Hesperetin inhibits rat coronary constriction by inhibiting Ca2+ influx and enhancing voltage-gated K+ channel currents of the myocytes

Hesperetin (HSP, one of the most common flavonoids in Citrus) has been reported to possess many benificial effects and is indicated for many diseases both as a therapeutic drug and as a supplement. Although its vascular effects have been extensively studied, little is known about its effects and the underlying mechanisms on coronary artery. In the present study, the myogenic effects of HSP were studied with a wire myograph in isolated rat coronary artery (RCA). Molecular probe and the patch clamp technique were used to study effects of HSP on intracellular free Ca2+ concentration, inward Ca2+ currents through L-type voltage-gated Ca2+ channels (LVGC) and outward K+ currents through voltage-gated K+ channels (K-V). HSP (0.01-0.1 mM) concentration-dependently depressed concentration-contraction curves of both KCl and thromboxane receptor agonist 9,11-Dideoxy-9 alpha,11 alpha-methanoepoxy prostaglandin F-2 alpha (U46619), and relaxed RCA precontracted by the both vasoconstrictors. The vasospasmolytic effect was more potent in KCl- than in U46619-induced contraction. The vasorelaxation was attenuated by 4-aminopyridine, a specific K-V inhibitor, but not affected by NG-nitro-L-arginine methylester ester, indomethacin, glibenclamide, iberiotoxin, BaCl2 or endothelium denudation. At the same concentrations, HSP inhibited extracellular Ca2+ influx-induced contraction, reduced intracellular free Ca2+ concentration, inhibited inward Ca2+ currents through LVGC and increased outward K+ currents through K-V in the vascular smooth muscle cells (VSMCs) freshly isolated from RCA. Collectively, our results show that HSP is vasospasmolytic in RCA and suggest that the vasospasmolysis is mediated by inhibition of LVGC and enhancement of K-V currents in RCA VSMCs. (C) 2014 Elsevier B.V. All rights reserved.