title: Dantrolene suppresses spontaneous Ca2+ release without altering excitation-contraction coupling in cardiomyocytes of aged mice.
abstract: 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.
authors.affiliation: Department of Medical Pharmacology and Physiology, University of Missouri School of Medicine, Columbia, Missouri; and domeiert@health.missouri.edu.
authors.forename: Timothy L
authors.initials: TL
authors.lastname: Domeier
authors.affiliation: Department of Medical Pharmacology and Physiology, University of Missouri School of Medicine, Columbia, Missouri; and.
authors.forename: Cale J
authors.initials: CJ
authors.lastname: Roberts
authors.affiliation: Department of Medical Pharmacology and Physiology, University of Missouri School of Medicine, Columbia, Missouri; and.
authors.forename: Anne K
authors.initials: AK
authors.lastname: Gibson
authors.affiliation: Department of Medical Pharmacology and Physiology, University of Missouri School of Medicine, Columbia, Missouri; and.
authors.forename: Laurin M
authors.initials: LM
authors.lastname: Hanft
authors.affiliation: Department of Medical Pharmacology and Physiology, University of Missouri School of Medicine, Columbia, Missouri; and.
authors.forename: Kerry S
authors.initials: KS
authors.lastname: McDonald
authors.affiliation: Department of Medical Pharmacology and Physiology, University of Missouri School of Medicine, Columbia, Missouri; and Dalton Cardiovascular Research Center, University of Missouri School of Medicine, Columbia, Missouri.
authors.forename: Steven S
authors.initials: SS
authors.lastname: Segal
mesh_terms: D000200:Action Potentials; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000367:Age Factors; D000375:Aging; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D020013:Calcium Signaling / Q000187:drug effects*; D002304:Cardiac Pacing, Artificial; D003620:Dantrolene / Q000494:pharmacology*; D056966:Excitation Contraction Coupling / Q000187:drug effects*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009200:Myocardial Contraction / Q000187:drug effects*; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism; D019837:Ryanodine Receptor Calcium Release Channel / Q000187:drug effects / Q000378:metabolism; D012519:Sarcoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism
chemical_list: D000318:Adrenergic beta-Agonists; D000889:Anti-Arrhythmia Agents; D019837:Ryanodine Receptor Calcium Release Channel; D003620:Dantrolene
keywords: Ca2+ sparks; Ca2+ waves; aging; heart; ventricular myocytes