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Inhibition of cyclic GMP export by multidrug resistance protein 4 : a new strategy to treat erectile dysfunction?

Charlotte Boydens (UGent) , Bart Pauwels (UGent) , Laura Vanden Daele (UGent) and Johan Van de Voorde (UGent)
(2017) JOURNAL OF SEXUAL MEDICINE. 14(4). p.502-509
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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.
Keywords
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

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Chicago
Boydens, Charlotte, Bart Pauwels, Laura Vanden Daele, and Johan Van de Voorde. 2017. “Inhibition of Cyclic GMP Export by Multidrug Resistance Protein 4 : a New Strategy to Treat Erectile Dysfunction?” Journal of Sexual Medicine 14 (4): 502–509.
APA
Boydens, C., Pauwels, B., Vanden Daele, L., & Van de Voorde, J. (2017). Inhibition of cyclic GMP export by multidrug resistance protein 4 : a new strategy to treat erectile dysfunction? JOURNAL OF SEXUAL MEDICINE, 14(4), 502–509.
Vancouver
1.
Boydens C, Pauwels B, Vanden Daele L, Van de Voorde J. Inhibition of cyclic GMP export by multidrug resistance protein 4 : a new strategy to treat erectile dysfunction? JOURNAL OF SEXUAL MEDICINE. 2017;14(4):502–9.
MLA
Boydens, Charlotte, Bart Pauwels, Laura Vanden Daele, et al. “Inhibition of Cyclic GMP Export by Multidrug Resistance Protein 4 : a New Strategy to Treat Erectile Dysfunction?” JOURNAL OF SEXUAL MEDICINE 14.4 (2017): 502–509. Print.
@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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