To investigate the cellular mechanisms for altered Ca2+ homeostasis and contractility in cardiac hypertrophy, we measured whole-cell L-type Ca2+ currents (I(Ca,L)), whole-cell Ca2+ transients ([Ca2+](i)), and Ca2+ sparks in ventricular cells from 6-month-old spontaneously hypertensive rats (SHRs) and from age- and sex-matched Wistar-Kyoto and Sprague-Dawley control rats. By echocardiography, SHR hearts had cardiac hypertrophy and enhanced contractility (increased fractional shortening) and no signs of heart failure. SHR cells had a voltage-dependent increase in peak [Ca2+](i) amplitude (at 0 mV, 1330 ± 62 nmol/L [SHRs] versus 836 ± 48 nmol/L [controls], P < 0.05) that was not associated with changes in I(Ca,L) density or kinetics, resting [Ca2+](i), or Ca2+ content of the sarcoplasmic reticulum (SR). SHR cells had increased time of relaxation. Ca2+ sparks from SHR cells had larger average amplitudes (173 ± 192 nmol/L [SHRs] versus 109 ± 64 nmol/L [control]; P < 0.05), which was due to redistribution of Ca2+ sparks to a larger amplitude population. This change in Ca2+ spark amplitude distribution was not associated with any change in the density of ryanodine receptors, calsequestrin, junctin, triadin 1, Ca2+-ATPase, or phospholamban. Therefore, SHRs with cardiac hypertrophy have increased contractility, [Ca2+](i) amplitude, time to relaxation, and average Ca2+ spark amplitude ('big sparks'). Importantly, big sparks occurred without alteration in the trigger for SR Ca2+ release (I(Ca.L)), SR Ca2+ content, or the expression of several SR Ca2+-cycling proteins. Thus, cardiac hypertrophy in SHRs is linked with an alteration in the coupling of Ca2+ entry through L-type Ca2+ channels and the release of Ca2+ from the SR, leading to big sparks and enhanced contractility. Alterations in the microdomain between L-type Ca2+ channels and SR Ca2+ release channels may underlie the changes in Ca2+ homeostasis observed in cardiac hypertrophy. Modulation of SR Ca2+ release may provide a new therapeutic strategy for cardiac hypertrophy and for its progression to heart failure and sudden death.
- Ca spark
- Ca transient
- Cardiac hypertrophy
- Spontaneously hypertensive rat