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Article: Indazole inhibition of cystic fibrosis transmembrane conductance regulator Cl- channels in rat epididymal epithelial cells

TitleIndazole inhibition of cystic fibrosis transmembrane conductance regulator Cl- channels in rat epididymal epithelial cells
Authors
Issue Date2002
PublisherSociety for the Study of Reproduction. The Journal's web site is located at http://www.biolreprod.org/
Citation
Biology Of Reproduction, 2002, v. 67 n. 6, p. 1888-1896 How to Cite?
AbstractPrevious studies have shown that two indazole compounds, lonidamine [1-(2,4-dichlorobenzyl)-indazole-3-carboxylic acid] and its analogue AF2785 [(1-(2,4-dichlorobenzyl)-indazol-3-acrylic acid], suppress fertility in male rats. We also found that these compounds inhibit the cystic fibrosis transmembrane conductance regulator chloride (CFTR-Cl-) current in epididymal epithelial cells. To further investigate how lonidamine and AF2785 inhibit the current, we used a spectral analysis protocol to study whole-cell CFTR current variance. Application of Ionidamine or AF2785 to the extracellular membrane of rat epididymal epithelial cells introduced a new component to the whole-cell current variance. Spectral analysis of this variance suggested a block at a rate of 3.68 μmol-1/sec-1 and an off rate of 69.01 sec-1 for Ionidamine, and an on rate of 3.27 μmol-1/sec-1 and an off rate of 108 sec-1 for AF2785. Single CFTR-Cl- channel activity using excised inside-out membrane patches from rat epididymal epithelial cells revealed that addition of Ionidamine to the intracellular solution caused a flickery block (a reduction in channel-open time) at lower concentration (10 μM) without any effect on open channel probability or single-channel current amplitude. At higher concentrations (50 and 100 μM), Ionidamine showed a flickery block and a decrease in open-channel probability. The flickery block by Ionidamine was both voltage-dependent and concentration-dependent. These results suggest that Ionidamine and AF2785, which are open-channel blockers of CFTR at low concentrations, also affect CFTR gating at high concentrations. We conclude that these indazole compounds provide new pharmacological tools for the investigation of CFTR. By virtue of their interference with reproductive processes, these drugs have the potential for being developed into novel male contraceptives.
Persistent Identifierhttp://hdl.handle.net/10722/171285
ISSN
2015 Impact Factor: 3.471
2015 SCImago Journal Rankings: 1.646
ISI Accession Number ID
References

 

DC FieldValueLanguage
dc.contributor.authorGong, XDen_US
dc.contributor.authorLinsdell, Pen_US
dc.contributor.authorCheung, KHen_US
dc.contributor.authorLeung, GPHen_US
dc.contributor.authorWong, PYDen_US
dc.date.accessioned2012-10-30T06:13:11Z-
dc.date.available2012-10-30T06:13:11Z-
dc.date.issued2002en_US
dc.identifier.citationBiology Of Reproduction, 2002, v. 67 n. 6, p. 1888-1896en_US
dc.identifier.issn0006-3363en_US
dc.identifier.urihttp://hdl.handle.net/10722/171285-
dc.description.abstractPrevious studies have shown that two indazole compounds, lonidamine [1-(2,4-dichlorobenzyl)-indazole-3-carboxylic acid] and its analogue AF2785 [(1-(2,4-dichlorobenzyl)-indazol-3-acrylic acid], suppress fertility in male rats. We also found that these compounds inhibit the cystic fibrosis transmembrane conductance regulator chloride (CFTR-Cl-) current in epididymal epithelial cells. To further investigate how lonidamine and AF2785 inhibit the current, we used a spectral analysis protocol to study whole-cell CFTR current variance. Application of Ionidamine or AF2785 to the extracellular membrane of rat epididymal epithelial cells introduced a new component to the whole-cell current variance. Spectral analysis of this variance suggested a block at a rate of 3.68 μmol-1/sec-1 and an off rate of 69.01 sec-1 for Ionidamine, and an on rate of 3.27 μmol-1/sec-1 and an off rate of 108 sec-1 for AF2785. Single CFTR-Cl- channel activity using excised inside-out membrane patches from rat epididymal epithelial cells revealed that addition of Ionidamine to the intracellular solution caused a flickery block (a reduction in channel-open time) at lower concentration (10 μM) without any effect on open channel probability or single-channel current amplitude. At higher concentrations (50 and 100 μM), Ionidamine showed a flickery block and a decrease in open-channel probability. The flickery block by Ionidamine was both voltage-dependent and concentration-dependent. These results suggest that Ionidamine and AF2785, which are open-channel blockers of CFTR at low concentrations, also affect CFTR gating at high concentrations. We conclude that these indazole compounds provide new pharmacological tools for the investigation of CFTR. By virtue of their interference with reproductive processes, these drugs have the potential for being developed into 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.meshCystic Fibrosis Transmembrane Conductance Regulator - Antagonists & Inhibitors - Physiologyen_US
dc.subject.meshElectric Conductivityen_US
dc.subject.meshEpididymis - Chemistry - Cytologyen_US
dc.subject.meshEpithelial Cells - Chemistry - Physiologyen_US
dc.subject.meshIndazoles - Pharmacologyen_US
dc.subject.meshMaleen_US
dc.subject.meshPatch-Clamp Techniquesen_US
dc.subject.meshRatsen_US
dc.subject.meshRats, Sprague-Dawleyen_US
dc.titleIndazole inhibition of cystic fibrosis transmembrane conductance regulator Cl- channels in rat epididymal epithelial cellsen_US
dc.typeArticleen_US
dc.identifier.emailCheung, KH:kingho.cheung@hku.hken_US
dc.identifier.emailLeung, GPH:gphleung@hkucc.hku.hken_US
dc.identifier.authorityCheung, KH=rp01463en_US
dc.identifier.authorityLeung, GPH=rp00234en_US
dc.description.naturelink_to_subscribed_fulltexten_US
dc.identifier.doi10.1095/biolreprod.102.007450en_US
dc.identifier.pmid12444067-
dc.identifier.scopuseid_2-s2.0-0036892905en_US
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-0036892905&selection=ref&src=s&origin=recordpageen_US
dc.identifier.volume67en_US
dc.identifier.issue6en_US
dc.identifier.spage1888en_US
dc.identifier.epage1896en_US
dc.identifier.isiWOS:000179472900030-
dc.publisher.placeUnited Statesen_US
dc.identifier.scopusauthoridGong, XD=7201999007en_US
dc.identifier.scopusauthoridLinsdell, P=7004694661en_US
dc.identifier.scopusauthoridCheung, KH=14007487800en_US
dc.identifier.scopusauthoridLeung, GPH=35963668200en_US
dc.identifier.scopusauthoridWong, PYD=7403980262en_US

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