Chronotropic and Inotropic Effects of Sudachitin, a Polymethoxyflavone from the Peel of <i>Citrus sudachi</i> on Isolated Rat Atria and Its Underlying Mechanisms

Sudachitin, a polymethoxyflavone found in sudachi peel, has been reported to improve hyperlipidemia in humans, and is thus attracting research attention. However, its effect on cardiac function remains unclear. We investigated the mechanisms underlying the chronotropic and inotropic effects of sudachitin on rat atria. Sudachitin (0.3-30 µM) produced concentration-dependent positive chronotropic and inotropic effects. Other polymethoxyflavones, including demethoxysudachitin (0.3-30 µM) and nobiletin (0.3-30 µM), also produced positive chronotropic and inotropic effects; however, the maximum efficacy of all polymethoxyflavones, including sudachitin, was lower than that of isoproterenol. Propranolol (0.1 µM) did not affect the positive chronotropic and inotropic effects of sudachitin. The concentration-response curves for the chronotropic and inotropic effects of dibutyryl-cAMP (1-100 µM) were shifted to the left upon pretreatment with sudachitin (3, 10 µM). Phosphodiesterase inhibitors (3-isobutyl-1-methylxanthine 1 µM or milrinone 10 µM) alone, sudachitin alone (10, 30 µM), and a combination of phosphodiesterase inhibitors and sudachitin exhibited positive chronotropic and inotropic effects, whereas the lack of any interaction between each phosphodiesterase inhibitor and sudachitin indicated an additive effect of the two substances. These results suggest that sudachitin-induced positive chronotropic and inotropic effects similar to those of other polymethoxyflavones, but its maximum efficacy was lower than that of isoproterenol. Both demethoxysudachitin and nobiletin exhibited similar positive chronotropic and inotropic effects, indicating that these effects are not specific to sudachitin, but are common to polymethoxyflavones. The mechanism of action of sudachitin was associated with the enhancement of cAMP-dependent pathways, without the involvement of β-adrenoceptors.