Empagliflozin Induces Vascular Relaxation in Rat Coronary Artery Due to Activation of BK Channels

Qi Kong,1 Ling-ling Qian,1 Lei Zhang,1 Huan-huan Liu,1,2 Fan Yang,1 Xiao-lu Zhang,1 Chao Wang,1 Xiao-xi Zhao,1 Ku-lin Li,1 Ru-xing Wang1,2 1Department of Cardiology, The Affiliated Wuxi People’s Hospital of Nanjing Medical University, Wuxi People’s Hospital, Wuxi Medical Center, Nanjing Medical University, Wuxi, 214023, People’s Republic of China; 2Wuxi School of Medicine, Jiangnan University, Wuxi, 214122, People’s Republic of ChinaCorrespondence: Ru-xing Wang; Ku-lin Li, Department of Cardiology, The Affiliated Wuxi People’s Hospital of Nanjing Medical University, Wuxi People’s Hospital, Wuxi Medical Center, Nanjing Medical University, Wuxi, 214023, People’s Republic of China, Email ruxingw@aliyun.com; liyantong2002@126.comPurpose: The aim of this study was to investigate the effects and mechanisms of SGLT2 inhibitor empagliflozin on diabetic coronary function.Methods: A rat diabetic model was established by injection of streptozotocin. Rats in the treated group were administered empagliflozin by gavage and rat coronary vascular tensions were measured after eight weeks. Large conductance calcium activated K+ channel currents were recorded using a patch clamp technique, while human coronary artery smooth muscle cells were used to explore the underlying mechanisms.Results: After incubation with empagliflozin (10, 30, 100, 300, 1000 μmol/L), the Δ relaxation % of rat coronary arteries were 2.459 ± 1.304, 3.251 ± 1.119, 6.946 ± 3.407, 28.36 ± 11.47, 86.90 ± 3.868, respectively. Without and with empagliflozin in the bath solution, BK channel opening probabilities at a membrane potential of +60 mV were 0.0458 ± 0.0517 and 0.3413 ± 0.2047, respectively (p < 0.05, n = 4 cells). After incubation with iberiotoxin, the Δ tensions of rat coronary arteries in the control (Ctrl), untreated (DM), low empagliflozin (10 mg/kg/d)-treated (DM+L-EMPA) and high empagliflozin (30mg/kg/d)-treated (DM+H-EMPA) group were 103.20 ± 5.85, 40.37 ± 22.12, 99.47 ± 28.51, 78.06 ± 40.98, respectively (p < 0.01 vs Ctrl, n = 3– 7; p < 0.001 vs DM+L-EMPA, n = 5– 7). Empagliflozin restored high glucose-induced downregulation of Sirt1, Nrf2, and BK-β 1, while the effect of empagliflozin disappeared in the presence of EX-527, a Sirt1 selective inhibitor.Conclusion: Empagliflozin has a vasodilation effect on the coronary arteries in a concentration-dependent manner and can activate BK channels via the Sirt1-Nrf2 mechanism.Keywords: diabetes, SGLT2 inhibitor, vasodilatation, large conductance calcium activated potassium channel