Excess adenosine in murine penile erectile tissues contributes to priapism via A2B adenosine receptor signaling
Tiejuan Mi, Shahrzad Abbasi, Hong Zhang, Karen Uray, Janci L. Chunn, Ling Wei Xia, Jose G. Molina, Norman W. Weisbrodt, Rodney E. Kellems, Michael R. Blackburn, Yang Xia
Tiejuan Mi, Shahrzad Abbasi, Hong Zhang, Karen Uray, Janci L. Chunn, Ling Wei Xia, Jose G. Molina, Norman W. Weisbrodt, Rodney E. Kellems, Michael R. Blackburn, Yang Xia
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Research Article Cardiology

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 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.

Authors

Tiejuan Mi, Shahrzad Abbasi, Hong Zhang, Karen Uray, Janci L. Chunn, Ling Wei Xia, Jose G. Molina, Norman W. Weisbrodt, Rodney E. Kellems, Michael R. Blackburn, Yang Xia

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Figure 2

Priapic activity seen in Ada–/– mice is dependent on elevated adenosine in the penis.

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Priapic activity seen in Ada–/– mice is dependent on elevated adenosine ...
(A) Adenosine levels were elevated in the penes of Ada–/– mice. Inset bar graph shows the average adenosine levels from 3 Ada–/– mice and 3 wild-type mice. Data are means ± SEM (n = 3). *P < 0.005 versus Ada+. (B) The prolonged penile erection in Ada–/– mice was corrected by intraperitoneal injection of PEG-ADA. n = 3–5. (C) Representative recordings of EFS-induced CCS relaxation (5 V and 30 Hz) using 10 μM phenylephrine–precontracted CCSs of Ada+ mice and Ada–/– mice treated with or without PEG-ADA. (D–F) Average EFS-induced relaxation from the phenylephrine-precontracted CCSs of Ada+ mice, Ada–/– mice, and Ada–/– mice treated with PEG-ADA. EFS-induced changes in the force of CCS relaxation (D), the duration of relaxation (E), and the combination of force and duration (area under baseline; F). Data are means ± SEM (n = 5–6). *P < 0.05 versus Ada+; **P < 0.05 versus untreated Ada+; ***P < 0.05 versus untreated Ada–/–.