Abstract 1507: Role of Sarcolemmal ATP-Sensitive K+ Channels in Sinoatrial Node Cells: Evaluation Using Kir6.2 Knockout Mice
Cardiac sarcolemmal ATP-sensitive K+ (KATP) channels are composed of two structurally distinct subunits, the inwardly rectifying K+ channel pore subunit Kir6.2 and the sulfonylurea receptor SUR2A. Although KATP channels are known to exist in sinoatrial (SA) node cells, the pathophysiological roles of KATP channels in SA nodal cells are not well-defined. This study was undertaken to elucidate the functional role of KATP channels in SA nodal cells during hypoxia or metabolic blockade using isolated hearts and SA node cells of wild-type (WT) and Kir6.2 knockout (KO) mice. Atrial and ventricular electrograms were recorded from Langendorff-perfused mouse hearts and the hearts were exposed to a hypoxic and glucose-free condition (hypoxia) for 10 min and then to a normal condition for 10 min. Sinus cycle lengths were more markedly prolonged in WT hearts (to 367±135% of control value) than in KO hearts (to 189±53% of control) during hypoxia. The recovery of SA node function after reoxygenation in KO hearts was incomplete (complete recovery:1/4 hearts) compared to WT hearts (complete recovery: 5/5 hearts) in 5 min of reoxygenation. Action potential (AP) of SA node cells isolated from WT and KO mice was recorded with whole-cell current clamp techniques. Spontaneous cycle lengths were prolonged to 168±28% of control values by the KATP channel opener pinacidil (100 μM) in WT SA node cells. The metabolic inhibitor 2,4-dinitrophenol (50 μM) also prolonged the spontaneous cycle length by 177±33% in nystatin-perforated WT SA nodal cells. However, such an increase in the spontaneous cycle length was not observed in KO SA nodal cells. These electrophysiological changes were reversed by addition of the KATP channel blocker glibenclamide (1 μM) in WT SA node cells. These findings suggest that the activation of sarcolemmal KATP channels in SA node cells produces bradycardia during hypoxia or metabolic inhibition, which may lead to protection of SA node cells.