Can principles of the surface potential be combined with knowledge of natural products to reduce atrial rhythm disturbances?

Long-lasting or chronic electrophysiological abnormalities in human atria are significant contributors to morbidity during healthy ageing. Although both paroxysmal (brief) and chronic atrial fibrillation (AF) were considered to be benign, the notable association between maintained AF and stroke has resulted in AF now being a target for surgical intervention (ablation) and/or drug therapy. An interesting, forward-looking paper from the Elinder group in this issue of Acta Physiologica reveals novel pharmacological agents and principles that could be the basis for more effective antiarrhythmic therapies for AF. Salari et al. rigorously evaluate the possibility that altering the activity of not one, but several different transmembrane ionic currents that are essential for generation of the atrial action potential can reduce spontaneous firing and prolong the action potential. Salari et al. accomplish this by utilizing a surrogate for a mouse atrial myocyte (HL-1 cells) in culture and applying selected natural compounds (resin acids) that they have previously studied in other model systems. Their detailed electrophysiological testing (voltage clamp recordings) reveals that these small acids, when superfused at lM levels, can alter this HL-1-based arrhythmic substrate by simultaneously reducing Na, and Ca currents, while enhancing K currents, while enhancing K currents. These effects arise mainly from a common mechanism: the ability of these compounds (in particular isopimaric acid) to bind to discreet charged sites very near these ion channel gating regulators on the myocyte surface membrane (sarcolemma). In doing so, they alter the fixed or localized surface charges that strongly regulate the opening, closing and ‘availability’ of these channels. These effects are concentration-dependent and reversible. Mathematical modelling suggests that they also can be predicted and understood based on the ability of these natural compounds to change the surface potential (or zeta potential), as opposed to altering the conventional electrochemical transmembrane voltage profile. Surface charge regulation of ion channel gating has a long history, much of which is tied closely to papers in this journal from a number of internationally acclaimed Scandinavian investigators. Frankenhaeuser and Hodgkin first identified and explained the functional importance of ‘surface potentials’ in their studies on the effects of divalent cations (with an emphasis on Ca) on the threshold for action potential firing and the conduction velocity in squid axons. Subsequent work by the Arhem group and others documented these effects on Na channels in myelinated nerve, while also demonstrating similar changes in K channel gating and identifying its molecular basis. These findings can perhaps be put into a translational context by addressing the question: Would similar electrophysiological changes be observed in a human atrial myocyte, in response to the surface charge-mediated modifications of the ion channels reported by Salari et al.? Our mathematical simulations in Figure 1 provide some of this information. We have used the human atrial electrophysiology simulation resource published by our colleagues to introduce the isopimaric acid-induced changes in four of the transmembrane ionic currents that underlie the human atrial action potential. Sets of simulations have been carried out using both (i) the healthy or baseline mathematical model of a single left atrial human myocyte (left column) and (ii) a version of this mathematical model that incorporates many of the known AF-induced changes in the underlying ionic currents, producing altered action potential waveforms that are characteristic of chronic atrial fibrillation. In the first of four rows of Figure 1, one of the ion channel-specific isopimaric acid-induced hyperpolarizing shifts in the steady-state activation and inactivation relationships has been introduced in silico. Baseline (control) data are shown in black; results generated after incorporating a 5 mV shift in these variables are shown in red and the data produced by a 10 mV shift are illustrated by the blue broken lines. It is apparent that these isopimaric acid-induced changes in the Na current INa (panel a) and those in the Ca 2+ current ICa-L (panel d) produce the most marked changes in the upstroke and phase I of the action potential or the AP waveforms. The data in panel (e) were computed based on a combination of all of these isopimaric acid-induced changes. Note that