Mechanisms underlying the vasodilatory effects of canagliflozin in the rabbit thoracic aorta: Involvement of the SERCA pump and Kv channels

Abstract

AimsCanagliflozin is an anti-diabetic agent and sodium glucose co-transporter-2 inhibitor. Despite numerous clinical trials demonstrating its beneficial effects on blood pressure, the cellular mechanisms underlying the effects of canagliflozin on vascular reactivity have yet to be clarified. We investigated the vasodilatory effect of canagliflozin on aortic rings isolated from rabbits. Main methodsWe used rabbit thoracic aortic rings and its arterial tone was tested by using wire myography system. Key findingsCanagliflozin caused concentration-dependent vasodilation in aortic rings pre-constricted with phenylephrine or high K+. However, the degree of canagliflozin-induced vasodilation of the aortic rings pre-constricted with high K+ was less than that of rings pre-constricted with phenylephrine. Application of 4-aminopyridine, a voltage-dependent K+ (Kv) channel inhibitor, reduced canagliflozin-induced vasodilation. However, pre-incubation of an inwardly rectifying K+ channel inhibitor, a large-conductance Ca2+-activated K+ channel inhibitor, and an ATP-sensitive K+ inhibitor did not modulate the vasodilatory effects of canagliflozin. Indeed, canagliflozin increased Kv currents in aortic smooth muscle cells. Pre-treatment with thapsigargin or cyclopiazonic acid, a sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) pump inhibitors, reduced the vasodilatory effects of canagliflozin. Conversely, pre-treatment with a Ca2+ channel inhibitor, adenylyl cyclase/PKA inhibitors, and guanylyl cyclase/PKG inhibitors did not modulate the vasodilatory effects of canagliflozin. Endothelium removal, and pre-treatment with the nitric oxide synthase inhibitor L-NAME, and small- and intermediate-conductance Ca2+-activated K+ channel inhibitor apamin and TRAM-34, did not diminish the vasodilatory effects of canagliflozin. SignificanceOur results indicate that canagliflozin induces vasodilation, which is dependent on the robust SERCA activity and Kv channel activation.