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

Priapism,�abnormallyprolongedpenileerectionintheabsenceofsexualexcitation,�isassociatedwithisch- emia-mediatederectiletissuedamageandsubsequenterectiledysfunction.�Itiscommonamongmaleswith� sicklecelldisease�(SCD),�andSCDtransgenicmiceareanacceptedmodelofthedisorder.�Currentstrategies� tomanagepriapismsufferfromapoorfundamentalunderstandingofthemolecularmechanismsunderlying� thedisorder.�Herewereportthatmicelackingadenosinedeaminase�(ADA),�anenzymenecessaryforthebreak- downofadenosine,�displayedunexpectedpriapicactivity.�ADAenzymetherapysuccessfullycorrectedthe� priapicactivitybothinvivoandinvitro,�suggestingthatitwasdependentonelevatedadenosinelevels.�Further� geneticandpharmacologicevidencedemonstratedthatA2Badenosinereceptor-mediated�(A2BR-mediated)� cAMPandcGMPinductionwasrequiredforelevatedadenosine-inducedprolongedpenileerection.�Finally,� priapicactivityinSCDtransgenicmicewasalsocausedbyelevatedadenosinelevelsandA2BRactivation.�Thus,� wehaveshownthatexcessiveadenosineaccumulationinthepeniscontributestopriapismthroughincreased� A2BRsignalinginbothAda -/- �andSCDtransgenicmice.�Thesefindingsprovideinsightregardingthemolecular� basisofpriapismandsuggestthatstrategiestoeitherreduceadenosineorblockA2BRactivationmayprove� beneficialinthetreatmentofthisdisorder.