Role of ATP-sensitive K+ channels in electrophysiological alterations during myocardial ischemia: a study using Kir6.2-null mice.

The role of cardiac ATP-sensitive K(+) (K(ATP)) channels in ischemia-induced electrophysiological alterations has not been thoroughly established. Using mice with homozygous knockout (KO) of Kir6.2 (a pore-forming subunit of cardiac K(ATP) channel) gene, we investigated the potential contribution of K(ATP) channels to electrophysiological alterations and extracellular K(+) accumulation during myocardial ischemia. Coronary-perfused mouse left ventricular muscles were stimulated at 5 Hz and subjected to no-flow ischemia. Transmembrane potential and extracellular K(+) concentration ([K(+)](o)) were measured by using conventional and K(+)-selective microelectrodes, respectively. In wild-type (WT) hearts, action potential duration (APD) at 90% repolarization (APD(90)) was significantly decreased by 70.1 +/- 5.2% after 10 min of ischemia (n = 6, P < 0.05). Such ischemia-induced shortening of APD(90) did not occur in Kir6.2-deficient (Kir6.2 KO) hearts. Resting membrane potential in WT and Kir6.2 KO hearts similarly decreased by 16.8 +/- 5.6 (n = 7, P < 0.05) and 15.0 +/- 1.7 (n = 6, P < 0.05) mV, respectively. The [K(+)](o) in WT hearts increased within the first 5 min of ischemia by 6.9 +/- 2.5 mM (n = 6, P < 0.05) and then reached a plateau. However, the extracellular K(+) accumulation similarly occurred in Kir6.2 KO hearts and the degree of [K(+)](o) increase was comparable to that in WT hearts (by 7.0 +/- 1.7 mM, n = 6, P < 0.05). In Kir6.2 KO hearts, time-dependent slowing of conduction was more pronounced compared with WT hearts. In conclusion, the present study using Kir6.2 KO hearts provides evidence that the activation of K(ATP) channels contributes to the shortening of APD, whereas it is not the primary cause of extracellular K(+) accumulation during early myocardial ischemia.