High Capability of Pentagalloylglucose (PGG) in Inhibiting Multiple Types of Membrane Ionic Currents

Pentagalloyglucose (PGG, penta-O-galloyl-β-d-glucose; 1,2,3,4,6-pentagalloyl glucose), a pentagallic acid ester of glucose, is recognized to possess anti-bacterial, anti-oxidative and anti-neoplastic activities. However, to what extent PGG or other polyphenolic compounds can perturb the magnitude and/or gating of different types of plasmalemmal ionic currents remains largely uncertain. In pituitary tumor (GH3) cells, we found out that PGG was effective at suppressing the density of delayed-rectifier K+ current (IK(DR)) concentration-dependently. The addition of PGG could suppress the density of proton-activated Cl− current (IPAC) observed in GH3 cells. The IC50 value required for the inhibitory action of PGG on IK(DR) or IPAC observed in GH3 cells was estimated to be 3.6 or 12.2 μM, respectively, while PGG (10 μM) mildly inhibited the density of the erg-mediated K+ current or voltage-gated Na+ current. The presence of neither chlorotoxin, hesperetin, kaempferol, morin nor iberiotoxin had any effects on IPAC density, whereas hydroxychloroquine or 4-[(2-butyl-6,7-dichloro-2-cyclopentyl-2,3-dihydro-1-oxo-1H-inden-5yl)oxy] butanoic acid suppressed current density effectively. The application of PGG also led to a decrease in the area of voltage-dependent hysteresis of IPAC elicited by long-lasting isosceles-triangular ramp voltage command, suggesting that hysteretic strength was lessened in its presence. In human cardiac myocytes, the exposure to PGG also resulted in a reduction of ramp-induced IK(DR) density. Taken literally, PGG-perturbed adjustment of ionic currents could be direct and appears to be independent of its anti-oxidative property.

Numerical Simulations of Fractionated Electrograms and Pathological Cardiac Action Potential

The aim of this work is twofold. First we focus on the complex phenomenon of electrogram fractionation, due to the presence of discontinuities in the conduction properties of the cardiac tissue in a bidomain model. Numerical simulations of paced activation may help to understand the role of the membrane ionic currents and of the changes in cellular coupling in the formation of conduction blocks and fractionation of the electrogram waveform. In particular, we show that fractionation is independent ofINAalterations and that it can be described by the bidomain model of cardiac tissue. Moreover, some deflections in fractionated electrograms may give nonlocal information about the shape of damaged areas, also revealing the presence of inhomogeneities in the intracellular conductivity of the medium at a distance.The second point of interest is the analysis of the effects of space–time discretization on numerical results, especially during slow conduction in damaged cardiac tissue. Indeed, large discretization steps can induce numerical artifacts such as slowing down of conduction velocity, alteration in extracellular and transmembrane potential waveforms or conduction blocks, which are not predicted by the continuous bidomain model. Several possible numerical and physiological explanations of these effects are given. Essentially, the discrete system obtained at the end of the approximation process may be interpreted as a discrete model of the cardiac tissue made up of isopotential cells where the effective intracellular conductivity tensor depends on the space discretization steps; the increase of these steps results in an increase of the effective intracellular resistance and can induce conduction blocks if a certain critical value is exceeded.

MEMORY AND BISTABILITY IN A ONE-DIMENSIONAL LOOP OF MODEL CARDIAC CELLS

Unidirectional propagation has been studied in a one-dimensional loop of model cardiac cells represented as a homogeneous and isotropic cable. Membrane ionic currents were represented by a modified Beeler-Reuter model. The time constants of the gate variables of the slow inward current acting during the plateau of the action potential were divided by a parameter K ≥1. In the space-clamped model, increasing K shortens the action potential duration, changes the shape of the restitution curve and adds a slow memory component to the dynamics. In a paced regime, it promotes bistability in which period-1 and period-2 patterns coexist over an interval of pacing frequencies. In the loop, bistability is created between periodic and aperiodic modes of sustained reentry for an interval of loop length. The bistability of the space-clamped and loop model are both related to the form of the restitution curve.