HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: 67/6/1888    most recent biolreprod.102.007450v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal My Folders Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Gong, X.D. Articles by Wong, P.Y.D. Search for Related Content PubMed PubMed Citation Articles by Gong, X.D. Articles by Wong, P.Y.D. Agricola Articles by Gong, X.D. Articles by Wong, P.Y.D.

Indazole Inhibition of Cystic Fibrosis Transmembrane Conductance Regulator Cl^- Channels in Rat Epididymal Epithelial Cells¹

^a Department of Physiology and Biophysics, Dalhousie University, Halifax, Nova Scotia, Canada ^b Department of Physiology, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong

Previous 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 lonidamine 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 lonidamine, 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 lonidamine 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), lonidamine showed a flickery block and a decrease in open-channel probability. The flickery block by lonidamine was both voltage-dependent and concentration-dependent. These results suggest that lonidamine 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.

¹ This work was supported by grants from the Rockefeller Foundation/Ernst Schering Research Foundation to P.Y.D.W. and by the Canadian Cystic Fibrosis Foundation (CCFF) to P.L. X.G. is a CCFF postdoctoral fellow.

² Correspondence. FAX: 852 26035022; patrickwong{at}cuhk.edu.hk

This article has been cited by other articles:

				H.-F. Huang, R.-H. He, C.-C. Sun, Y. Zhang, Q.-X. Meng, and Y.-Y. Ma Function of aquaporins in female and male reproductive systems Hum. Reprod. Update, November 1, 2006; 12(6): 785 - 795. [Abstract] [Full Text] [PDF]