Xanthohumol Modulates Calcium Signaling in Rat Ventricular Myocytes: Possible Antiarrhythmic Properties.
Cardiac arrhythmia is a major cause of mortality in cardiovascular pathologies. A host of drugs targeted to sarcolemmal Na+, Ca2+, and K+channels has had limited success clinically. Recently, Ca2+signaling has been target of pharmacotherapy based on finding that leaky ryanodine receptors elevate local Ca2+concentrations causing membrane depolarizations that trigger arrhythmias. In this study, we report that xanthohumol, an antioxidant extracted from hops showing therapeutic effects in other pathologies, suppresses aberrant ryanodine receptor Ca2+release. The effects of xanthohumol (5-1000 nM) on Ca2+signaling pathways were probed in isolated rat ventricular myocytes incubated with Fluo-4 AM using the perforated patch-clamp technique. We found that 5-50 nM xanthohumol reduced the frequency of spontaneously occurring Ca2+sparks (>threefold) and Ca2+waves in control myocytes and in cells subjected to Ca2+overload caused by the following: 1) exposure to low K+solutions, 2) periods of high frequency electrical stimulation, 3) exposures to isoproterenol, or 4) caffeine. At room temperatures, 50-100 nM xanthohumol reduced the rate of relaxation of electrically- or caffeine-triggered Ca2+transients, without suppressing ICa, but this effect was small and reversed by isoproterenol at physiologic temperatures. Xanthohumol also suppressed the Ca2+content of the SR and its rate of recirculation. The stabilizing effects of xanthohumol on the frequency of spontaneously triggered Ca2+sparks and waves combined with its antioxidant properties, and lack of significant effects on Na+and Ca2+channels, may provide this compound with clinically desirable antiarrhythmic properties.
Cardiac Signaling Center of University of South Carolina, Medical University of South Carolina, and Clemson University, Charleston, South Carolina.
Juan Jose
JJ
Arnaiz-Cot
Cardiac Signaling Center of University of South Carolina, Medical University of South Carolina, and Clemson University, Charleston, South Carolina.
Lars
L
Cleemann
Cardiac Signaling Center of University of South Carolina, Medical University of South Carolina, and Clemson University, Charleston, South Carolina moradm@musc.edu.
Martin
M
Morad
D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000378:metabolism / Q000494:pharmacology*; D020013:Calcium Signaling / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D005419:Flavonoids / Q000378:metabolism / Q000494:pharmacology*; D006352:Heart Ventricles / Q000166:cytology*; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D032383:Myocytes, Cardiac / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D011427:Propiophenones / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism; D012519:Sarcoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D013696:Temperature
D000889:Anti-Arrhythmia Agents; D005419:Flavonoids; D011427:Propiophenones; D017382:Reactive Oxygen Species; C000612605:RyR2 protein, rat; D019837:Ryanodine Receptor Calcium Release Channel; D007545:Isoproterenol; C104536:xanthohumol