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

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TitleLonidamine and analogue AF2785 block the cyclic adenosine 3',5'-monophosphate-activated chloride current and chloride secretion in the rat epididymis
AuthorsGong, XD1
Wong, YL1
Leung, GPH1
Cheng, CY1
Silvestrini, B1
Wong, PYD1
Issue Date2000
PublisherSociety for the Study of Reproduction. The Journal's web site is located at http://www.biolreprod.org/
CitationBiology 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.
ISSN0006-3363
2011 Impact Factor: 4.009
2011 SCImago Journal Rankings: 0.316
ReferencesReferences in Scopus
DC Field
Value
dc.contributor.authorGong, XD
dc.contributor.authorWong, YL
dc.contributor.authorLeung, GPH
dc.contributor.authorCheng, CY
dc.contributor.authorSilvestrini, B
dc.contributor.authorWong, PYD
dc.date.accessioned2012-10-30T06:12:51Z
dc.date.available2012-10-30T06:12:51Z
dc.date.issued2000
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.
dc.description.natureLink_to_subscribed_fulltext
dc.identifier.citationBiology Of Reproduction, 2000, v. 63 n. 3, p. 833-838 [How to Cite?]
dc.identifier.epage838
dc.identifier.issn0006-3363
2011 Impact Factor: 4.009
2011 SCImago Journal Rankings: 0.316
dc.identifier.issue3
dc.identifier.pmid10952928
dc.identifier.scopuseid_2-s2.0-0033842224
dc.identifier.spage833
dc.identifier.urihttp://hdl.handle.net/10722/171235
dc.identifier.volume63
dc.languageeng
dc.publisherSociety for the Study of Reproduction. The Journal's web site is located at http://www.biolreprod.org/
dc.publisher.placeUnited States
dc.relation.ispartofBiology of Reproduction
dc.relation.referencesReferences in Scopus
dc.subject.meshAnimals
dc.subject.meshBenzyl Compounds - Pharmacology
dc.subject.meshBicarbonates - Administration & Dosage
dc.subject.meshChloride Channels - Antagonists & Inhibitors - Physiology
dc.subject.meshChlorides - Administration & Dosage - Metabolism
dc.subject.meshCyclic Amp - Pharmacology
dc.subject.meshCystic Fibrosis Transmembrane Conductance Regulator - Antagonists & Inhibitors - Physiology
dc.subject.meshElectric Conductivity
dc.subject.meshEpididymis - Drug Effects - Physiology
dc.subject.meshEpithelial Cells - Drug Effects - Physiology
dc.subject.meshIndazoles - Pharmacology
dc.subject.meshMale
dc.subject.meshRats
dc.subject.meshRats, Sprague-Dawley
dc.titleLonidamine and analogue AF2785 block the cyclic adenosine 3',5'-monophosphate-activated chloride current and chloride secretion in the rat epididymis
dc.typeArticle
Author Affiliations
  1. Chinese University of Hong Kong