Effects of mechanical load on calcium handling in cardiac myocytes

• Main Author: Iribe, Gentaro
• Published: University of Oxford 2007
• Subjects: 571.6
• Online Access: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.487260

In the 'in sitrl heart, electrical excitation of cardiac myocytes induces Ca2+ influx into the cytosolic space, which initiates muscle contraction (excitation contraction coupling) against a background of dynamically changing pre- and afterload conditions. On the other hand, mechanical load affects Ca2+ handling, either directly, or indirectly via modulation of electrical activity (mechano-electric feedback). The aim of this Thesis is to investigate and quantitatively describe the interactions between mechanical activity and Ca2+ handling, using experimental and mathematical modelling tools. Although there are a number of mathematical cardiac cell models available, few are aimed at reproducing beat-by-beat behaviour of Ca2+ handling. Therefore, we developed an original cell model which allows one to reproduce beat-by-beat changes in Ca2+ handling and resultant force production, which formed the basis for mathematical integration of the experimental findings of our Ca2+ handling study in this thesis. For e};perimental research, we developed a novel single cell force-length clamp (MyoStretcher), which uses piezo-control of carbon fibres (CF) to dynamically restrain the mechanical environment of isolated intact cardiomyocytes.Using the M):oStretcher, we subjected single isolated myocardial cells to dynamic contractions with work-loop style force-length (FL) relation, similar to those experienced by the cell 'in sittl. Single cell mechanics studies revealed that the end-systolic FL relation (ESFLR) IS load-independent In ventricular cardiomyoeytes of small mammals (Guinea pig). Modelling-based simulation studies suggest that the load-independent behaviour of ESFLR is the result of the combined effects ofload-dependent Ca2+ and crossbridge kinetics. Furthermore, the impact of diastolic stretch on sarcoplasmic reticulum (SR) Ca2+ handling was investigated. Axial cell stretch increased SR Ca2+ leak, but also and re-uptake of Ca2+ into the previously depleted SR of ventricular cardiomyocytes isolated from Guinea pig. The results were reproduced in model simulations. Axial stretch furthermore caused an acute increase in the Ca2+ spark rate of rat myoeytes. The mechanisms underlying this stretch-induced increase in spark rate act locally, are independent of nitric oxide and stretch-activated ion channels, and require an intact cytoskeleton. In conclusion, this thesis revealed that the interaction between cellular mechanics and Ca2+ handling is an important factor for integrative function of the heart, established several hitherto unknown mechanisms, and provided a novel set of experimental and theoretical tools for further research.