The mechanism of opiorphin-induced experimental priapism in rats involves activation of the polyamine synthetic pathway

Abstract

Intracorporal injection of plasmids encoding opiorphins into retired breeder rats can result in animals developing a priapic-like condition. Microarray analysis demonstrated that following intracorporal gene transfer of plasmids expressing opiorphins the most significantly upregulated gene in corporal tissue was the ornithine decarboxylase gene (ODC). Quantitative RT-PCR confirmed the upregulation of ODC, as well as other genes involved in polyamine synthesis, such as arginase-I and -II, polyamine oxidase, spermidine synthase, spermidine acetyltransferase (SAT), and S-adenosylmethionine decarboxylase. Western blot analysis demonstrated upregulation of arginase-I and -II, ODC, and SAT at the protein level. Levels of the polyamine putrescine were upregulated in animals treated with opiorphin-expressing plasmids compared with controls. A direct role for the upregulation of polyamine synthesis in the development of the priapic-like condition was supported by the observation that the ODC inhibitor 1,3-diaminopropane, when added to the drinking water of animals treated with plasmids expressing opiorphins, prevented experimental priapism. We also demonstrate that in sickle cell mice, another model of priapism, there is increased expression of the mouse opiorphin homologue in corporal tissue compared with the background strain at a life stage prior to evidence of priapism. At a life stage when there is onset of priapism, there is increased expression of the enzymes involved in polyamine synthesis (ODC and arginase-I and -II). Our results suggest that the upregulation of enzymes involved in the polyamine synthetic pathway may play a role in the development of experimental priapism and represent a target for the prevention of priapism.

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

“…73 These results have suggested that upregulation of enzymes in the polyamine synthetic pathway may play a role in the development of priapism and thus represent future targets for the prevention of priapism. 73 Adenosine. Adenosine is a signaling nucleoside that shares multiple features with NO; both are potent vasodilators, induce cyclic nucleotide second messengers and both affect penile erection.…”

“…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.…”

“…73 Recent reports have suggested that they play an important role in erectile physiology, and in sickle-cell mice, there is increased expression of the mouse opiorphin homologue in corporal tissue compared to wild-type mice. 73 Plasmids expressing genes encoding for opiorphins, were intracorporally injected into retired breeder rats and following Medical management of ischemic stuttering priapism HR Levey et al 161 intracavernous injection, the breeder rats expressed a priapic-like condition. Analysis of these rats demonstrated that enzymes in the polyamine synthesis pathway were notably upregulated in these rats as compared to controls.…”

“…Analysis of these rats demonstrated that enzymes in the polyamine synthesis pathway were notably upregulated in these rats as compared to controls. 73 Further, when inhibitors of the polyamine synthesis pathway were given to breeder rats prior to injection with these plasmids, it prevented the occurrence of experimental priapism. 73 These results have suggested that upregulation of enzymes in the polyamine synthetic pathway may play a role in the development of priapism and thus represent future targets for the prevention 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.…”