Streptozotocin‐induced diabetes modulates action potentials and ion channel currents from the rat atrioventricular node

Abstract

The present study was conducted to evaluate whether experimentally induced type 1 diabetes results in alterations to atrioventricular nodal (AVN) electrophysiology at the cellular level. Spontaneous action potentials (APs) and ionic currents were recorded from AVN myocytes isolated from the hearts of control rats and from those with streptozotocin-induced diabetes. Perforated patch-clamp recordings were used to assess changes in cellular AP parameters and in ionic currents. Type 1 diabetes significantly increased AP duration, whilst reducing AP firing rate, upstroke velocity and rate of diastolic depolarization. The diabetes-induced changes in AP parameters were accompanied by a significant leftward shift in the zero current potential under voltage clamp, a reduction in peak L-type Ca 2+ current density and reduced amplitude of delayed rectifier and hyperpolarization-activated currents. These findings demonstrate that experimentally induced type 1 diabetes can lead to remodelling of AVN cellular electrophysiology.

Glutathione oxidation unmasks proarrhythmic vulnerability of chronically hyperglycemic guinea pigs

“…More importantly, most EP studies in t1DM have been performed in animal models that exhibited highly artificial rises (Ͼ300%) in blood glucose levels that are well beyond what is commonly encountered in patients with diabetes (20,33,36,40,46). Such extreme levels of hyperglycemia, which are known to affect ion channels, preclude the direct translation of some of these earlier findings to humans.…”

“…This distinction is important because unlike rodents, patients with t1DM do not exhibit heart rate corrected QT-interval prolongation in the absence of confounding factors, such as diabetic ketoacidosis (24) or spontaneous hypoglycemia (11). Clinically, these additional stimuli are required to unmask pathological QT-interval prolongation in patients with t1DM (11,14,17,24).More importantly, most EP studies in t1DM have been performed in animal models that exhibited highly artificial rises (Ͼ300%) in blood glucose levels that are well beyond what is commonly encountered in patients with diabetes (20,33,36,40,46). Such extreme levels of hyperglycemia, which are known to affect ion channels, preclude the direct translation of some of these earlier findings to humans.…”

“…Several studies identified prolongation of the action potential duration (APD) as an important electrophysiological (EP) signature of myocytes from diabetic hearts (25,46). Because APD and QT-interval prolongation promote early afterdepolarization-mediated triggers and polymorphic ventricular tachycardia and ventricular fibrillation (VT/VF) in acquired and congenital forms of the long QT syndrome and heart failure, it was proposed that APD prolongation in t1DM may also be arrhythmogenic.…”

“…Growing evidence implicates oxidative stress (OS) in general and glutathione (GSH) depletion, in particular in the pathophysiology of t1DM (13a, 25a, 34, 42). Whether OS is a required component of the arrhythmia substrate of the diabetic heart is unknown.Previous studies of arrhythmia mechanisms in t1DM hearts have extensively focused on ion channel remodeling at the isolated myocyte level (25,40,45,46). Several studies identified prolongation of the action potential duration (APD) as an important electrophysiological (EP) signature of myocytes from diabetic hearts (25, 46).…”

Assessing the Efficiency of the Diabetic Heart at Subcellular, Tissue and Organ Level

“…The literature is replete with reports showing a constellation of consequences for the diabetic heart: prolongation of the duration of the action potential [100][101][102][103][104], thereby diminishing the period of electrical diastole, slowing the relaxation phase of the Ca 2+ transient [79,80,105,106], thereby prolonging the 'activated state', and reducing activity of the actomyosin ATPase [107][108][109][110][111][112], consistent with a switch from the α (fast twitch) to the β (slow twitch) isoform of the actomyosin ATPase [107,109,[113][114][115]. Each of these phenomena contributes to prolongation of twitch duration and, effectively, an abbreviation of the period of mechanical diastole.…”