Intra-sarcoplasmic reticulum free [Ca2+] and buffering in arrhythmogenic failing rabbit heart.
Smaller Ca2+ transients and systolic dysfunction in heart failure (HF) can be largely explained by reduced total sarcoplasmic reticulum (SR) Ca2+ content ([Ca]SRT). However, it is unknown whether low [Ca]SRT is manifest as reduced: (1) intra-SR free [Ca2+] ([Ca2+]SR), (2) intra-SR Ca2+ buffering, or (3) SR volume (as percentage of cell volume). Here we assess these possibilities in a well-characterized rabbit model of nonischemic HF. In HF versus control myocytes, diastolic [Ca2+]SR is similar at 0.1-Hz stimulation, but the increase in both [Ca2+]SR and [Ca]SRT as frequency increases to 1 Hz is blunted in HF. Direct measurement of intra-SR Ca2+ buffering (by simultaneous [Ca2+]SR and [Ca]SRT measurement) showed no change in HF. Diastolic [Ca]SRT changes paralleled [Ca2+]SR, suggesting that SR volume is not appreciably altered in HF. Thus, reduced [Ca]SRT in HF is associated with comparably reduced [Ca2+]SR. Fractional [Ca2+]SR depletion increased progressively with stimulation frequency in control but was blunted in HF (consistent with the blunted force-frequency relationship in HF). By studying a range of [Ca2+]SR, analysis showed that for a given [Ca]SR, fractional SR Ca2+ release was actually higher in HF. For both control and HF myocytes, SR Ca2+ release terminated when [Ca2+]SR dropped to 0.3 to 0.5 mmol/L during systole, consistent with a role for declining [Ca2+]SR in the dynamic shutoff of SR Ca2+ release. We conclude that low total SR Ca2+ content in HF, and reduced SR Ca2+ release, is attributable to reduced [Ca2+]SR, not to alterations in SR volume or Ca2+ buffering capacity.
Guo
Tao
T
Department of Physiology, Loyola University Chicago, Stritch School of Medicine, Maywood, IL 60153, USA.
Ai
Xun
X
Shannon
Thomas R
TR
Pogwizd
Steven M
SM
Bers
Donald M
DM
D000818:Animals; D001145:Arrhythmias, Cardiac / Q000378:metabolism* / Q000473:pathology; D002118:Calcium / Q000378:metabolism* / Q000502:physiology; D005260:Female; D006333:Heart Failure / Q000378:metabolism* / Q000473:pathology; D008297:Male; D032342:Muscle Cells / Q000378:metabolism / Q000473:pathology; D011817:Rabbits; D012519:Sarcoplasmic Reticulum / Q000378:metabolism* / Q000473:pathology
D002118:Calcium