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 A2B
adenosine receptor-mediated (A2BR-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 A2BR activation. Thus, we have shown that excessive
adenosine accumulation in the penis contributes to
priapism through increased A2BR 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 A2BR activation may prove beneficial in the treatment of this disorder.