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Alterations in action potential profile enhance excitation-contraction coupling in rat cardiac myocytes

Rajan Sah, Rafael J. Ramirez, Roger Kaprielian and Peter H. Backx

1. Action potential (AP) prolongation typically occurs in heart disease due to reductions in transient outward potassium currents (I_to), and is associated with increased Ca²⁺ transients. We investigated the underlying mechanisms responsible for enhanced Ca²⁺ transients in normal isolated rat ventricular myocytes in response to the AP changes that occur following myocardial infarction.
2. Normal myocytes stimulated with a train of long post-myocardial infarction (MI) APs showed a 2.2-fold elevation of the peak Ca²⁺ transient and a 2.7-fold augmentation of fractional cell shortening, relative to myocytes stimulated with a short control AP.
3. The steady-state Ca²⁺ load of the sarcoplasmic reticulum (SR) was increased 2.0-fold when myocytes were stimulated with trains of long post-MI APs (111 ± 21.6 µmol l^-1) compared with short control APs (56 ± 7.2 µmol l^-1).
4. Under conditions of equal SR Ca²⁺ load, long post-MI APs still resulted in a 1.7-fold increase in peak [Ca²⁺]_i and a 3.8-fold increase in fractional cell shortening relative to short control APs, establishing that changes in the triggering of SR Ca²⁺ release are largely responsible for elevated Ca²⁺ transients following AP prolongation.
5. Fractional SR Ca²⁺ release calculated from the measured SR Ca²⁺ load and the integrated SR Ca²⁺ fluxes was 24 ± 3 and 11 ± 2 % following post-MI and control APs, respectively.
6. The fractional release (FR) of Ca²⁺ from the SR divided by the integrated L-type Ca²⁺ flux (FR/F_Ca,L) was increased 1.2-fold by post-MI APs compared with control APs. Similar increases in excitation-contraction (E-C) coupling gains were observed establishing enhanced E-C coupling efficiency.
7. Our findings demonstrate that AP prolongation alone can markedly enhance E-C coupling in normal myocytes through increases in the L-type Ca²⁺ current (I_Ca,L) trigger combined with modest enhancements in Ca²⁺ release efficiency. We propose that such changes in AP profile in diseased myocardium may contribute significantly to alterations in E-C coupling independent of other biochemical or genetic changes.

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