Inhibition of Na+-K+ pump and L-type Ca2+ channel by glibenclamide in Guinea pig ventricular myocytes.

Abstract

Glibenclamide, a potent cystic fibrosis transmembrane conductance regulator (CFTR) Cl(-) channel blocker, is frequently used to study function and regulation of CFTR Cl(-) channels. In this study, the effects of glibenclamide on intracellular Na(+) concentration ([Na(+)](i)), contraction, Ca(2+) transient, and membrane potential were investigated in isolated guinea pig ventricular myocytes. Glibenclamide increased [Na(+)](i) and decreased contraction and Ca(2+) transient. However, glibenclamide did not change membrane potential. To determine whether inhibition of Na(+)-K(+) pumps and L-type Ca(2+) channels is responsible for the increase of [Na(+)](i) and the decrease of contraction, we tested the effects of glibenclamide on Na(+)-K(+) pump current and L-type Ca(2+) current (I(Ca,L)). Glibenclamide decreased Na(+)-K(+) pump current and I(Ca,L) in a concentration-dependent manner. In the presence of Cl(-) channel inhibitors, glibenclamide depolarized diastolic membrane potential and reduced action potential duration. This result suggests that the reason for lack of effect of glibenclamide on membrane potential might be due to its combined inhibitory effects on the Na(+)-K(+) pump, the L-type Ca(2+) channel, and Cl(-) channels, which may have opposing effects on membrane potential. These results indicate that glibenclamide increases [Na(+)(i)] by inhibiting the Na(+)-K(+) pump and decreases contraction and Ca(2+) transient, in addition, by blocking the L-type Ca(2+) channel.