ATP-sensitive Potassium Channels and Cardiac Arrhythmia

Abstract

ATP-sensitive potassium channels (KATP) open in response to metabolic challenge. They form of pore subunits (Kir6.1 or Kir6.2) and modulatory subunits (SUR1, SUR2A or SUR2B) and are ubiquitously expressed. Differential subunit composition between cardiac chambers was investigated, as were atrial anti-arrhythmic effects of KATP modulation. Selective pharmacology of KATP openers and inhibitors was confirmed in a heterologous expression system through whole-cell patch clamp. Isolated HL-1 cells (a murine atrial cardiomyocyte model) and murine atrial cardiomyocytes showed identical KATP pharmacological responses representing Kir6.2/SUR1 channels. Relative quantification of murine whole atrial RNA concurred, and was distinct from the ventricles (Kir6.2/SUR2). Human whole heart RNA from normal hearts exhibited a different pattern with no obvious chamber specificity. Kir6.1-/- and Kir6.2-/- mice demonstrated that both pore types contribute to electrophysiological parameters in isolated atrial cardiomyocytes, but Kir6.2 appears more important. In atrial tissue (Langendorff hearts), Kir6.2-/- more than Kir6.1-/- mice demonstrated increased effective refractory periods and reduced conduction velocity at baseline, and during hypoxia, compared to wildtype. A trend to reduced arrhythmogenicity was observed during programmed electrical stimulation in the Kir6.2-/- mouse. In syncytia of spontaneously beating HL-1 cells, KATP activation with diazoxide was met with rotational to uniform wavefront organisation and silencing of electrical activity in a dose-dependent manner, reversed with channel blockade. In Langendorff mouse hearts KATP inhibition reversed hypoxia induced slowing of spontaneous sinus node activation, but pharmacological activation alone did not, suggesting different mechanisms with hypoxic channel activation. Thus, both pore subunits contribute to the cardiac electrophysiology of murine atria, but Kir6.2 appears more important. HL-1 cells exhibit identical KATP pharmacology to murine atrial myocytes, which have a differential subunit composition compared to the ventricle. Any human cardiac KATP differential subunit expression needs further exploration. KATP activation and inhibition have anti-arrhythmic effects and this might be explored further clinically.