SGLT2 inhibitors (SGLT2i) are new agents for patients with heart failure (HF) irrespective of diabetes. However, the effects of in vasoconstriction remain unclear. This study examined the mechanism of vasorelaxation induced by SGLT2i in endothelium-intact and -denuded rat aorta and mesenteric artery. 1) Dapagliflozin and empagliflozin inhibited phenylephrine (PE)-induced contraction in a dose-dependent manner. However, this relaxation was lower in the absence of the endothelium in aorta and mesenteric artery. 2) Increase in dapagliflozin and empagliflozin-induced relaxation in the presence of the endothelium was attenuated by preincubation in L-NAME (100 μM) and the removal of the endothelium, but not indomethacin (10 μM) in aorta and mesenteric artery. 3)Remove of glucose from PSS did not affect dapagliflozin and empagliflozin -induced relaxation in endothelium-denuded aorta. 4) In fura 2-loaded endothelium-denuded aorta, empagliflozin inhibited high K⁺- or PE-induced muscle tension and increase of intracellular Ca²⁺ ([Ca²⁺]_i) level. These results may suggest that dapagliflozin and empagliflozin causes vasorelaxation by increasing cGMP content in correlation with the release of NO from endothelial cells and by decreasing [Ca²⁺]_i) level via inhibiting voltage-dependent Ca²⁺ channel.