Abstract
This perspective attempts to shed light on an old and not yet solved controversy in cardiac physiology, i.e., the impact of increasing ryanodine receptor (RyR)2 open probability on myocardial function. Based on an already proven myocyte model, it was shown that increasing RyR2 open probability results in a purely short-lived increase in Ca2+ transient amplitude, and, therefore, it does not increase cardiac contractility. However, potentiation of RyR2 activity permanently enhances fractional Ca2+ release, shifting the intracellular Ca2+ transient versus sarcoplasmic reticulum (SR) Ca2+ content curve to a new state of higher efficiency. This would allow the heart to maintain a given contractility despite a decrease in SR Ca2+ content, to enhance contractility if SR Ca2+ content is simultaneously preserved or to successfully counteract the effects of a negative inotropic intervention.NEW & NOTEWORTHY Increasing ryanodine receptor (RyR)2 open probability does not increase cardiac contractility. However, RyR2 potentiation shifts the intracellular Ca2+ transient-sarcoplasmic reticulum (SR) Ca2+ content relationship toward an enhanced efficiency state, which may contribute to a positive inotropic effect, preserve contractility despite decreased SR Ca2+ content, or successfully counteract the effects of a negative inotropic action.
Highlights
NEW & NOTEWORTHY Increasing ryanodine receptor (RyR)2 open probability does not increase cardiac contractility
For a given Ca2ϩ triggering signal, the sarcoplasmic reticulum (SR) releases a fraction of its Ca2ϩ content [fractional SR Ca2ϩ release (FCaR)], which has been shown to be dependent on SR Ca2ϩ load [18]
As noted by different reports by Greensmith et al [12] and Trafford et al [32], our model indicates that the temporary increase in Ca2ϩ transient when the enhanced RyR2 conductance is applied results in decreased Ca2ϩ entry into the cell and increased Ca2ϩ efflux, producing the subsequent drop in both, SR Ca2ϩ content and the systolic Ca2ϩ transient
Summary
NEW & NOTEWORTHY Increasing ryanodine receptor (RyR)2 open probability does not increase cardiac contractility. As shown, RyR2 potentiation enhanced FCaR in association with the brief increase of the Ca2ϩ transient.
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