{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T15:54:27Z","timestamp":1785426867824,"version":"3.56.0"},"reference-count":27,"publisher":"Oxford University Press (OUP)","issue":"4","license":[{"start":{"date-parts":[[2017,2,28]],"date-time":"2017-02-28T00:00:00Z","timestamp":1488240000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"},{"start":{"date-parts":[[2017,2,28]],"date-time":"2017-02-28T00:00:00Z","timestamp":1488240000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/tdm\/userlicense\/1.0\/"}],"funder":[{"name":"Special Investigation Fund of Ghent University","award":["01G02410"],"award-info":[{"award-number":["01G02410"]}]}],"content-domain":{"domain":["jsm.jsexmed.org","elsevier.com","sciencedirect.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2017,4,1]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>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\u00a05.<\/jats:p><\/jats:sec><jats:sec><jats:title>Aim<\/jats:title><jats:p>To evaluate the functional effect of MRP-4 inhibition and the role of MRP-4\u2013mediated cGMP export in mouse corpora cavernosa.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>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\u00a0vivo 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.<\/jats:p><\/jats:sec><jats:sec><jats:title>Outcomes<\/jats:title><jats:p>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.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>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\u00a0vitro 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.<\/jats:p><\/jats:sec><jats:sec><jats:title>Clinical Translation<\/jats:title><jats:p>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.<\/jats:p><\/jats:sec><jats:sec><jats:title>Strengths and Limitations<\/jats:title><jats:p>This study is the first to demonstrate an in\u00a0vitro direct relaxant and an in\u00a0vivo pro-erectile effect of the MRP-4 inhibitor, MK-571, on mouse corpora cavernosa. However, the functional effect of MRP-5\u2013mediated export in mouse corpora cavernosa was not explored, which has been suggested to play the predominant role in cGMP export.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>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.<\/jats:p><\/jats:sec>","DOI":"10.1016\/j.jsxm.2017.02.005","type":"journal-article","created":{"date-parts":[[2017,3,1]],"date-time":"2017-03-01T19:16:53Z","timestamp":1488395813000},"page":"502-509","update-policy":"https:\/\/doi.org\/10.1016\/elsevier_cm_policy","source":"Crossref","is-referenced-by-count":13,"title":["Inhibition of Cyclic GMP Export by Multidrug Resistance Protein 4: A New Strategy to Treat Erectile Dysfunction?"],"prefix":"10.1093","volume":"14","author":[{"given":"Charlotte","family":"Boydens","sequence":"first","affiliation":[{"name":"Department of Pharmacology \u00a0 , Ghent , Belgium"},{"name":"Ghent University \u00a0 , Ghent , Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bart","family":"Pauwels","sequence":"additional","affiliation":[{"name":"Department of Pharmacology \u00a0 , Ghent , Belgium"},{"name":"Ghent University \u00a0 , Ghent , Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Vanden Daele","sequence":"additional","affiliation":[{"name":"Department of Pharmacology \u00a0 , Ghent , Belgium"},{"name":"Ghent University \u00a0 , Ghent , Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johan","family":"Van de Voorde","sequence":"additional","affiliation":[{"name":"Department of Pharmacology \u00a0 , Ghent , Belgium"},{"name":"Ghent University \u00a0 , Ghent , Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2017,2,28]]},"reference":[{"key":"2023011111052257000_bib1","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1152\/physrev.1995.75.1.191","article-title":"Physiology of penile erection","volume":"75","author":"Andersson","year":"1995","journal-title":"Physiol Rev"},{"key":"2023011111052257000_bib2","doi-asserted-by":"crossref","first-page":"1333","DOI":"10.1016\/S0169-409X(02)00166-7","article-title":"Therapeutic and biological importance of getting nucleotides out of cells: a case for the ABC transporters, MRP4 and 5","volume":"54","author":"Adachi","year":"2002","journal-title":"Adv Drug Deliv Rev"},{"key":"2023011111052257000_bib3","doi-asserted-by":"crossref","first-page":"661","DOI":"10.1007\/s00424-006-0054-9","article-title":"Multidrug resistance-associated proteins 3, 4, and 5","volume":"453","author":"Borst","year":"2007","journal-title":"Pflugers Arch"},{"key":"2023011111052257000_bib4","doi-asserted-by":"crossref","first-page":"33747","DOI":"10.1074\/jbc.M104833200","article-title":"Transport of cyclic nucleotides and estradiol 17-beta-D-glucuronide by multidrug resistance protein 4. 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