Korean J Physiol Pharmacol.  2008 Oct;12(5):267-274. 10.4196/kjpp.2008.12.5.267.

Modeling of Arrhythmogenic Automaticity Induced by Stretch in Rat Atrial Myocytes

• Youm JB
• Leem CH
• Zhang YH
• Kim N
• Han J
• Earm YE

• KMID: 1486109
• DOI: http://doi.org/10.4196/kjpp.2008.12.5.267

Abstract

Since first discovered in chick skeletal muscles, stretch-activated channels (SACs) have been proposed as a probable mechano-transducer of the mechanical stimulus at the cellular level. Channel properties have been studied in both the single-channel and the whole-cell level. There is growing evidence to indicate that major stretch-induced changes in electrical activity are mediated by activation of these channels. We aimed to investigate the mechanism of stretch-induced automaticity by exploiting a recent mathematical model of rat atrial myocytes which had been established to reproduce cellular activities such as the action potential, Ca2+ transients, and contractile force. The incorporation of SACs into the mathematical model, based on experimental results, successfully reproduced the repetitive firing of spontaneous action potentials by stretch. The induced automaticity was composed of two phases. The early phase was driven by increased background conductance of voltage-gated Na+ channel, whereas the later phase was driven by the reverse-mode operation of Na+/Ca2+ exchange current secondary to the accumulation of Na+ and Ca2+ through SACs. These results of simulation successfully demonstrate how the SACs can induce automaticity in a single atrial myocyte which may act as a focus to initiate and maintain atrial fibrillation in concert with other arrhythmogenic changes in the heart.

Keyword

Stretch; Automaticity; Atrial fibrillation; Modeling

MeSH Terms

Action Potentials
Animals
Atrial Fibrillation
Fires
Heart
Models, Theoretical
Muscle Cells
Muscle, Skeletal
Rats

Figure

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  Fig. 1. Simulation of SACs-induced automaticity in the heart. Increasing SACs conductance (13.6 μS/μF) triggered repetitive firing of action potentials (APs) in otherwise quiescent model cell of rat atrial myocytes. The AP train is composed of early and delayed phases with different frequency (2.8 Hz vs 1.2 Hz). Upon releasing the SACs activation, the model cell stopped firing, leaving very small depolarizations (A). Contractile force (B) and Ca2+ (C) show time course similar to that of membrane potential during the SACs activation. After release of SACs activation, however, the contractile force and Ca2+ continue oscillation with decreasing frequency. Na+ (D) is slowly accumulated with activation of SACs and decreased slowly on release of activation.

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  Fig. 2. Role of INa in the SACs-induced automaticity. The length of early phase in the repetitive firing of APs is dependent on the maximal conductance of voltage-gated Na+ channel. Reducing the maximal conductance to 40% of control failed to generate the repetitive firing of APs. As the maximal conductance of voltage-gated Na+ channel was more increased, however, the automaticity appeared and the length of early phase in repetitive firing of APs was increased. The length of delayed phase was relatively unaffected when the maximal conductance was varied between 80% and 120% relative to the control. When the maximal conductance was increased to 140% relative to the control, two phases merged together.

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  Fig. 3. Role of INaCa in SACs-induced automaticity. Clamping of INaCa just before the delayed phase of repetitive firing of APs by SACs activation abolished the delayed phase, leaving oscillations of contractile force and Ca2+ unaffected. Time course of [Na+]i was also unaffected compared with that of the control (see Fig. 1D).

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  Fig. 4. Role of intracellular cations in the SACs-induced automaticity. Clamping of cation concentrations during the SACs activation abolished the delayed phase of SACs-induced automaticity, leaving only the early phase under conditions of 60% (A) and 80% (B) in maximal conductance of voltage-gated Na+ channel relative to the control. The firing of APs continued during the SACs activation under the condition of 100% (C) in maximal conductance relative to the control, indicating that the early phase is driven by purely electrical means.

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