Role of sarcolemmal ATP-sensitive K+ channels in the regulation of sinoatrial node automaticity: an evaluation using Kir6.2-deficient mice.

The role of cardiac sarcolemmal ATP-sensitive K+ (K(ATP)) channels in the regulation of sinoatrial node (SAN) automaticity is not well defined. Using mice with homozygous knockout (KO) of the Kir6.2 (a pore-forming subunit of cardiac K(ATP) channel) gene, we investigated the pathophysiological role of K(ATP) channels in SAN cells during hypoxia. Langendorff-perfused mouse hearts were exposed to hypoxic and glucose-free conditions (hypoxia). After 5 min of hypoxia, sinus cycle length (CL) was prolonged from 207 +/- 10 to 613 +/- 84 ms (P < 0.001) in wild-type (WT) hearts. In Kir6.2 KO hearts, CL was slightly prolonged from 198 +/- 17 to 265 +/- 32 ms. The CL of spontaneous action potentials of WT SAN cells, recorded in the current-clamp mode, was markedly prolonged from 410 +/- 56 to 605 +/- 108 ms (n = 6, P < 0.05) with a decrease of the slope of the diastolic depolarization (SDD) after the application of the K+ channel opener pinacidil (100 microm). Pinacidil induced a glibenclamide (1 microm)-sensitive outward current, which was recorded in the voltage-clamp mode, only in WT SAN cells. During metabolic inhibition by 2,4-dinitrophenol, CL was prolonged from 292 +/- 38 to 585 +/- 91 ms (P < 0.05) with a decrease of SDD in WT SAN cells but not in Kir6.2 KO SAN cells. Diastolic Ca2+ concentration, measured by fluo-3 fluorescence, was decreased in WT SAN cells but increased in Kir6.2 KO SAN cells after short-term metabolic inhibition. In conclusion, the present study using Kir6.2 KO mice indicates that, during hypoxia, activation of sarcolemmal K(ATP) channels in SAN cells inhibits SAN automaticity, which is important for the protection of SAN cells.