An unexpected priapic phenotype associated with ADA-deficient mice prompted us to hypothesize that increased adenosine contributes to priapism. This hypothesis was confirmed and significantly extended by analysis of SCD Tg mice, a well-accepted animal model of priapism [26
]. We have demonstrated that excessive adenosine-induced cavernosal relaxation via A2B
adenosine receptor signaling is an underlying mechanism responsible for priapism in these two distinct lines of mice with priapism. Our discovery immediately suggests that targeting on adenosine signaling pathway represents a mechanism-based therapeutic possibility for the treatment and prevention of priapism. Here, we report that chronic reduction of adenosine by PEG–ADA in penile tissues prevented and/or reversed increased cavernosal relaxation, a major underlying mechanism responsible for priapism in both ADA-deficient mice and SCD Tg mice. Thus, our studies have revealed previously unrecognized application of PEG–ADA as a safe, an effective, and a mechanism-based drug to treat and prevent the elevated cavernosal relaxation in two independent animal models of priapism.
Priapism is a dangerous and painful condition that, without intervention, will develop penile vascular damage and fibrosis, eventually resulting in ED. For example, Pryor et al. revealed that 90% of patients result in ED if the priapism episode lasts more than 24 hours [46
]. Recently, Bennett and Mulhall demonstrated that no patient is able to generate a functional erection if the patient experiences priapism more than 36 hours [47
]. In contrast, 44% of patients are able to maintain penetration quality erections after 24–36 hours of priapism episode [47
]. Overall, the rate of ED seen in priapism patients is high, and therefore it is urgent to find a way to prevent and treat priapism, and avoid the erectile tissue damage, fibrosis, and loss of erectile function in SCD patients. This highlights the need for basic research aimed at understanding the molecular mechanisms of the disease. Such efforts will lead to better treatment and prevention of priapism.
Multiple factors may contribute to priapism. Previous research indicates dysregulated nitric oxide signaling may lead to priapism. Champion et al. found decreased PDE5 expression and activity in the penises of genetically altered mouse models lacking eNOS and in SCD Tg mice. Each of these mice display a priapism-like phenotype [14
]. These observations imply that pathological changes in PDE5 may contribute to priapism. In addition to NO, soluble guanylyl cyclase is also activated by carbon monoxide (CO) which is produced by the enzyme heme oxygenase. An inducible isoform of heme oxygenase (HO-1) is activated under hypoxic conditions to regulate vascular smooth muscle tone [15
]. Jin et al. recently reported that the synthesis and activity of HO-1 are increased in experimentally induced low-flow priapism in rat penile tissues [48
], suggesting that hypoxia-mediated CO production may contribute to low-flow priapism. In addition, Munarriz et al. presented an interesting finding that in the rabbit corpus cavernosum, ischemic priapism is associated with decreased binding affinity of adrenergic ligands for their receptors; therefore, resulting in decreased contractile ability [49
]. These findings imply that imbalance of vasoconstrictors and vasodilators may be an underlying mechanism for priapism. Intriguingly, our current studies revealed that excess adenosine, one of best-known molecule to be induced under hypoxic/ischemic conditions, is a causative factor contributing to priapism by increasing cavernosal relaxation in both ADA-deficient mice and SCD Tg mice [26
]. Adenosine is well known for its potent direct vascular relaxation effect. We have revealed that increased cGMP mediated via A2B
R is an underlying mechanism responsible for excess adenosine-mediated priapism in these mice [26
]. Based on the fact that adenosine is highly induced under ischemic and hypoxic conditions, and the study reported by Lin et al. showing that PDE5 is down-regulated in ischemic corpus cavernosal smooth muscle cells in vitro [50
], it is also possible that increased adenosine caused by ischemia may be a potential factor to down-regulate PDE5 via A2B
R, and can lead to elevated cGMP production in priapism associated with SCD Tg mice or eNOS-deficient mice. It is also possible that excess adenosine signaling may also contribute to priapism via regulation of HO-1 expression/activity and adrenergic receptor affinity to its ligand. These will be important issues to address in the near future.
