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.