@article{8515843,
  abstract     = {Background: Intracellular cyclic guanosine monophosphate (cGMP) concentrations are regulated by degradation enzymes (phosphodiesterases) and by active transport across the plasma membrane by multidrug resistance proteins (MRPs) 4 and 5. 
Aim: To evaluate the functional effect of MRP-4 inhibition and the role of MRP-4-mediated cGMP export in mouse corpora cavernosa. 
Methods: Isometric tension of mouse corpora cavernosa was measured after cumulative addition of MK-571, an inhibitor of MRP-4, or sildenafil, a phosphodiesterase type 5 inhibitor. In addition, the effect of MRP-4 inhibition on cGMP-independent and cGMP-dependent relaxations was studied. In vivo intracavernosal pressure and mean arterial pressure measurements were performed after intracavernosal injection of MK-571. The effect of MRP-4 inhibition on cGMP content was determined using an enzyme immunoassay kit. 
Outcomes: Measurement of the effect of MK-571 on cGMP content, relaxant responses of mouse corpora cavernosa to cGMP-independent and cGMP-dependent vasodilating substances, and determination of the ratio of intracavernosal pressure to mean arterial pressure after intracavernosal injection of MK-571. 
Results: MK-571 and sildenafil relaxed the corpora cavernosa concentration dependently, with sildenafil being the more potent relaxing compound. Furthermore, MK-571 enhanced relaxing responses to cGMP-dependent substances, such as sodium nitroprusside, sildenafil, acetylcholine, and electrical field stimulation, with the latter even under in vitro diabetic conditions. In contrast, cGMP-independent relaxations were not altered by MRP-4 inhibition. Intracavernosal administration of MK-571 significantly increased intracavernosal pressure, with minimal effect on mean arterial pressure. The cGMP analysis showed that MRP-4 inhibition was accompanied by increased cGMP levels. 
Clinical Translation: MRP-4, at least when targeted locally in the penis or when combined with a phosphodiesterase type 5 inhibitor, might be a valuable alternative strategy for the treatment of (diabetic) erectile dysfunction. 
Strengths and Limitations: This study is the first to demonstrate an in vitro direct relaxant and an in vivo pro-erectile effect of the MRP-4 inhibitor, MK-571, on mouse corpora cavernosa. However, the functional effect of MRP-5-mediated export in mouse corpora cavernosa was not explored, which has been suggested to play the predominant role in cGMP export. 
Conclusion: Inhibition of MRP-4 increases basal and stimulated levels of cGMP, leading to corpora cavernosa relaxation and penile erection. Therefore, in addition to degradation of cGMP, export of cGMP by MRP-4 could contribute substantially to regulating cGMP levels in mouse corpora cavernosa.},
  author       = {Boydens, Charlotte and Pauwels, Bart and Vanden Daele, Laura and Van de Voorde, Johan},
  issn         = {1743-6095},
  journal      = {JOURNAL OF SEXUAL MEDICINE},
  keyword      = {Corpora Cavernosa,Cyclic Guanosine Monophosphate,Erectile Dysfunction,Multidrug Resistance Protein,Relaxation,SENSITIVE GUANYLYL CYCLASE,CORPUS CAVERNOSUM,PENILE ERECTION,NUCLEOTIDES,TRANSPORT,MRP4,MRP4/ABCC4,PUMP,RELAXATION,SILDENAFIL},
  language     = {eng},
  number       = {4},
  pages        = {502--509},
  title        = {Inhibition of cyclic GMP export by multidrug resistance protein 4 : a new strategy to treat erectile dysfunction?},
  url          = {http://dx.doi.org/10.1016/j.jsxm.2017.02.005},
  volume       = {14},
  year         = {2017},
}

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