Effects of pH upon the inhibition by sulphonylurea drugs of ATP-sensitive K+ channels in cardiac muscle

Abstract

The effect of pH was tested upon the inhibition of ATP-sensitive K+ (KATP) channels caused by the sulphonylurea drugs tolbutamide and glibenclamide. KATP channels and currents (I-KATP) were activated with SR 44866 in ventricular myocytes isolated from guinea pig hearts. Modification of either external or internal pH had little effect upon the background K+ current (IK1). External pH had no consistent effects upon I-KATP. The application of NH4Cl inhibited I-KATP and its withdrawal caused a slight rebound activation. Compared with the results obtained at pHo 7.4, inhibition of I-KATP by the sulphonylurea drugs was enhanced at pHo 6.5 and reduced at pHo 8.4. The kinetics of the recovery of I-KATP was independent of pHo. Neither internal pH 6.5 nor NH4Cl had any effect upon sulphonylurea-induced inhibition of I-KATP. The dose-response curves for inhibition of I-KATP at different pHo's were found to coincide when plotted for the unionized concentrations of the drugs. It is concluded that it is the unionized forms of the sulphonylurea drugs which are responsible for closure of KATP channels in cardiac muscle. In consequence, extracellular acidification during ischemia will increase the effective concentration of glibenclamide and may be responsible for the cardiovascular disorders associated with this treatment in noninsulin-dependent diabetics.