Adenosine Signaling in Priapism and Novel Therapies

Abstract

Abstract 1006 Objective:Priapism is abnormal prolonged penile erection occurring without sexual interest. The condition is prevalent among men with sickle cell disease (SCD). Priapism is a urological emergency which needs early intervention to avoid the risks of penile fibrosis and eventual erectile dysfunction. Due to poorly understood pathogenesis of priapism no effective approaches to manage the disorder. Recent studies have revealed excess adenosine (Ado) in priapism via Ado A2B receptor (ADORA2B), suggesting novel therapeutic possibilities. Here, we aim to conduct preclinical studies to assess the efficacy and safety of Ado-based therapy in priapism. Materials and Methods:ADA-deficient mice (ADA−/−) and SCD Berkeley mice are two independent priapism animal models. We treated both mice with polyethylene glycol-modified ADA (PEG-ADA) to lower penile adenosine level or PSB1115, a selective ADORA2BR antagonist. The erectile function are measured by the changes of intracavernosal pressure (ICP) induced by cavernous nerve stimulation (CNS). Penile fibrosis is evaluated by histological studies and RT-PCR analysis of fibrotic marker gene. In vitro human microvascular endothelial cells (HMECs) were used to determine mechanism underlying ADORA2B-induced priapism. Results:Both ADA−/− and SCD mice with elevated Ado levels in penile tissue displayed priapic feature defined by prolonged and heightened erectile in response to CNS. Chronic reduction of accumulation of penile Ado levels by PEG-ADA enzyme therapy or PSB1115 corrected the priapic feature in both priapic animal models and further prevented progression of penile fibrosis. Significantly, both HIF-1α and eNOS mRNA level were elevated but reversed by PSB1115 treatment in penile tissues of ADA−/− mice and SCD mice. Finally, we provide in vitro direct evidence that PSB1115 treatment or siRNA knockdown HIF-1α in HMECs significantly reduced Ado-induced eNOS mRNA, implicating that ADORA2B-mediated HIF-1α induction contributes to elevated eNOS mRNA and underlies Ado-mediated priapism. Conclusions:PEG-ADA and PSB1115 are effective and safe to treat priapism and exacerbation of the disease by decreasing penile Ado levels or interfering its signaling. This study provides direct preclinical evidence for the novel and general utility of PEG-ADA enzyme therapy or ADORA2B antagonists for priapism and sets up a solid foundation for future clinical trials to assess the usefulness of Adobased therapeutics to treat priapism. Disclosures:No relevant conflicts of interest to declare.