ATP-sensitive K+ current (IK(ATP)) plays an important role in the regulation of cardiac electrical activity. In the myocardium, IK(ATP) is regulated by the sulfonylurea receptor (SURIIA) which mediates the inhibition of IK(ATP) due to glibenclamide (Gli). The role played by SURIIA in the sensitivity of IK(ATP) to metabolic inhibition is unclear. We studied the effect of SURIIA antisense oligonucleotides (ODNs) on the properties of IK(ATP) in cultured guinea-pig atrial myocytes. IK(ATP) was measured by the whole-cell voltage clamp method and was activated with cromakalim (Cro; 200 microns) and dinitrophenole (DNP; 100 microns). Mean IK(ATP) density activated by DNP and Cro in nonincubated cells was 117 +/- 12 pA/pF (n = 17) and 17 +/- 9 pA/pF (n = 16) respectively. No significant difference was observed after incubation with nODN [DNP: 121 +/- 13 pA/pF (n = 20); Cro:19 +/- 4 pA/pF (n = 8)]. Cells incubated with ODNs showed a significant reduction of IK(ATP) due to DNP (19 +/- 13 pA/pF; P < 0.05, n = 6), whereas Cro-induced IK(ATP) was unaffected (16 +/- 8 pA/pF, n = 8). The effectiveness of DNP-induced metabolic inhibition was apparent in a concomitant reduction of the nucleotide-phosphate dependent muscarinic K+ current (inhibition of IK(ACh) in ODN incubated myocytes without activation of IK(ATP)). The ATP sensitivity of IK(ATP) appears mediated by SURIIA. Activation of this current by Cro seems to be SURIIA-independent. ODN-induced metabolic uncoupling of IK(ATP) may be a useful experimental tool. A reduced sensitivity of IK(ATP) to intracellular ATP concentrations may be of clinical interest.