From cell metabolism due to antisense oligonucleotides against sulfonylurea receptor in guinea-pig atrial myocytes

ATP-sensitive K+ current (I-K(ATP)) plays an important role in the regulati on of cardiac electrical activity. In the myocardium, I-K(ATP) is regulated by the sulfonylurea receptor (SURIIA) which mediates the inhibition of I-K (ATP) due to glibenclamide (Gli). The role played by SURIIA in the sensitiv ity of I-K(ATP) to metabolic inhibition is unclear. We studied the effect o f SURIIA antisense oligonucleotides (ODNs) on the properties of I-K(ATP) in cultured guinea-pig atrial myocytes. I-K(ATP) was measured by the whole-ce ll voltage clamp method and was activated with cromakalim (Cro; 200 mum) an d dinitrophenole (DNP; 100 mum). Mean I-K(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 incuba tion 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 I-K(ATP) due to DNP (19 +/- 13 pA/pF; P < 0.05, n = 6), whereas Cro-induced I-K(ATP) was unaffected (16 +/- 8 pA/pF, n = 8). The effectiveness of DNP-induced metab olic inhibition n ns apparent in a concomitant reduction of the nucleotide- phosphate dependent muscarinic K+ current (inhibition of I-K(ACh) in ODN in cubated myocytes without activation of I-K(ATP)). The ATP sensitivity of I- K(ATP) appears mediated by SURIIA. Activation of this current by Cro seems to be SURIIA-independent. ODN-induced metabolic uncoupling of I-K(ATP) may be a useful experimental tool. A reduced sensitivity of I-K(ATP) to intrace llular ATP concentrations may be of clinical interest.