Although the therapeutic strategies for priapism are limited, several studies shed light on the potential of prevention and treatment of priapism based on our current progress in understanding of the pathogenesis of priapsim as described earlier [49
]. For example, Burnett et al. showed that chronic reduction of PDE5 by its inhibitor is successfully used to treat several patients in decreasing the priapic episode by normalization of dysregulated PDE5 activity [51
]. In addition, Munarriz et al. presented a finding on the use of high dosage of intracavernosal phenylepherine in the management of ischemic priapism in two patients [49
]. Notably, our published studies provide the in vivo evidence that direct injection of PEG–ADA into ADA-deficient mice quickly corrects the spontaneously prolonged penile erection by lowering adenosine-mediated cavernosal relaxation. These findings suggest that PEG–ADA is likely a potential therapy to treat priapism under urgent conditions [26
]. In the current study, we test the therapeutic possibility of chronic reduction of adenosine by PEG–ADA enzyme therapy in priapism. Here, we demonstrate that chronic reduction of adenosine levels by PEG–ADA treatment since birth in ADA-deficient mice prevents the increased cavernosal relaxation, a major cause of priapism. Additionally, we discovered that PEG–ADA enzyme therapy corrects excess adenosine-induced cavernosal relaxation, the underlying mechanism contributing to priapism in ADA-deficient mice and SCD Tg mice. We believe our current studies demonstrate that PEG–ADA is a novel and an effective mechanism-based drug to prevent and treat excess adenosine-induced cavernosal relaxation in these two animal models of priapism.
Early studies hinted at a potential role for adenosine signaling in penile erection [18
]. However, attention was diverted from adenosine signaling to NO by the discovery of PDE5 inhibitors, such as sildenafil (i.e., Viagra), that promote penile erection [12
]. Attention has recently returned to adenosine signaling with reports indicating that impaired A2B
R signaling is associated with ED in men [58
], and our study showing that excess adenosine contributes to priapism via A2B
R signaling in both ADA-deficient mice and SCD Tg mice [26
]. Taken together, substantial evidence now suggests a general role for adenosine signaling in normal penile erection as a vasorelaxant and neuromodulator. From this perspective, it is not surprising that impaired adenosine signaling is associated with ED [58
], and excessive adenosine signaling is associated with priapism [26
]. Thus, adenosine signaling represents a potentially important therapeutic target for the treatment of priapism and ED. Notably, the discovery of excess adenosine as the causative factor for priapism in mice opens up the possibility of treating and even preventing this painful and dangerous disorder with PEG–ADA enzyme therapy to reduce adenosine or specific antagonists to block A2B
R signaling. Finally, the role of adenosine signaling in sickle cell anemia has not been previously identified; it will be very interesting to determine whether this signaling pathway plays a role in sickle cell anemia in the future.
Our preclinical studies suggest that PEG–ADA is likely a novel mechanism-based therapy for priapism in men by attenuation of increased cavernosal relaxation. Over 150 patients worldwide have received PEG–ADA enzyme therapy for the treatment of ADA deficiency (SCID), and approximately 90 patients were alive as of 2006 when the most recent survey was reported [59
]. Approximately one-third of the 90 individuals currently alive have received PEG–ADA for 10–19 years [34
]. PEG–ADA has generally been well tolerated, and no allergic or hypersensitivity reactions have been reported. PEG–ADA is effective and life-saving for ADA-deficient individuals. More importantly, we also treated SCD Tg mice for over 2 months with PEG–ADA. We have not observed any adverse effects of PEG–ADA use in these mice. Thus, PEG–ADA treatment may be safe for humans with SCD and priapism. We believe our animal studies are important, and point the way to future clinical studies in men suffering from priapism.