Glycyrrhizin and glycyrrhetinic acid directly modulate rat cardiac performance

Root extract of liquorice is traditionally used to treat several diseases. Liquorice-derived constituents present several biological actions. In particular, glycyrrhizin and its aglycone, glycyrrhetinic acid, exhibit well-known cardiovascular properties. The aim of this research was to explore the direct cardiac activity of glycyrrhizin and glycyrrhetinic acid. The effects of synthetic glycyrrhizin and glycyrrhetinic acid were evaluated on the isolated and Langendorff perfused rat heart. The intracellular signaling involved in the effects of the two substances was analyzed on isolated and perfused heart and by Western blotting on cardiac extracts. Under basal conditions, both glycyrrhizin and glycyrrhetinic acid influenced cardiac contractility and relaxation. Glycyrrhizin induced significant positive inotropic and lusitropic effects starting from very low concentrations, while both inotropism and lusitropism were negatively affected by glycyrrhetinic acid. Both substances significantly increased heart rate. Analysis of the signal transduction mechanisms suggested that glycyrrhizin acts through the endothelin receptor type A/phospholipase C axis while glycyrrhetinic acid acts through endothelin receptor type B/Akt/nitric oxide synthase/nitric oxide axis. To our knowledge, these data reveal, for the first time, that both glycyrrhizin and glycyrrhetinic acid directly affect cardiac performance. Additional information on the physiological significance of these substances and their cardiac molecular targets may provide indication on their biomedical application.