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Glibenclamide blocks volume-sensitive Cl- channels by dual mechanisms
1Department of Cellular and Molecular Physiology, National Institute for Physiological Sciences, Okazaki 444-8585, Japan.
The American Journal of Physiology
|August 4, 1998
Summary
Glibenclamide inhibits volume-sensitive chloride channels from outside the cell. Its uncharged form blocks current, while the charged form affects channel inactivation in Intestine 407 cells.
Area of Science:
- Cellular Physiology
- Ion Channel Function
- Pharmacology
Background:
- Volume-sensitive chloride channels (VSCs) play crucial roles in cell volume regulation.
- Glibenclamide is a known modulator of various ion channels, but its precise mechanism on VSCs is not fully understood.
Purpose of the Study:
- To elucidate the mechanisms by which glibenclamide affects volume-sensitive chloride currents.
- To investigate the role of pH and glibenclamide's charged/uncharged states in its channel interactions.
Main Methods:
- Whole-cell patch-clamp electrophysiology was employed.
- Studies were conducted on human epithelial Intestine 407 cells.
- Experiments were performed at various extracellular pH levels to differentiate glibenclamide's effects.
Main Results:
- Extracellular glibenclamide reversibly suppressed VSCs across a wide voltage range.
- At acidic pH (uncharged glibenclamide), inhibition was voltage-independent.
- At alkaline pH (charged glibenclamide), glibenclamide accelerated inactivation and shifted the steady-state inactivation curve.
Conclusions:
- Glibenclamide inhibits swelling-activated chloride channels from the extracellular side.
- The uncharged form of glibenclamide primarily mediates voltage-independent inhibition of instantaneous currents.
- The charged (anionic) form of glibenclamide contributes to voltage-dependent channel inactivation.