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, Ca, and K channels has had limited success clinically. Recently, Ca signaling has been target of pharmacotherapy based on finding that leaky ryanodine receptors elevate local Ca 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 Ca release. The effects of xanthohumol (5-1000 nM) on Ca 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 Ca sparks (>threefold) and Ca waves in control myocytes and in cells subjected to Ca 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 Catransients, without suppressing I, but this effect was small and reversed by isoproterenol at physiologic temperatures. Xanthohumol also suppressed the Ca content of the SR and its rate of recirculation. The stabilizing effects of xanthohumol on the frequency of spontaneously triggered Ca sparks and waves combined with its antioxidant properties, and lack of significant effects on Na and Ca channels, may provide this compound with clinically desirable antiarrhythmic properties.