Optical Mapping of Cardiac ATP Sensitive Potassium Channel Function under Metabolic Inhibition

Abstract

ATP-sensitive potassium channel (KATP) 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 KATP in atria and ventricles may respond differently to metabolic stress. We performed optical mapping with voltage-sensitive dyes on Langendorff-perfused hearts from C57BL wild-type (WT), Kir6.2 deficient (Kir6.2-/-), and SUR1 deficient (SUR1-/-) mice to examine APD during metabolic inhibition (MI, 0mM glucose+2mM sodium cyanide). In WT hearts, significant shortening of atrial APD after variable delay occurred before ventricular APD shortening after a variable delay. Atrial APD shortened by 60.5±2.7% at 5.5±1.3 min (n=6, p<0.01) earlier than comparable ventricular APD shortening (56.4±10.0% shortening 20.33 min after onset of MI). Interestingly, prolongation (48.6±5.2%, p<0.01) preceded ventricular APD shortening. In SUR1-/- hearts (n=6), atrial APD shortening was abolished but ventricular shortening (65.0±15.4%, p<0.01) was maintained. Atrioventricular block occurred earlier in WT (3.85±1.21 minutes before 50% shortening of ventricular APD) than in SUR1-/- (1.08±3.98 minutes before 50% shortening of ventricular APD, p=0.15, NS). In Kir6.2-/- hearts, two disparate responses to MI were observed; 3 of 5 hearts displayed slight shortening 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). Prolongation of ventricular APD was observed in the remaining hearts (327% and 489% prolongation). The results confirm that Kir6.2 contributes to APD shortening in both atria and ventricle during metabolic stress, and SUR1 is required for atrial APD shortening. Moreover, the results show the atrial action potential is more susceptible to MI with SUR1 underlying atrial KATP.