Key result
Acute caffeine potentiates RyR opening only transiently, failing to sustain systolic Ca transient increases.
Why the study?
Does RyR potentiation with caffeine produce a maintained increase in the amplitude of the systolic Ca transient in large animal ventricular myocytes?
Does RyR potentiation with caffeine produce a maintained increase in the amplitude of the systolic Ca transient in large animal ventricular myocytes?
This study demonstrates that potentiating RyR opening does not cause a sustained increase in systolic calcium transients, suggesting RyR potentiation is unlikely to be an effective strategy for maintained positive inotropy.
RyR potentiation unlikely to sustain inotropy in large mammals; leaves open alternative Ca-handling targets for HF.
AIMS: Most of the calcium that activates contraction is released from the sarcoplasmic reticulum (SR) through the ryanodine receptor (RyR). It is controversial whether activators of the RyR produce a maintained increase in the amplitude of the systolic Ca transient. We therefore aimed to examine the effects of activation of the RyR in large animals under conditions designed to be as physiological as possible while simultaneously measuring SR and cytoplasmic Ca. METHODS AND RESULTS: Experiments were performed on ventricular myocytes from canine and ovine hearts. Cytoplasmic Ca was measured with fluo-3 and SR Ca with mag-fura-2. Application of caffeine resulted in a brief increase in the amplitude of the systolic Ca transient accompanied by an increase of action potential duration. These effects disappeared with a rate constant of ∼3 s(-1). Similar effects were seen in cells taken from sheep in which heart failure had been induced by rapid pacing. The decrease of Ca transient amplitude was accompanied by a decrease of SR Ca content. During this phase, the maximum (end-diastolic) SR Ca content fell while the minimum systolic increased. CONCLUSIONS: This study shows that, under conditions designed to be as physiological as possible, potentiation of RyR opening has no maintained effect on the systolic Ca transient. This result makes it unlikely that potentiation of the RyR has a maintained role in positive inotropy.
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Greensmith et al. (2014) studied Normal and heart failure (preclinical model). Caffeine (RyR potentiation) vs. Control (pre-caffeine baseline) was evaluated on Amplitude of the systolic Ca transient. Potentiation of RyR opening with caffeine produced only a brief, transient increase in the amplitude of the systolic Ca transient, with no maintained effect.
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