Excess adenosine in murine penile erectile tissues contributes to priapism via A2B adenosine receptor signaling

Abstract

Priapism, abnormally prolonged penile erection in the absence of sexual excitation, is associated with ischemia-mediated erectile tissue damage and subsequent erectile dysfunction. It is common among males with sickle cell disease (SCD), and SCD transgenic mice are an accepted model of the disorder. Current strategies to manage priapism suffer from a poor fundamental understanding of the molecular mechanisms underlying the disorder. Here we report that mice lacking adenosine deaminase (ADA), an enzyme necessary for the breakdown of adenosine, displayed unexpected priapic activity. ADA enzyme therapy successfully corrected the priapic activity both in vivo and in vitro, suggesting that it was dependent on elevated adenosine levels. Further genetic and pharmacologic evidence demonstrated that A 2B adenosine receptor-mediated (A 2B R-mediated) cAMP and cGMP induction was required for elevated adenosine-induced prolonged penile erection. Finally, priapic activity in SCD transgenic mice was also caused by elevated adenosine levels and A 2B R activation. Thus, we have shown that excessive adenosine accumulation in the penis contributes to priapism through increased A 2B R signaling in both Ada -/-and SCD transgenic mice. These findings provide insight regarding the molecular basis of priapism and suggest that strategies to either reduce adenosine or block A 2B R activation may prove beneficial in the treatment of this disorder.

A2B Adenosine Receptor Agonist Improves Erectile Function in Diabetic Rats

“…It has been demonstrated that endogenous adenosine through A2B adenosine receptor play important role in the physiological process of penile erection (Wen et al 2011a, b) and excess adenosine, also via ADORA2B, leads to priapism in ADA deficient mice and sickle cell disease Tg mice (Mi et al 2008;Wen et al 2010a, b). In additional, Faria et al (2006) reported that vasculogenic erectile dysfunction is resistant to adenosine relaxation due to endothelial dysfunction caused by decreased activation of ADORA2B.…”

“…It is reported by our early work that endogenous adenosine through ADORA2B plays important role in the physiological process of penile erection in smooth muscle cells by two mechanisms: direct induction of cAMP production and indirect induction of cGMP production following the activation of eNOS in endothelial cells via the PI3K/AKT signaling cascade (Wen et al 2011a, b). Additionally, excess adenosine lead to priapism in adenosine deaminase (ADA) deficient mice and sickle cell disease transgenic (Tg) mice, also via ADORA2B (Mi et al 2008;Wen et al 2010a, b). Moreover, Faria et al (2006) reported that adenosine regulates smooth muscle tone of human corpus cavernosum through the activation of A2A and A2B adenosine receptors, which are located on smooth muscle fibers and on endothelial cells, respectively.…”

Purinergic signalling in the reproductive system in health and disease

“…The possibility has been raised that elevated adenosine signalling contributes to priapism, a condition of persistent penile erection lasting at least 4 h in the absence of sexual excitation [86,305]. Excess adenosine in penile erectile tissue in mice lacking adenosine deaminase contributes to priapism via A 2B receptor signalling [272]. A recent review highlights adenosine signalling pathways operating in penile tissue as significant therapeutic targets for the treatment of erectile disorders [430].…”

Animal models of erectile dysfunction (ED): potential utility of non-human primates as a model of atherosclerosis-induced vascular ED

“…80 Adenosine actions on ED have been explored in obese and type 2 diabetic db/db mouse 81 as well as in A2B receptor-knockout mice. 82 Mouse models of NO pathway disruption have been critical in defining the role of vasodilators as targets for the treatment of ED. 83 --86 The cGMP kinase I-deficient mouse has also been used to better understand the role of smooth muscle cells in the pathogenesis of ED.…”