Key result
Dantrolene significantly reduced spontaneous Ca2+ wave frequency from 10.2 to 7.4 waves/min in aged murine cardiomyocytes without altering excitation-contraction coupling.
Dantrolene attenuates diastolic Ca2+ release in aged murine cardiomyocytes without altering excitation-contraction coupling, suggesting potential utility in preventing age-related cardiac dysfunction.
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Hypothesis-generating for dantrolene in age-related Ca2+ leak; human trials needed before clinical consideration.
Cardiac dysfunction in the aged heart reflects abnormalities in cardiomyocyte Ca 2+ homeostasis including altered Ca 2+ cycling through the sarcoplasmic reticulum (SR). The ryanodine receptor antagonist dantrolene exerts antiarrhythmic effects by preventing spontaneous diastolic Ca 2+ release from the SR. We tested the hypothesis that dantrolene prevents spontaneous Ca 2+ release without altering excitation-contraction coupling in aged myocardium. Left ventricular cardiomyocytes isolated from young (3 to 4 mo) and aged (24–26 mo) C57BL/6 mice were loaded with the Ca 2+ indicator fluo-4. Amplitudes of action potential-induced Ca 2+ transients at 1-Hz pacing were similar between young and aged mice, yet cell shortening was impaired in aged mice. Isoproterenol (1 μM) increased Ca 2+ transient amplitude and cell shortening to identical levels in young and aged; dantrolene (1 μM) had no effect on Ca 2+ transients or cell shortening during pacing. Under Ca 2+ overload conditions induced with 10 mM extracellular Ca 2+ concentration, spontaneous Ca 2+ waves were of diminished amplitude and associated with lower SR Ca 2+ content in aged versus young mice. Despite no effect in young mice, dantrolene increased SR Ca 2+ content and Ca 2+ wave amplitude in aged mice. In the presence of isoproterenol following rest from 1-Hz pacing, Ca 2+ spark frequency was elevated in aged mice, yet the time to spontaneous Ca 2+ wave was similar between young and aged mice; dantrolene decreased Ca 2+ spark frequency and prolonged the time to Ca 2+ wave onset in aged mice with no effect in young mice. Thus dantrolene attenuates diastolic Ca 2+ release in the aged murine heart that may prove useful in preventing cardiac dysfunction.
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Domeier et al. (2014) studied Aging (cardiomyocyte dysfunction) (n=65). Dantrolene vs. Control (vehicle/no dantrolene) was evaluated on Spontaneous Ca2+ wave frequency in aged mice under Ca2+ overload (waves/min) (p=0.01). Dantrolene significantly reduced spontaneous Ca2+ wave frequency from 10.2 to 7.4 waves/min in aged murine cardiomyocytes without altering excitation-contraction coupling.
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