Adenosine deaminase enzyme therapy prevents and reverses the heightened cavernosal relaxation in priapism.
BACKGROUND
Priapism featured with painful prolonged penile erection is dangerous and commonly seen in sickle cell disease (SCD). The preventive approaches or effective treatment options for the disorder are limited because of poor understanding of its pathogenesis. Recent studies have revealed a novel role of excess adenosine in priapism caused by heightened cavernosal relaxation, and therefore present an intriguing mechanism-based therapeutic possibility.


OBJECTIVE
The aim of this study was to determine the therapeutic effects of adenosine deaminase (ADA) enzyme therapy to lower adenosine in priapism.


METHODS
Both ADA-deficient mice and SCD transgenic (Tg) mice display priapism caused by excessive adenosine. Thus, we used these two distinct lines of mouse models of priapism as our investigative tools. Specifically, we treated both of these mice with different dosages of polyethylene glycol-modified ADA (PEG-ADA) to reduce adenosine levels in vivo. At the end points of the experiments, we evaluated the therapeutic effects of PEG-ADA treatment by measuring adenosine levels and monitoring the cavernosal relaxation.


METHODS
Adenosine levels in penile tissues were measured by high-performance liquid chromatography, and cavernosal relaxation was quantified by electrical field stimulation (EFS)-induced corporal cavernosal strip (CCS) assays.


RESULTS
We found that lowering adenosine levels in penile tissues by PEG-ADA treatment from birth in ADA-deficient mice prevented the increased EFS-induced CCS relaxation associated with priapism. Intriguingly, in both ADA-deficient mice and SCD Tg mice with established priapism, we found that normalization of adenosine levels in penile tissues by PEG-ADA treatment relieved the heightened EFS-induced cavernosal relaxation in priapism.


CONCLUSIONS
Our studies have identified that PEG-ADA is a novel, safe, and mechanism-based drug to prevent and correct excess adenosine-mediated increased cavernosal relaxation seen in two independent priapic animal models, and suggested its therapeutic possibility in men suffering from priapism.
Department of Biochemistry and Molecular Biology, University of Texas-Houston Medical School, Houston, TX 77030, USA.
Jiaming
J
Wen
Xianzhen
X
Jiang
Yingbo
Y
Dai
Yujin
Y
Zhang
Yuxin
Y
Tang
Hong
H
Sun
Tiejuan
T
Mi
Rodney E
RE
Kellems
Michael R
MR
Blackburn
Yang
Y
Xia
D000243:Adenosine Deaminase / Q000172:deficiency / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D002851:Chromatography, High Pressure Liquid; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009126:Muscle Relaxation / Q000187:drug effects*; D009130:Muscle, Smooth / Q000187:drug effects; D010413:Penis / Q000201:enzymology / Q000294:innervation; D011092:Polyethylene Glycols; D011317:Priapism / Q000188:drug therapy* / Q000201:enzymology*
D011092:Polyethylene Glycols; D000243:Adenosine Deaminase