Mechanism of canagliflozin-induced vasodilation in resistance mesenteric arteries and the regulation of systemic blood pressure

Canagliflozin, a sodium glucose co-transporter 2 (SGLT2) inhibitor, is reported to produce beneficial cardiovascular effects including a reduction in arterial contractility, and blood pressure. However, whether canagliflozin could directly relax resistance mesenteric arteries, underlying molecular mecha-nism and its role in regulating systemic blood pressure remain unclear. Here, we investigated the mechanism of regulation of small mesenteric artery contractility and its relevance for blood pressure regulation. Our pressure myography data showed that canagliflozin application rapidly produces a concentration-dependent vasodilation in mesenteric arteries. Such vasodilation was inhibited by con-current inhibition of smooth muscle cell voltage-gated K thorn channels KV1.5 (by 1 mu M DPO-1), KV2.1 (by 100 nM guangxitoxin), and KV7 (by 10 mu M linopirdine) but not by the inhibition of small-, intermediate-, and large-conductance Ca2 thorn -activated K thorn channels (SKCa by 1 mu M apamin, IKCa 10 mu M TRAM-34, and BKCa by 10 mu M paxilline, respectively), ATP-sensitive (KATP) channels (by 10 mu M glibenclamide), or SERCA pump (by 0.1 mu M thapsigargin). Inhibition of SGLTs (by 1 mu M phlorizin or the inhibition of endothelial signaling did not alter canagliflozin-evoked vasodilation. Consistently, acute canagliflozin treatment (4 mg/kg body weight) lowered systemic blood pressure in vivo. Overall, our data suggests that cana-gliflozin stimulates KV1.5, KV2.1, and KV7 channels, leading to vasodilation and a reduction of systemic blood pressure.(c) 2022 The Authors. Production and hosting by Elsevier B.V. on behalf of Japanese Pharmacological Society. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/ licenses/by-nc-nd/4.0/).