{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T03:47:40Z","timestamp":1791085660841,"version":"4.1.0"},"reference-count":53,"publisher":"American Physiological Society","issue":"4","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["American Journal of Physiology-Heart and Circulatory Physiology"],"published-print":{"date-parts":[[2012,2,15]]},"abstract":"<jats:p>In heart failure (HF), arrhythmogenic Ca<jats:sup>2+<\/jats:sup>release and chronic Ca<jats:sup>2+<\/jats:sup>depletion of the sarcoplasmic reticulum (SR) arise due to altered function of the ryanodine receptor (RyR) SR Ca<jats:sup>2+<\/jats:sup>-release channel. Dantrolene, a therapeutic agent used to treat malignant hyperthermia associated with mutations of the skeletal muscle type 1 RyR (RyR1), has recently been suggested to have effects on the cardiac type 2 RyR (RyR2). In this investigation, we tested the hypothesis that dantrolene exerts antiarrhythmic and inotropic effects on HF ventricular myocytes by examining multiple aspects of intracellular Ca<jats:sup>2+<\/jats:sup>handling. In normal rabbit myocytes, dantrolene (1 \u03bcM) had no effect on SR Ca<jats:sup>2+<\/jats:sup>load, postrest decay of SR Ca<jats:sup>2+<\/jats:sup>content, the threshold for spontaneous Ca<jats:sup>2+<\/jats:sup>wave initiation (i.e., the SR Ca<jats:sup>2+<\/jats:sup>content at which spontaneous waves initiate) and Ca<jats:sup>2+<\/jats:sup>spark frequency. In cardiomyocytes from failing rabbit hearts, SR Ca<jats:sup>2+<\/jats:sup>load and the wave initiation threshold were decreased compared with normal myocytes, Ca<jats:sup>2+<\/jats:sup>spark frequency was increased, and the postrest decay was potentiated. Using a novel approach of measuring cytosolic and intra-SR Ca<jats:sup>2+<\/jats:sup>concentration (using the low-affinity Ca<jats:sup>2+<\/jats:sup>indicator fluo-5N entrapped within the SR), we showed that treatment of HF cardiomyocytes with dantrolene rescued postrest decay and increased the wave initiation threshold. Additionally, dantrolene decreased Ca<jats:sup>2+<\/jats:sup>spark frequency while increasing the SR Ca<jats:sup>2+<\/jats:sup>content in HF myocytes. These data suggest that dantrolene exerts antiarrhythmic effects and preserves inotropy in HF cardiomyocytes by decreasing the incidence of diastolic Ca<jats:sup>2+<\/jats:sup>sparks, increasing the intra-SR Ca<jats:sup>2+<\/jats:sup>threshold at which spontaneous Ca<jats:sup>2+<\/jats:sup>waves occur, and decreasing the loss of Ca<jats:sup>2+<\/jats:sup>from the SR. Furthermore, the observation that dantrolene reduces arrhythmogenicity while at the same time preserves inotropy suggests that dantrolene is a potentially useful drug in the treatment of arrhythmia associated with HF.<\/jats:p>","DOI":"10.1152\/ajpheart.00936.2011","type":"journal-article","created":{"date-parts":[[2011,12,17]],"date-time":"2011-12-17T03:41:38Z","timestamp":1324093298000},"page":"H953-H963","source":"Crossref","is-referenced-by-count":83,"title":["Dantrolene prevents arrhythmogenic Ca<sup>2+<\/sup>release in heart failure"],"prefix":"10.1152","volume":"302","author":[{"given":"Joshua T.","family":"Maxwell","sequence":"first","affiliation":[{"name":"Department of Molecular Biophysics and Physiology, Rush University Medical Center, Chicago, Illinois"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timothy L.","family":"Domeier","sequence":"additional","affiliation":[{"name":"Department of Molecular Biophysics and Physiology, Rush University Medical 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