Voltage-independent changes in L-type Ca2+ current uncoupled from SR Ca2+ release in cardiac myocytes

Andrzej M. Janczewski, Edward G. Lakatta, Michael D. Stern

Research output: Contribution to journalArticlepeer-review

Abstract

To determine the effect of voltage-independent alterations of L-type Ca2+ current (I(Ca)) on the sarcoplasmic reticular (SR) Ca2+ release in cardiac myocytes, we measured I(Ca) and cytosolic Ca2+ transients (Ca(i)/2+; intracellular Ca2+ concentration) in voltage-clamped rat ventricular myocytes during 1) an abrupt increase of extracellular [Ca2+] (Ca(o)/2+) or 2) application of 1 ♂m FPL-64176, a Ca2+ channel agonist, to selectively alter I(Ca) in the absence of changes in SR Ca2+ loading. On the first depolarization in higher Ca(o)/2+, peak I(Ca) was increased by 46 ± 6% (P < 0.001), but the increases in the maximal rate of rise of Ca(i)/2+ (dCa(i)/2+/dt(max), where t is time; an index of SR Ca2+ release flux) and the Ca(i)/2+ transient amplitude were not significant. Rapid exposure to FPL-64176 greatly slowed inactivation of I(Ca), increasing its time integral by 117 ± 8% (P < 0.001) without significantly increasing peak I(Ca), Dca(i)/2+/dt(max), or amplitude of the corresponding Ca(i)/2+ transient. Prolongation of exposure to higher Ca(o)/2+ or FPL-64176 did not further increase peak I(Ca) but greatly increased Dca(i)/2+/dt(max), Ca(i)/2+ transient amplitude, and the gain of Ca2+ release (Dca(i)/2+/dt(max)/I(Ca), evidently due to augmentation of the SR Ca2+ loading. Also, the time to peak Dca(i)/2+/dt(max) was significantly increased in the continuous presence of higher Ca(o)/2+ (by 37 ± 5%, P < 0.001) or FPL-64176 (by 63 ± 5%, P < 0.002). Our experiments provide the first evidence of a marked disparity between an increased peak I(Ca) and the corresponding SR Ca2+ release. We attribute this to saturation of the SR Ca2+ release flux as predicted by local control theory. Prolongation of the SR Ca2+ release flux, caused by combined actions of a larger I(Ca) and maximally augmented SR Ca2+ loading, might reflect additional Ca2+ release from corbular SR.

Original languageEnglish (US)
Pages (from-to)H2024-H2031
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume279
Issue number4 48-4
DOIs
StatePublished - 2000
Externally publishedYes

Keywords

  • Corbular sarcoplasmic reticulum
  • Excitation-contraction coupling
  • FPL-64176
  • Local Ca control
  • Ryanodine receptor

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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