Abstract

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.