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- Publisher Website: 10.1095/biolreprod63.3.833
- Scopus: eid_2-s2.0-0033842224
- PMID: 10952928
- WOS: WOS:000088972400024
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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
Title | 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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Authors | |
Keywords | cAMP Epididymis Signal transduction |
Issue Date | 2000 |
Publisher | Society 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? |
Abstract | The 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 Identifier | http://hdl.handle.net/10722/171235 |
ISSN | 2023 Impact Factor: 3.1 2023 SCImago Journal Rankings: 1.022 |
ISI Accession Number ID | |
References |
DC Field | Value | Language |
---|---|---|
dc.contributor.author | Gong, XD | en_US |
dc.contributor.author | Wong, YL | en_US |
dc.contributor.author | Leung, GPH | en_US |
dc.contributor.author | Cheng, CY | en_US |
dc.contributor.author | Silvestrini, B | en_US |
dc.contributor.author | Wong, PYD | en_US |
dc.date.accessioned | 2012-10-30T06:12:51Z | - |
dc.date.available | 2012-10-30T06:12:51Z | - |
dc.date.issued | 2000 | en_US |
dc.identifier.citation | Biology Of Reproduction, 2000, v. 63 n. 3, p. 833-838 | en_US |
dc.identifier.issn | 0006-3363 | en_US |
dc.identifier.uri | http://hdl.handle.net/10722/171235 | - |
dc.description.abstract | The 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.language | eng | en_US |
dc.publisher | Society for the Study of Reproduction. The Journal's web site is located at http://www.biolreprod.org/ | en_US |
dc.relation.ispartof | Biology of Reproduction | en_US |
dc.subject | cAMP | - |
dc.subject | Epididymis | - |
dc.subject | Signal transduction | - |
dc.subject.mesh | Animals | en_US |
dc.subject.mesh | Benzyl Compounds - Pharmacology | en_US |
dc.subject.mesh | Bicarbonates - Administration & Dosage | en_US |
dc.subject.mesh | Chloride Channels - Antagonists & Inhibitors - Physiology | en_US |
dc.subject.mesh | Chlorides - Administration & Dosage - Metabolism | en_US |
dc.subject.mesh | Cyclic Amp - Pharmacology | en_US |
dc.subject.mesh | Cystic Fibrosis Transmembrane Conductance Regulator - Antagonists & Inhibitors - Physiology | en_US |
dc.subject.mesh | Electric Conductivity | en_US |
dc.subject.mesh | Epididymis - Drug Effects - Physiology | en_US |
dc.subject.mesh | Epithelial Cells - Drug Effects - Physiology | en_US |
dc.subject.mesh | Indazoles - Pharmacology | en_US |
dc.subject.mesh | Male | en_US |
dc.subject.mesh | Rats | en_US |
dc.subject.mesh | Rats, Sprague-Dawley | en_US |
dc.title | Lonidamine and analogue AF2785 block the cyclic adenosine 3',5'-monophosphate-activated chloride current and chloride secretion in the rat epididymis | en_US |
dc.type | Article | en_US |
dc.identifier.email | Leung, GPH:gphleung@hkucc.hku.hk | en_US |
dc.identifier.authority | Leung, GPH=rp00234 | en_US |
dc.description.nature | link_to_subscribed_fulltext | en_US |
dc.identifier.doi | 10.1095/biolreprod63.3.833 | - |
dc.identifier.pmid | 10952928 | - |
dc.identifier.scopus | eid_2-s2.0-0033842224 | en_US |
dc.relation.references | http://www.scopus.com/mlt/select.url?eid=2-s2.0-0033842224&selection=ref&src=s&origin=recordpage | en_US |
dc.identifier.volume | 63 | en_US |
dc.identifier.issue | 3 | en_US |
dc.identifier.spage | 833 | en_US |
dc.identifier.epage | 838 | en_US |
dc.identifier.isi | WOS:000088972400024 | - |
dc.publisher.place | United States | en_US |
dc.identifier.scopusauthorid | Gong, XD=7201999007 | en_US |
dc.identifier.scopusauthorid | Wong, YL=36853077800 | en_US |
dc.identifier.scopusauthorid | Leung, GPH=35963668200 | en_US |
dc.identifier.scopusauthorid | Cheng, CY=7404797787 | en_US |
dc.identifier.scopusauthorid | Silvestrini, B=7006825900 | en_US |
dc.identifier.scopusauthorid | Wong, PYD=7403980262 | en_US |
dc.identifier.issnl | 0006-3363 | - |