A Novel Method for Quantifying the Contribution of Different Intracellular Mechanisms to Mechanically Induced Changes in Action Potential Characteristics
We introduce the Difference-Current Integral (DCI) method as a tool for quantitative assessment of contributions by individual model components to dynamic responses at the system’s level. Using a detailed model of cardiac electrophysiology and mechanics, we assess the relative effects of mechano-sensitive ion channels and intracellular calcium handling to stretch-induced changes in action potential (AP) characteristics. DCI supports the hypothesis that some of the experimentally observed variability in cardiac AP responses to mechanical stimulation may be caused by differences in activation of underlying mechanisms, rather than solely species or technical differences. In particular, the model suggests that systems with a pronounced reverse mode Na+-Ca2+ exchange during the AP will respond to mechanical interventions that affect primarily cellular Ca2+ handling with AP shortening, whereas a predominant contribution of mechano-sensitive ion channels, in particular cation non-selective ones, may cause late AP prolongation and cross-over of repolarisation.
KeywordsAction Potential Duration Action Potential Amplitude Action Potential Shape Intracellular Calcium Handling Action Potential Characteristic
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- 2.Kohl, P., Hunter, P., Noble, D.: Stretch-Induced Changes in Heart Rate and Rhythm: Clinical Observations, Experiments and Mathematical Models. Prog. Biophys. Mol. Biol. 71.1 (1999) 91–138Google Scholar
- 3.Solovyova, O., Vikulova, N., Katsnelson, L.B., Markhasin, V.S., Noble, P.J., Garny, A.F., Kohl, P., Noble, D.: Mechanical Interaction of Heterogeneous Cardiac Muscle Segments in Silico: Effects on Ca2+ Handling and Action Potential. Int. J. Bifurcation and Chaos (2003) in pressGoogle Scholar
- 4.Noble, D., Varghese, A., Kohl, P., Noble, P.: Improved Guinea-Pig Ventricular Cell Model Incorporating a Diadic Space, Ikr and Iks, and Length-and Tension-Dependent Processes. Can. J. Cardiol. 14.1 (1998) 123–134Google Scholar
- 6.Gordon, A.M., Regnier, M., Homsher, E.: Skeletal and Cardiac Muscle Contractile Activation: Tropomyosin “Rocks and Rolls”. News Physiol. Sci. 16 (2001) 49–55Google Scholar
- 8.Hongo, K., White, E., Le Guennec, J.Y., Orchard, C.H.: Changes in [Ca2+]I, [Na+]I and Ca2+ Current in Isolated Rat Ventricular Myocytes Following an Increase in Cell Length. J. Physiol. 491.3 (1996) 609–619Google Scholar
- 10.Kohl, P., Day, K., Noble, D.: Cellular Mechanisms of Cardiac Mechano-Electric Feedback in a Mathematical Model. Can. J. Cardiol. 14.1 (1998) 111–119Google Scholar
- 11.Lab, M.J., Allen, D.G., Orchard, C.H.: The Effects of Shortening on Myoplasmic Calcium Concentration and on the Action Potential in Mammalian Ventricular Muscle. Circ. Res. 55.6 (1984) 825–829Google Scholar
- 12.White, E., Le Guennec, J.Y., Nigretto, J.M., Gannier, F., Argibay, J.A., Garnier, D.: The Effects of Increasing Cell Length on Auxotonic Contractions; Membrane Potential and Intracellular Calcium Transients in Single Guinea-Pig Ventricular Myocytes. Exp. Physiol. 78.1 (1993) 65–78Google Scholar
- 13.Hansen, D.E.: Mechanoelectrical Feedback Effects of Altering Preload, Afterload, and Ventricular Shortening. Am. J. Physiol. 264 (1993) H423–H432Google Scholar