title: Polydatin modulates Ca(2+) 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 Ca(2+) 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 Ca(2+) transient, but slightly increased cell shortening. The contradictory response could be attributed to PD increasing myofilament Ca(2+) sensitivity. Exploring the activities of the two types of Ca(2+) channels, L-type Ca(2+) channels (LCCs) and ryanodine receptors (RyRs), reveals that PD dose-dependently decreased LCC current (I(Ca)), but increased frequency of spontaneous Ca(2+) sparks, the elementary Ca(2+) releasing events reflecting RyR activity in intact cells. PD dose-dependently increased the gain of EC coupling. In contrast, PD dose-dependently decreased SR Ca(2+) content. Furthermore, PD remarkably negated β-adrenergic receptor (AR) stimulation-induced enhancement of I(Ca) and Ca(2+) transients, but did not inhibit β-AR-mediated inotropic effect. Inhibition of nitric oxide synthase (NOS) with L-NAME abolished PD regulation of I(Ca) and Ca(2+) spark rate, and significantly inhibited the alteration of Ca(2+) 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 Ca(2+) sensitivity through increasing intracrine NO, resulting in suppression of Ca(2+) 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 Ca(2+) mishandling related heart diseases.
authors.affiliation: Department of Pathophysiology, Southern Medical University, Guangzhou 510515, China.
authors.forename: Jianxin
authors.initials: J
authors.lastname: Deng
authors.forename: Wenjuan
authors.initials: W
authors.lastname: Liu
authors.forename: Yanru
authors.initials: Y
authors.lastname: Wang
authors.forename: Ming
authors.initials: M
authors.lastname: Dong
authors.forename: Ming
authors.initials: M
authors.lastname: Zheng
authors.forename: Jie
authors.initials: J
authors.lastname: Liu
mesh_terms: D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000378:metabolism; D020746:Calcium Channels, L-Type / Q000378:metabolism / Q000502:physiology; D002316:Cardiotonic Agents / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D056966:Excitation Contraction Coupling; D005260:Female; D005960:Glucosides / Q000494:pharmacology*; D006352:Heart Ventricles / Q000166:cytology*; D008297:Male; D008564:Membrane Potentials; D009200:Myocardial Contraction; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D009210:Myofibrils / Q000378:metabolism / Q000502:physiology; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism / Q000502:physiology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D018408:Patch-Clamp Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley; D011943:Receptors, Adrenergic, beta / Q000378:metabolism*; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism; D012519:Sarcoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D013267:Stilbenes / Q000494:pharmacology*
chemical_list: D000318:Adrenergic beta-Agonists; D020746:Calcium Channels, L-Type; D002316:Cardiotonic Agents; D005960:Glucosides; D011943:Receptors, Adrenergic, beta; D019837:Ryanodine Receptor Calcium Release Channel; D013267:Stilbenes; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D002118:Calcium; D019331:NG-Nitroarginine Methyl Ester; C058229:polydatin