Irisin, a newly discovered myokine, has been shown to produce modest weight loss and improve glucose intolerance in mice. The purpose of this study was to investigate the effects of irisin on vascular activity and the mechanisms involved. Experiments were performed on mouse mesenteric arteries. We demonstrated that irisin induced relaxation in mesenteric arteries with or without endothelium in a concentration-dependent manner. It was further demonstrated that the irisin-induced vasorelaxation effects on endothelium-intact mesenteric arteries were reduced by pretreatment with N omega-nitro-L-arginine methyl ester (L-NAME) or 1H-[1, 2, 4] oxadizolo [4, 3-a] quinoxalin-1-one (ODQ). However, pretreatment with indomethacin (INDO), a nonselective cyclooxygenase inhibitor did not modulate irisin-induced relaxation. In addition, the contraction due to extracellular Ca2+ influx and intracellular Ca2+ release was also inhibited by irisin. In summary, these results suggested that the endothelium-dependent relaxation of irisin is mediated by the nitric oxide (NO)-guanosine 3', 5'-cyclic phosphate (cGMP)-dependent pathway but not the prostaglandin I-2 (PGI(2))-cyclic adenosine monophosphate (cAMP)-dependent mechanism. Endothelium-independent relaxation may be depend on inhibiting Ca2+ influx through blocking VDCCs and intracellular Ca2+ release through both IP3R and RyR channels. (C) 2015 Published by Elsevier Inc.