Inhibition of ATP-sensitive K+ channels in cardiac muscle by the sulphonylurea drug glibenclamide.

The effects of the sulphonylurea drug glibenclamide were tested upon ATP-sensitive K+ (KATP) channels activated by 20 microM SR 44866 in isolated ventricular myocytes from guinea pig hearts. Glibenclamide inhibited the openings of KATP channels in both cell-attached and excised inside-out membrane patches. Glibenclamide inhibited the whole-cell KATP current (I-KATP) with an EC50 of 6 nM and Hill Coefficient of 1.26. The kinetics of the onset of inhibition of I-KATP were complex and dose-dependent. The recovery of I-KATP from inhibition was largely dose-independent. The application of glibenclamide for short periods of time was followed by the continued development of inhibition. These results suggest that the cell was loaded with the drug before it interacted with the KATP channel. It is proposed that the sulphonylurea receptor site is to be found in the lipid phase of the membrane. In consequence critical factors involved in the sulphonylurea drug-induced inhibition of KATP channels will include the rates of drug absorption into and exit from the membrane lipid. That sulphonylureas will be concentrated in the membrane lipid suggests that the EC50 value for channel inhibition does not represent the true affinity of the drugs for their receptor.