resulted in eugonadal levels of serum testosterone without decreasing intratesticular testosterone production. Normalized testosterone levels, in turn, decreased priapism. At the molecular level, TSPO restored phosphodiesterase 5 activity and decreased NADPH oxidase-mediated oxidative stress in the penis, which are major molecular signaling molecules involved in penile erection and are dysregulated in SCD. These results indicate that pharmacologic activation of TSPO could be a novel, targetable pathway for treating hypogonadal men, particularly patients with SCD, without adverse effects on fertility.
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PMID:TSPO ligand FGIN-1-27 controls priapism in sickle cell mice via endogenous testosterone production. 3297 10


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