Phloretin differentially inhibits volume-sensitive and cyclic AMP-activated, but not Ca-activated, Cl(-) channels

Br J Pharmacol. 2001 Aug;133(7):1096-106. doi: 10.1038/sj.bjp.0704159.

Abstract

Some phenol derivatives are known to block volume-sensitive Cl(-) channels. However, effects on the channel of the bisphenol phloretin, which is a known blocker of glucose uniport and anion antiport, have not been examined. In the present study, we investigated the effects of phloretin on volume-sensitive Cl(-) channels in comparison with cyclic AMP-activated CFTR Cl(-) channels and Ca(2+)-activated Cl(-) channels using the whole-cell patch-clamp technique. Extracellular application of phloretin (over 10 microM) voltage-independently, and in a concentration-dependent manner (IC(50) approximately 30 microM), inhibited the Cl(-) current activated by a hypotonic challenge in human epithelial T84, Intestine 407 cells and mouse mammary C127/CFTR cells. In contrast, at 30 microM phloretin failed to inhibit cyclic AMP-activated Cl(-) currents in T84 and C127/CFTR cells. Higher concentrations (over 100 microM) of phloretin, however, partially inhibited the CFTR Cl(-) currents in a voltage-dependent manner. At 30 and 300 microM, phloretin showed no inhibitory effect on Ca(2+)-dependent Cl(-) currents induced by ionomycin in T84 cells. It is concluded that phloretin preferentially blocks volume-sensitive Cl(-) channels at low concentrations (below 100 microM) and also inhibits cyclic AMP-activated Cl(-) channels at higher concentrations, whereas phloretin does not inhibit Ca(2+)-activated Cl(-) channels in epithelial cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcium / pharmacology*
  • Cell Size / drug effects
  • Cell Size / physiology
  • Chloride Channels / drug effects*
  • Chloride Channels / physiology
  • Cyclic AMP / pharmacology*
  • Dose-Response Relationship, Drug
  • Humans
  • Hypotonic Solutions / pharmacology
  • Ionomycin / pharmacology
  • Ionophores / pharmacology
  • Isotonic Solutions / pharmacology
  • Membrane Potentials / drug effects
  • Patch-Clamp Techniques
  • Phloretin / pharmacology*
  • Tumor Cells, Cultured

Substances

  • Chloride Channels
  • Hypotonic Solutions
  • Ionophores
  • Isotonic Solutions
  • Ionomycin
  • Cyclic AMP
  • Phloretin
  • Calcium