Cardiac arrhythmia is a major cause of mortality in cardiovascular pathologies. A host of drugs targeted to sarcolemmal Na+, Ca2+, and K+ channels have 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. Here we report that xanthohumol, an antioxidant extracted from hops and showing therapeutic effects in other pathologies, may have antiarrhythmic properties by stabilizing ryanodine receptor's activity. The effects of xanthohumol on Ca2+ signaling pathways were probed in isolated rat ventricular myocytes incubated with Fluo-4AM using the perforated patch-clamp technique. We found that 5-50nM xanthohumol reduced the frequency of spontaneously occurring Ca2+ sparks and Ca2+ waves in control myocytes and in cells subjected to Ca2+ overload caused by: (1) exposure to low K+ solutions, (2) periods of high frequency electrical stimulation, (3) exposures to isoproterenol or (4) caffeine. At room temperatures, 50-100nM 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 physiological 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 anti-oxidant properties, and lack of significant effects on Na+ and Ca2+ channels, may provide this compound with clinically desirable antiarrhythmic properties.
- The American Society for Pharmacology and Experimental Therapeutics