Inhibition of cyclic GMP export by multidrug resistance protein 4 : a new strategy to treat erectile dysfunction?
(2017) JOURNAL OF SEXUAL MEDICINE. 14(4). p.502-509- 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.
Please use this url to cite or link to this publication:
http://hdl.handle.net/1854/LU-8515843
- author
- Charlotte Boydens UGent, Bart Pauwels, Laura Vanden Daele UGent and Johan Van de Voorde UGent
- organization
- year
- 2017
- type
- journalArticle (original)
- publication status
- published
- subject
- 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
- journal title
- JOURNAL OF SEXUAL MEDICINE
- J. Sex. Med.
- volume
- 14
- issue
- 4
- pages
- 502 - 509
- Web of Science type
- Article
- Web of Science id
- 000400583800006
- ISSN
- 1743-6095
- DOI
- 10.1016/j.jsxm.2017.02.005
- language
- English
- UGent publication?
- yes
- classification
- A1
- copyright statement
- I have transferred the copyright for this publication to the publisher
- id
- 8515843
- handle
- http://hdl.handle.net/1854/LU-8515843
- date created
- 2017-03-27 11:49:17
- date last changed
- 2017-09-18 13:25:56
@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}, }
- 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.