CALL FOR PAPERS Cardiovascular and Cerebrovascular Aging–New Mechanisms and Insights Dantrolene suppresses spontaneous Ca release without altering excitation-contraction coupling in cardiomyocytes of aged mice

Domeier TL, Roberts CJ, Gibson AK, Hanft LM, McDonald KS, Segal SS. Dantrolene suppresses spontaneous Ca release without altering excitation-contraction coupling in cardiomyocytes of aged mice. Am J Physiol Heart Circ Physiol 307: H818–H829, 2014. First published July 18, 2014; doi:10.1152/ajpheart.00287.2014.—Cardiac dysfunction in the aged heart reflects abnormalities in cardiomyocyte Ca homeostasis including altered Ca cycling through the sarcoplasmic reticulum (SR). The ryanodine receptor antagonist dantrolene exerts antiarrhythmic effects by preventing spontaneous diastolic Ca release from the SR. We tested the hypothesis that dantrolene prevents spontaneous Ca 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 indicator fluo-4. Amplitudes of action potential-induced Ca transients at 1-Hz pacing were similar between young and aged mice, yet cell shortening was impaired in aged mice. Isoproterenol (1 M) increased Ca transient amplitude and cell shortening to identical levels in young and aged; dantrolene (1 M) had no effect on Ca transients or cell shortening during pacing. Under Ca overload conditions induced with 10 mM extracellular Ca concentration, spontaneous Ca waves were of diminished amplitude and associated with lower SR Ca content in aged versus young mice. Despite no effect in young mice, dantrolene increased SR Ca content and Ca wave amplitude in aged mice. In the presence of isoproterenol following rest from 1-Hz pacing, Ca spark frequency was elevated in aged mice, yet the time to spontaneous Ca wave was similar between young and aged mice; dantrolene decreased Ca spark frequency and prolonged the time to Ca wave onset in aged mice with no effect in young mice. Thus dantrolene attenuates diastolic Ca release in the aged murine heart that may prove useful in preventing cardiac dysfunction.