Intra-sarcoplasmic reticulum free [Ca2+] and buffering in arrhythmogenic failing rabbit heart

Tao Guo, Xun Ai, Thomas R. Shannon, Steven M. Pogwizd, Donald M Bers

Research output: Contribution to journalArticle

28 Scopus citations

Abstract

Smaller Ca transients and systolic dysfunction in heart failure (HF) can be largely explained by reduced total sarcoplasmic reticulum (SR) Ca content ([Ca]SRT). However, it is unknown whether low [Ca]SRT is manifest as reduced: (1) intra-SR free [Ca] ([Ca]SR), (2) intra-SR Ca 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 [Ca]SR is similar at 0.1-Hz stimulation, but the increase in both [Ca]SR and [Ca]SRT as frequency increases to 1 Hz is blunted in HF. Direct measurement of intra-SR Ca buffering (by simultaneous [Ca]SR and [Ca]SRT measurement) showed no change in HF. Diastolic [Ca]SRT changes paralleled [Ca]SR, suggesting that SR volume is not appreciably altered in HF. Thus, reduced [Ca]SRT in HF is associated with comparably reduced [Ca]SR. Fractional [Ca]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 [Ca]SR, analysis showed that for a given [Ca]SR, fractional SR Ca release was actually higher in HF. For both control and HF myocytes, SR Ca release terminated when [Ca]SR dropped to 0.3 to 0.5 mmol/L during systole, consistent with a role for declining [Ca]SR in the dynamic shutoff of SR Ca release. We conclude that low total SR Ca content in HF, and reduced SR Ca release, is attributable to reduced [Ca]SR, not to alterations in SR volume or Ca buffering capacity.

Original languageEnglish (US)
Pages (from-to)802-810
Number of pages9
JournalCirculation Research
Volume101
Issue number8
DOIs
StatePublished - Oct 2007
Externally publishedYes

Keywords

  • [Ca]
  • [Ca]
  • Excitation-ontraction coupling
  • Heart failure
  • Intra-SR Ca buffering
  • Sarcoplasmic reticulum

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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