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

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.