Clock Changes in the Type 2 Diabetic Sinoatrial Node

Abstract

Diabetic patients have impaired heart rate control. In diabetic rats ex vivo heart rate was significantly decreased compared to non-diabetic animals. Why this is the case remains unknown. Within sinoatrial nodal cardiomyocytes heart rate is determined by rhythmic oscillations in Ca2+ and other ions, the so called Ca2+ and membrane clocks. The Ca2+ clock primarily involves the intracellular Ca2+ store, the sarcoplasmic reticulum, and ‘Ca2+-handling’ proteins such as the sarco/endoplasmic reticulum Ca2+-ATPase (SERCA2a) and its regulator phospholamban (PLB). The membrane clock involves membrane ion transporters such as the hyperpolarisation-activated cyclic nucleotide-gated channel (HCN4) and Na+-Ca2+ exchanger (NCX). The aim of this research was to investigate whether the reduced intrinsic heart rate in diabetes is due to changes in the Ca2+ and/ or membrane clocks. The sinoatrial node of non-diabetic and type 2 diabetic rats was isolated and protein expression was determined. A significant 1.6-fold increase in PLB expression was found in DM (p < 0.05), with no change to SERCA2a expression (p > 0.05). A significant 2.2-fold increase in NCX expression (p < 0.05) and a trend towards an increase in HCN4 (p = 0.08) in DM was found. The functional effects on heart rate were investigated by increasing external Ca2+ and ivabradine (HCN4 inhibitor) concentrations in isolated Langendorff hearts. Changes in external Ca2+ did not change intrinsic heart rate in both groups, however ivabradine reduced intrinsic heart rate in nDM, but not in DM. We conclude the lower intrinsic heart rate in diabetic rats is, in part, a result of change in membrane clock proteins (non-functional HCN4).