Diabetes Slows Heart Rate via Electrical Remodeling of K+ Currents in Sinoatrial Node Myocytes

Abstract

Diabetes mellitus is associated with sinoatrial node dysfunction, as evidenced by an increased risk of atrial fibrillation, pacemaker implantation due to bradycardia and cardiac death in diabetic patients. While sinoatrial node myocytes (SAMs) generate the spontaneous action potentials (APs) that initiate each heartbeat, little is known about how diabetes affects SAMs directly. In this study, we used streptozoticin (STZ) -treated mice as a model of diabetic hyperglycemia. Four weeks after STZ injections, we found that both intrinsic heart rate (measured during autonomic blockade) and maximum heart rate (measured during restraint stress) were reduced in diabetic animals compared to pre-treatment values. Current-clamp recordings from acutely isolated SAMs from diabetic animals revealed corresponding reductions in spontaneous AP firing rates. AP waveform analysis showed that the reduced firing rates in diabetic cells resulted from a prolongation of the AP duration and a slowing of the rate of repolarization. Accordingly, we observed significant decreases in steady state and transient outward K+ current densities in whole-cell voltage-clamp recordings from SAMs from diabetic animals. Diabetes caused little or no change in voltage-gated calcium currents in diabetic SAMs. The effects of diabetes on the AP waveform and firing rate were mimicked by application of 10 μM 4-aminopyridine in current clamp experiments and when the transient outward K+ current was reduced in a mathematical model of the sinoatrial AP. These results suggest that diabetic sinoatrial node dysfunction results in part from electrical remodeling of K+ currents in sinoatrial node myocytes, which paradoxically slows the spontaneous AP firing rate and thus heart rate.