Alterations in action potential profile enhance excitation-contraction coupling in rat cardiac myocytes.
Action potential (AP) prolongation typically occurs in heart disease due to reductions in transient outward potassium currents (Ito), 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. 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. 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 micromol l(-1)) compared with short control APs (56 +/- 7.2 micromol l(-1)). 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. 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. The fractional release (FR) of Ca2+ from the SR divided by the integrated L-type Ca2+ flux (FR/[integral]FCa,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. Our findings demonstrate that AP prolongation alone can markedly enhance E-C coupling in normal myocytes through increases in the L-type Ca2+ current (ICa,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.
Sah
R
R
Toronto General Hospital, CCRW 3-802, 101 College Street, Toronto, Ontario, Canada M5G 2C4.
Ramirez
R J
RJ
Kaprielian
R
R
Backx
P H
PH
D000200:Action Potentials / Q000502:physiology*; D000818:Animals; D002118:Calcium / Q000493:pharmacokinetics; D020746:Calcium Channels, L-Type / Q000378:metabolism; D006352:Heart Ventricles / Q000166:cytology; D066298:In Vitro Techniques; D008297:Male; D018485:Muscle Fibers, Skeletal / Q000502:physiology*; D009200:Myocardial Contraction / Q000502:physiology*; D009206:Myocardium / Q000166:cytology*; D018408:Patch-Clamp Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley; D012519:Sarcoplasmic Reticulum / Q000378:metabolism
D020746:Calcium Channels, L-Type; D002118:Calcium