Selective Inhibitory Effect of Hesperetin on the Automaticity of the Guinea Pig Pulmonary Vein Myocardium

The effect of a citrus-derived flavonoid, hesperetin, on the automaticity and contraction of isolated guinea pig myocardium was examined. Hesperetin inhibited the rate of ectopic action potential firing of the pulmonary vein myocardium; the slope of the diastolic depolarization was decreased with minimum change in the action potential waveform. The effect was dependent on the concentration; the EC₅₀ value for firing rate was 56.2 ± 14.2 µM and that for the diastolic depolarization slope was 41.6 ± 13.4 µM. In the right atria, hesperetin had no effect on the beating rate at concentrations up to 30 µM, but showed a negative chronotropic effect at 100 µM. In the ventricular papillary muscles, hesperetin had no effect on the contractile force at concentrations up to 30 µM, but showed a slight positive inotropic effect at 100 µM. In isolated pulmonary vein cardiomyocytes, 30 µM hesperetin decreased the firing rate of spontaneous Ca²⁺ transients. These results showed that hesperetin has a selective inhibitory action on the pulmonary vein automaticity with no inhibitory effect on the ventricular contractile force. Clarification of the mechanism of action of hesperetin as well as further exploration of flavonoids would provide clues for the development of pulmonary vein-selective therapeutic agents.