Luminal Ca2+ content regulates intracellular Ca2+ release in subepicardial myocytes of intact beating mouse hearts: effect of exogenous buffers

• Published in: American journal of physiology. Heart and circulatory physiology Vol. 298; no. 6; pp. H2138 - H2153
• Main Authors: Kornyeyev, Dmytro, Reyes, Mariano, Escobar, Ariel L.
• Format: Journal Article
• Language: English
• Published: Bethesda, MD American Physiological Society 01.06.2010
• DOI: 10.1152/ajpheart.00885.2009
• ISSN: 0363-6135

Ca + -induced Ca 2+ release tightly controls the function of ventricular cardiac myocytes under normal and pathological conditions. Two major factors contributing to the regulation of Ca 2+ release are the cytosolic free Ca 2+ concentration and sarcoplasmic reticulum (SR) Ca 2+ content. We hypothesized that the amount of Ca 2+ released from the SR during each heart beat strongly defines the refractoriness of Ca 2+ release. To test this hypothesis, EGTA AM, a high-affinity, slow-association rate Ca 2+ chelator, was used as a tool to modify luminal SR Ca 2+ content. An analysis of the cytosolic and luminal SR Ca 2+ dynamics recorded from the epicardial layer of intact mouse hearts indicated that the presence of EGTA reduced the diastolic SR free Ca 2+ concentration and fraction of SR Ca 2+ depletion during each beat. In addition, this maneuver shortened the refractory period and accelerated the restitution of Ca 2+ release. As a consequence of the accelerated restitution, the frequency dependence of Ca 2+ alternans was significantly shifted toward higher heart rates, suggesting a role of luminal SR Ca 2+ in the genesis of this highly arrhythmogenic phenomenon. Thus, intra-SR Ca 2+ dynamics set the refractoriness and frequency dependence of Ca 2+ transients in subepicardial ventricular myocytes.