Excitation-contraction coupling and extracellular calcium transients in rabbit atrium: reconstruction of basic cellular mechanisms.

D. W. Hilgemann, D. Noble

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Abstract

Interactions of electrogenic sodium-calcium exchange, calcium channel and sarcoplasmic reticulum in the mammalian heart have been explored by simulation of extracellular calcium transients measured with tetramethylmurexide in rabbit atrium. The approach has been to use the simplest possible formulations of these mechanisms, which together with a minimum number of additional mechanisms allow reconstruction of action potentials, intracellular calcium transients and extracellular calcium transients. A 3:1 sodium-calcium exchange stoichiometry is assumed. Calcium-channel inactivation is assumed to take place by a voltage-dependent mechanism, which is accelerated by a rise in intracellular calcium; intracellular calcium release becomes a major physiological regulator of calcium influx via calcium channels. A calcium release mechanism is assumed, which is both calcium- and voltage-sensitive, and which undergoes prolonged inactivation. 200 microM cytosolic calcium buffer is assumed. For most simulations only instantaneous potassium conductances are simulated so as to study the other mechanisms independently of time- and calcium-dependent outward current. Thus, the model reconstructs extracellular calcium transients and typical action-potential configuration changes during steady-state and non-steady-state stimulation from the mechanisms directly involved in trans-sarcolemmal calcium movements. The model predicts relatively small trans-sarcolemmal calcium movements during regular stimulation (ca. 2 mumol kg-1 fresh mass per excitation); calcium current is fully activated within 2 ms of excitation, inactivation is substantially complete within 30 ms, and sodium-calcium exchange significantly resists repolarization from approximately -30 mV. Net calcium movements many times larger are possible during non-steady-state stimulation. Long action potentials at premature excitations or after inhibition of calcium release can be supported almost exclusively by calcium current (net calcium influx 5-30 mumol kg-1 fresh mass); action potentials during potentiated post-stimulatory contractions can be supported almost exclusively by sodium-calcium exchange (net calcium efflux 4-20 mumol kg-1 fresh mass). Large calcium movements between the extracellular space and the sarcoplasmic reticulum can take place through the cytosol with virtually no contractile activation. The simulations provide integrated explanations of electrical activity, contractile function and trans-sarcolemmal calcium movements, which were outside the explanatory range of previous models.

Original languageEnglish (US)
Pages (from-to)163-205
Number of pages43
JournalProceedings of the Royal Society of London. Series B. Biological sciences
Volume230
Issue number1259
StatePublished - Mar 23 1987

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Excitation Contraction Coupling
contraction
calcium
rabbits
Rabbits
Calcium
action potentials
Action Potentials
calcium channels
Calcium Channels
Sodium
sodium
inactivation
sarcoplasmic reticulum
Sarcoplasmic Reticulum

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Agricultural and Biological Sciences (miscellaneous)

Cite this

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title = "Excitation-contraction coupling and extracellular calcium transients in rabbit atrium: reconstruction of basic cellular mechanisms.",
abstract = "Interactions of electrogenic sodium-calcium exchange, calcium channel and sarcoplasmic reticulum in the mammalian heart have been explored by simulation of extracellular calcium transients measured with tetramethylmurexide in rabbit atrium. The approach has been to use the simplest possible formulations of these mechanisms, which together with a minimum number of additional mechanisms allow reconstruction of action potentials, intracellular calcium transients and extracellular calcium transients. A 3:1 sodium-calcium exchange stoichiometry is assumed. Calcium-channel inactivation is assumed to take place by a voltage-dependent mechanism, which is accelerated by a rise in intracellular calcium; intracellular calcium release becomes a major physiological regulator of calcium influx via calcium channels. A calcium release mechanism is assumed, which is both calcium- and voltage-sensitive, and which undergoes prolonged inactivation. 200 microM cytosolic calcium buffer is assumed. For most simulations only instantaneous potassium conductances are simulated so as to study the other mechanisms independently of time- and calcium-dependent outward current. Thus, the model reconstructs extracellular calcium transients and typical action-potential configuration changes during steady-state and non-steady-state stimulation from the mechanisms directly involved in trans-sarcolemmal calcium movements. The model predicts relatively small trans-sarcolemmal calcium movements during regular stimulation (ca. 2 mumol kg-1 fresh mass per excitation); calcium current is fully activated within 2 ms of excitation, inactivation is substantially complete within 30 ms, and sodium-calcium exchange significantly resists repolarization from approximately -30 mV. Net calcium movements many times larger are possible during non-steady-state stimulation. Long action potentials at premature excitations or after inhibition of calcium release can be supported almost exclusively by calcium current (net calcium influx 5-30 mumol kg-1 fresh mass); action potentials during potentiated post-stimulatory contractions can be supported almost exclusively by sodium-calcium exchange (net calcium efflux 4-20 mumol kg-1 fresh mass). Large calcium movements between the extracellular space and the sarcoplasmic reticulum can take place through the cytosol with virtually no contractile activation. The simulations provide integrated explanations of electrical activity, contractile function and trans-sarcolemmal calcium movements, which were outside the explanatory range of previous models.",
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