Phosphodiesterase-5A dysregulation in penile erectile tissue is a mechanism of priapism

Abstract

The molecular mechanism for priapism is not well characterized. Although the nitric oxide (NO) pathway is known to mediate penile erection under normal conditions, we hypothesized that the mechanism of priapism rests in aberrant downstream signaling of this pathway based on our previous findings that mice lacking the gene for endothelial nitric oxide synthase (eNOS ؊/؊ ) and mice lacking both neuronal NOS (nNOS) and eNOS (nNOS ؊/؊ , eNOS ؊/؊ ) have a tendency for priapic activity. We investigated the role of downstream guanylate cyclase and phosphodiesterase type 5 (PDE5A) expression and function in mediating these responses in eNOS ؊/؊ and nNOS ؊/؊ , eNOS ؊/؊ mice. Erectile responses to both cavernous nerve stimulation and intracavernosal injection of the NO donor diethylamine-NONOate were augmented in eNOS ؊/؊ and nNOS ؊/؊ , eNOS ؊/؊ mice but not in WT or nNOS ؊/؊ mice. PDE5A protein expression and activity and cGMP levels were significantly lower in eNOS ؊/؊ and nNOS ؊/؊ , eNOS ؊/؊ mice, and this effect was reproduced in WT corpus cavernosum exposed to NOS inhibitors. Moreover, cavernous nerve stimulation was associated with a marked augmentation of cavernosal cGMP levels, suggesting that, although lower at baseline, the production of cGMP is unchecked in eNOS ؊/؊ and nNOS ؊/؊ , eNOS ؊/؊ mice upon neurostimulation. Transfection of eNOS ؊/؊ mice with an adenovirus encoding eNOS resulted in a normalization of PDE5A protein and activity as well as a correction of priapic activity. Coupled with the observation that sickle cell disease mice (which show a priapism phenotype) evince dysregulated PDE5A expression͞activity, these data suggest that PDE5A dysregulation is a fundamental mechanism for priapism.endothelial nitric oxide synthase ͉ gene transfer ͉ sickle cell disease

Impact of hydroxyurea on clinical events in the BABY HUG trial

“…When the primary reason for hospitalization was evaluated, hydroxyurea therapy was associated with fewer hospital admissions for fever (181 vs 240, P ϭ .01), pain (73 vs 128, P Ͻ .001), and ACS (8 vs 27, P ϭ .02). There was no difference in length of hospital stay between the 2 groups Subjects with 0 events 27 (28) 13 (13) Subjects with 1 event 22 (23) 16 (17) Subjects with 2 or 3 events 26 (27) 28 (29) Subjects with 4ϩ events 21 (22) 40 (41) ACS indicates acute chest syndrome. *P value was derived from the 2 test comparing difference in frequency of events between hydroxyurea and placebo groups.…”

Medical management of ischemic stuttering priapism: a contemporary review of the literature

“…Recent studies have shown recurrent priapism to be related to a defective PDE5 regulatory function in the penis, resulting from altered nitric oxide and cyclic guanosine monophosphate signaling mechanisms which control erectile function ( Figure 2). 4,8,15,22,64 A leading proposal in this regard, is that NO becomes dysfunctional in association with underlying disease states. While oral PDE5 inhibitors such as sildenafil or tadalafil, are commonly used as medical treatment for ED, exerting erectogenic effects, scientific evidence has shown they have a paradoxical effect in alleviating stuttering priapism.…”

“…Several groups have been looking at the molecular mechanisms that result in priapism in order to gain a better understanding of the disease and to identify targets useful for the development of pharmacotherapies to prevent stuttering priapism. 23,24,41,64,73 One exciting area of research involves the study of opiorphins. Opiorphins are a newly characterized class of peptides that act as potent endogenous neutral endopeptidase inhibitors.…”

“…25 An emerging and successful new therapy is the use of PDE5 inhibitors for the preventative treatment of stuttering episodes. 4,[64][65][66][67][68] PDE5 inhibitors may be used initially or in conjunction with concomitant administration of intracavernosal phenylephrine injections to treat acute episodes of priapism before PDE5 inhibitor therapy has taken full effect. Research is encouraging in this avenue and suggests PDE5 inhibitors as useful preventative therapy for mild-to-moderate cases of stuttering priapism with minimal side effects, commonly seen with other systemic therapies.…”

“…PDE5 inhibitor therapy is the first pharmacotherapy which targets the true molecular biology of priapism. 22,23,[64][65][66][67][68] While premature in its efforts to translate bench science to the clinic, novel discoveries in basic science research delving into opiorphins and adenosine as signaling pathways that may play a role in the development of stuttering ischemic priapism, represent exciting potential targets for future therapies directed at the prevention and thus treatment of priapism. 73,74 While further research is needed to evaluate the safety and efficacy of systemic therapies for the prevention of stuttering ischemic priapism, a greater understanding of the pathophysiology involved in the mechanisms behind SCDassociated priapism, will continue to pave the way for novel emerging therapies to be developed focusing on prevention as the goal.…”