Functional roles of K_ATP channel subunits in metabolic inhibition

ATP-sensitive potassium channel (K_ATP) activation can drastically shorten action potential duration (APD) in metabolically compromised myocytes. We showed previously that SUR1 with Kir6.2 forms the functional channel in mouse atria while Kir6.2 and SUR2A predominate in ventricles. SUR1 is more sensitive to metabolic stress than SUR2A, raising the possibility that K_ATP in atria and ventricles may respond differently to metabolic stress. Action potential duration (APD) and calcium transient duration (CaTD) were measured simultaneously in both atria and ventricles by optical mapping of the posterior surface of Langendorff-perfused hearts from C57BL wild-type (WT; n=11), Kir6.2^-/- (n=5), and SUR1^-/- (n=6) mice during metabolic inhibition (MI, 0mM glucose+2mM sodium cyanide). After variable delay, MI led to significant shortening of APD in WT hearts. On average, atrial APD shortened by 60.5±2.7% at 13.1±2.1min (n=6, p<0.01) after onset of MI. Ventricular APD shortening (56.4±10.0% shortening at 18.2±1.8min) followed atrial APD shortening. In SUR1^-/- hearts (n=6), atrial APD shortening was abolished, but ventricular shortening (65.0±15.4% at 25.33±4.48min, p<0.01) was unaffected. In Kir6.2^-/- hearts, two disparate responses to MI were observed; 3 of 5 hearts displayed slight shortening of APD in the ventricles (24±3%, p<0.05) and atria (39.0±1.9%, p<0.05) but this shortening occurred later and to much less extent than in WT (p<0.05). Marked prolongation of ventricular APD was observed in the remaining hearts (327% and 489% prolongation) and was associated with occurrence of ventricular tachyarrhythmias. The results confirm that Kir6.2 contributes to APD shortening in both atria and ventricle during metabolic stress, and that SUR1 is required for atrial APD shortening while SUR2A is required for ventricular APD shortening. Importantly, the results show that the presence of SUR1-dependent K_ATP in the atria results in the action potential being more susceptible to metabolically driven shortening than the ventricle.