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 I_CA, 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.