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Article: Lonidamine and analogue AF2785 block the cyclic adenosine 3',5'-monophosphate-activated chloride current and chloride secretion in the rat epididymis

TitleLonidamine and analogue AF2785 block the cyclic adenosine 3',5'-monophosphate-activated chloride current and chloride secretion in the rat epididymis
Authors
Issue Date2000
PublisherSociety for the Study of Reproduction. The Journal's web site is located at http://www.biolreprod.org/
Citation
Biology Of Reproduction, 2000, v. 63 n. 3, p. 833-838 How to Cite?
AbstractThe cystic fibrosis transmembrane conductance regulator (CFTR) or the small conductance cAMP-activated chloride channel encoded by the CFTR gene has been shown to play an important role in the formation of the epididymal fluid microenvironment. Mutation of the gene has led to widespread effects on male reproduction. Like other ion channels, CFTR is amenable to pharmacological intervention. Blocking CFTR in the epididymis could in principle lead to disruption of the epididymal fluid environment. We report for the first time two indazole compounds: Ionidamine and 1-(2,4-dichlorobenzyl)-indazole-3-acrylic acid (AF2785) are potent blockers of CFTR in the epididymis. When added to the external solution under whole-cell patch clamp conditions, AF2785 and Ionidamine inhibited the cAMP-activated chloride current in rat epididymal cells with apparent IC50 values of 170.6 and 631.5 μM, respectively; by comparison the IC50 value for diphenylamine-2-carboxylate, a well-known chloride channel blocker was 1294 μM. In cultured rat epididymal epithelia mounted in a Ussing chamber, AF2785 and Ionidamine inhibited the cAMP-stimulated short-circuit current (a measure of chloride secretion) when added to the apical bathing solution with potency greater than any known chloride channel studied. It is proposed that in view of the important role CFTR plays in male reproduction, further study with these and other new indazole compounds for their CFTR blocking actions can provide a new avenue of research into the development of novel male contraceptives.
Persistent Identifierhttp://hdl.handle.net/10722/171235
ISSN
2014 Impact Factor: 3.318
2014 SCImago Journal Rankings: 1.397
ISI Accession Number ID
References

 

DC FieldValueLanguage
dc.contributor.authorGong, XDen_US
dc.contributor.authorWong, YLen_US
dc.contributor.authorLeung, GPHen_US
dc.contributor.authorCheng, CYen_US
dc.contributor.authorSilvestrini, Ben_US
dc.contributor.authorWong, PYDen_US
dc.date.accessioned2012-10-30T06:12:51Z-
dc.date.available2012-10-30T06:12:51Z-
dc.date.issued2000en_US
dc.identifier.citationBiology Of Reproduction, 2000, v. 63 n. 3, p. 833-838en_US
dc.identifier.issn0006-3363en_US
dc.identifier.urihttp://hdl.handle.net/10722/171235-
dc.description.abstractThe cystic fibrosis transmembrane conductance regulator (CFTR) or the small conductance cAMP-activated chloride channel encoded by the CFTR gene has been shown to play an important role in the formation of the epididymal fluid microenvironment. Mutation of the gene has led to widespread effects on male reproduction. Like other ion channels, CFTR is amenable to pharmacological intervention. Blocking CFTR in the epididymis could in principle lead to disruption of the epididymal fluid environment. We report for the first time two indazole compounds: Ionidamine and 1-(2,4-dichlorobenzyl)-indazole-3-acrylic acid (AF2785) are potent blockers of CFTR in the epididymis. When added to the external solution under whole-cell patch clamp conditions, AF2785 and Ionidamine inhibited the cAMP-activated chloride current in rat epididymal cells with apparent IC50 values of 170.6 and 631.5 μM, respectively; by comparison the IC50 value for diphenylamine-2-carboxylate, a well-known chloride channel blocker was 1294 μM. In cultured rat epididymal epithelia mounted in a Ussing chamber, AF2785 and Ionidamine inhibited the cAMP-stimulated short-circuit current (a measure of chloride secretion) when added to the apical bathing solution with potency greater than any known chloride channel studied. It is proposed that in view of the important role CFTR plays in male reproduction, further study with these and other new indazole compounds for their CFTR blocking actions can provide a new avenue of research into the development of novel male contraceptives.en_US
dc.languageengen_US
dc.publisherSociety for the Study of Reproduction. The Journal's web site is located at http://www.biolreprod.org/en_US
dc.relation.ispartofBiology of Reproductionen_US
dc.subject.meshAnimalsen_US
dc.subject.meshBenzyl Compounds - Pharmacologyen_US
dc.subject.meshBicarbonates - Administration & Dosageen_US
dc.subject.meshChloride Channels - Antagonists & Inhibitors - Physiologyen_US
dc.subject.meshChlorides - Administration & Dosage - Metabolismen_US
dc.subject.meshCyclic Amp - Pharmacologyen_US
dc.subject.meshCystic Fibrosis Transmembrane Conductance Regulator - Antagonists & Inhibitors - Physiologyen_US
dc.subject.meshElectric Conductivityen_US
dc.subject.meshEpididymis - Drug Effects - Physiologyen_US
dc.subject.meshEpithelial Cells - Drug Effects - Physiologyen_US
dc.subject.meshIndazoles - Pharmacologyen_US
dc.subject.meshMaleen_US
dc.subject.meshRatsen_US
dc.subject.meshRats, Sprague-Dawleyen_US
dc.titleLonidamine and analogue AF2785 block the cyclic adenosine 3',5'-monophosphate-activated chloride current and chloride secretion in the rat epididymisen_US
dc.typeArticleen_US
dc.identifier.emailLeung, GPH:gphleung@hkucc.hku.hken_US
dc.identifier.authorityLeung, GPH=rp00234en_US
dc.description.naturelink_to_subscribed_fulltexten_US
dc.identifier.doi10.1095/biolreprod63.3.833-
dc.identifier.pmid10952928-
dc.identifier.scopuseid_2-s2.0-0033842224en_US
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-0033842224&selection=ref&src=s&origin=recordpageen_US
dc.identifier.volume63en_US
dc.identifier.issue3en_US
dc.identifier.spage833en_US
dc.identifier.epage838en_US
dc.identifier.isiWOS:000088972400024-
dc.publisher.placeUnited Statesen_US
dc.identifier.scopusauthoridGong, XD=7201999007en_US
dc.identifier.scopusauthoridWong, YL=36853077800en_US
dc.identifier.scopusauthoridLeung, GPH=35963668200en_US
dc.identifier.scopusauthoridCheng, CY=7404797787en_US
dc.identifier.scopusauthoridSilvestrini, B=7006825900en_US
dc.identifier.scopusauthoridWong, PYD=7403980262en_US

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