BIOPHYSICAL THEORY AND MODELING |
A dynamic model of excitation-contraction coupling
during acidosis in cardiac ventricular myocytes
Edmund J. Crampin 1* and Nicolas P. Smith 1
1 University of Auckland
* To whom correspondence should be addressed. E-mail: e.crampin{at}auckland.ac.nz.
Submitted on July 12, 2005
Revised on September 27, 2005
Accepted on 23 January 2006
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Abstract |
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Acidosis in cardiac myocytes is a major factor in the reduced inotropy that occurs in the ischaemic heart. During acidosis, diastolic calcium and the amplitude of the calcium transient increase, while the strength of contraction decreases. These effects have been attributed to the inhibition by protons of calcium uptake and release by the sarcoplasmic reticulum, to a rise of intracellular sodium caused by activation of sodium-proton exchange, decreased calcium binding affinity to Troponin~C and direct effects on the contractile machinery. The relative contributions and concerted action of these effects are, however, difficult to establish experimentally. We have developed a mathematical model to examine altered calcium-handling mechanisms during acidosis. Each of the alterations was incorporated into a dynamical model of pH regulation and excitation-contraction coupling to predict the time courses of key ionic species during acidosis, in particular intracellular pH, sodium and the calcium transient, and contraction. This modelling study suggests that the most significant effects are elevated sodium, inhibition of sodium-calcium exchange and the direct interaction of protons with the contractile machinery, and shows how these combine to produce the overall effects of acidosis in the beating heart.
Key Words:
Calcium-Induced Calcium Release, Heart, Ischemia, Mathematical Model, Respiratory Acidosis, pH Regulation
