Abstract
BACKGROUND: Computational biology is a powerful tool for elucidating
arrhythmogenic mechanisms at the cellular level, where complex interactions
between ionic processes determine behavior. A novel theoretical model
of the canine ventricular epicardial action potential and calcium
cycling was developed and used to investigate ionic mechanisms underlying
Ca$^2+$ transient (CaT) and action potential duration (APD)
rate dependence. METHODS AND RESULTS: The Ca$^2+$/calmodulin-dependent
protein kinase (CaMKII) regulatory pathway was integrated into the
model, which included a novel Ca$^2+$-release formulation, Ca$^2+$
subspace, dynamic chloride handling, and formulations for major ion
currents based on canine ventricular data. Decreasing pacing cycle
length from 8000 to 300 ms shortened APD primarily because of I(Ca(L))
reduction, with additional contributions from I(to1), I(NaK), and
late I(Na). CaT amplitude increased as cycle length decreased from
8000 to 500 ms. This positive rate-dependent property depended on
CaMKII activity. CONCLUSIONS: CaMKII is an important determinant
of the rate dependence of CaT but not of APD, which depends on
ion-channel kinetics. The model of CaMKII regulation may serve as
a paradigm for modeling effects of other regulatory pathways on cell
function.
- 15505083
- 4-aminopyridine,
- action
- animals,
- artificial,
- biology,
- calcium
- calcium,
- cardiac
- cardiac,
- cardiovascular,
- channel,
- channels,
- chlorides,
- computational
- computer
- conduction
- dependent
- dogs,
- exchanger,
- extramural,
- gov't,
- heart
- ion
- isoenzymes,
- kinase,
- l-,
- models,
- myocytes,
- n.i.h.,
- non-u.s.
- p.h.s.,
- pacing,
- pericardium,
- potassium
- potassium,
- potentials,
- protein
- rate,
- receptor
- release
- research
- reticulum,
- ryanodine
- sarcoplasmic
- signaling,
- simulation,
- sodium
- sodium,
- sodium-calcium
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