Polydatin modulates Ca2 + handling, excitation–contraction coupling and β-adrenergic signaling in rat ventricular myocytes

Abstract

Polydatin (PD), a resveratrol glucoside, has recently been suggested to have cardioprotective effects against heart diseases, including ischemia-reperfusion injury and pressure-overload induced ventricular remodeling. However, the mechanisms are poorly understood. This study aims to investigate the direct effects of PD on cardiac Ca2+ handling and excitation–contraction (EC) coupling to explore the potential role of which in PD-mediated cardioprotection. We found that micromolar PD decreased action potential-elicited Ca2+ transient, but slightly increased cell shortening. The contradictory response could be attributed to PD increasing myofilament Ca2+ sensitivity. Exploring the activities of the two types of Ca2+ channels, L-type Ca2+ channels (LCCs) and ryanodine receptors (RyRs), reveals that PD dose-dependently decreased LCC current (ICa), but increased frequency of spontaneous Ca2+ sparks, the elementary Ca2+ releasing events reflecting RyR activity in intact cells. PD dose-dependently increased the gain of EC coupling. In contrast, PD dose-dependently decreased SR Ca2+ content. Furthermore, PD remarkably negated β-adrenergic receptor (AR) stimulation-induced enhancement of ICa and Ca2+ transients, but did not inhibit β-AR-mediated inotropic effect. Inhibition of nitric oxide synthase (NOS) with L-NAME abolished PD regulation of ICa and Ca2+ spark rate, and significantly inhibited the alteration of Ca2+ transient and myocyte contractility stimulated by PD. These results collectively indicate that PD modulated cardiac EC coupling mainly by inversely regulating LCC and RyR activity and increasing myofilament Ca2+ sensitivity through increasing intracrine NO, resulting in suppression of Ca2+ transient without compromising cardiac contractility. The unique regulation of PD on cardiac EC coupling and responsiveness to β-AR signaling implicates that PD has potential cardioprotective effects against Ca2+ mishandling related heart diseases.