Stretch-activated channel activation promotes early afterdepolarizations in rat ventricular myocytes under oxidative stress

Abstract

BH. Stretch-activated channel activation promotes early afterdepolarizations in rat ventricular myocytes under oxidative stress. Am J Physiol Heart Circ Physiol 296: H1227-H1235, 2009. First published March 13, 2009 doi:10.1152/ajpheart.00808.2008.-Mechanical stretch and oxidative stress have been shown to prolong action potential duration (APD) and produce early afterdepolarizations (EADs). Here, we developed a simulation model to study the role of stretch-activated channel (SAC) currents in triggering EADs in ventricular myocytes under oxidative stress. We adapted our coupling clamp circuit so that a model ionic current representing the actual SAC current was injected into ventricular myocytes and added as a real-time current. This current was calculated as ISAC ϭ GSAC ‫ء‬ (Vm Ϫ ESAC), where GSAC is the stretch-activated conductance, Vm is the membrane potential, and ESAC is the reversal potential. In rat ventricular myocytes, application of GSAC did not produce sustained automaticity or EADs, although turn-on of GSAC did produce some transient automaticity at high levels of GSAC. Exposure of myocytes to 100 M H2O2 induced significant APD prolongation and increase in intracellular Ca 2ϩ load and transient, but no EAD or sustained automaticity was generated in the absence of GSAC. However, the combination of GSAC and H2O2 consistently produced EADs at lower levels of GSAC (2.6 Ϯ 0.4 nS, n ϭ 14, P Ͻ 0.05). Pacing myocytes at a faster rate further prolonged APD and promoted the development of EADs. SAC activation plays an important role in facilitating the development of EADs in ventricular myocytes under acute oxidative stress. This mechanism may contribute to the increased propensity to lethal ventricular arrhythmias seen in cardiomyopathies, where the myocardium stretch and oxidative stress generally coexist. arrhythmia mechanisms; action potential; patch clamp PREVIOUS STUDIES HAVE SHOWN that myocardial stretch, a process termed "mechanoelectric feedback," can induce myocyte depolarization and abnormal impulses by the stretch-activated channel (SAC) currents (7,21). A subset of SACs has been reported as nonselective cation channels (48), which allow Na ϩ , K ϩ , Cs ϩ , and Ca 2ϩ to permeate (36). A linear currentvoltage relationship has been described for SACs with reversal potentials measured in myocytes from Ϫ6 to Ϫ15 mV (17,33,48). In a review by Kohl et al. (24), they note that models incorporating SACs as pure charge carriers and models that include movement of ions through the channels both reproduced experimental phenomena, such as diastolic depolarization, positive chronotropic responses of pacemakers, and action potential (AP) generation due to stretch (25).It has been suggested that oxidative stress is a mechanism for Ca 2ϩ overload and the consequent electrical changes in cardiomyocytes (5). On the other hand, Ca 2ϩ overload increases oxidative stress by altering mitochondrial function, which leads to increased production of oxygen radicals (9). Oxidative stress alters the function of several elem...

Electromechanical feedback with reduced cellular connectivity alters electrical activity in an infarct injured left ventricle: a finite element model study

“…With even a simple single current model of MEF, we were able to simulate many of the features observed in experimental testing. Our model simulated increased action potential duration with increased stretch in the border zone, in line with a wide range of animal and experimental models where trends of increasing action potential duration with stretch were observed (7,23,26,42). In addition, we observe a slight reduction in action potential duration dispersion with increasing SAC activity, which is in line with experimental measures that show that stretch-activated channels in healthy tissue decrease action potential duration dispersion (36).…”

“…Although stretch has been shown to increase action potential duration both in single cell studies (42) as well as whole tissue preparations (26), in our simulations, we only see significant changes to action potential duration and dispersion in the presence of decreased connectivity. This could be because of the magnitude of SAC currents used in our model, since, even though we used currents that exceeded published values, there are indications that MEF is exacerbated in the heart when an MI is present (23,26).…”

Effects of obstructive sleep apnoea on heart rhythm

“…In vitro and in vivo studies on myocardial tissue have provided evidence for acute stretch-activated Ca 2+ channels which produce functionally significant repolarisation gradients and promote both early and delayed after-depolarisations, thereby predisposing to ventricular arrhythmias [49,50]. Similar results were found in an animal model, in which negative intrathoracic pressure during obstructive respiratory events induced shortening of the right atrial refractory period and consequently increased the susceptibility to premature beats and atrial fibrillation [51].…”

Metabolic stress, reactive oxygen species, and arrhythmia

“…The combination of mechanical stretch and low level oxidative stress triggers Ca 2+ overload and prolong APD through premature beat resulting early afterdepolarizations [152]. This may explain the reduction of ventricular arrhythmias with intra-aortic balloon counterpulsation [153, 154].…”