The antidiabetic drug ipragliflozin induces vasorelaxation of rabbit femoral artery by activating a Kv channel, the SERCA pump, and the PKA signaling pathway

Abstract

We explored the vasorelaxant effects of ipragliflozin, a sodium-glucose cotransporter-2 inhibitor, on rabbit femoral arterial rings. Ipragliflozin relaxed phenylephrine-induced pre-contracted rings in a dose-dependent manner. Pre-treatment with the ATP-sensitive K⁺ channel inhibitor glibenclamide (10 μM), the inwardly rectifying K⁺ channel inhibitor Ba²⁺ (50 μM), or the Ca²⁺-sensitive K⁺ channel inhibitor paxilline (10 μM) did not influence the vasorelaxant effect. However, the voltage-dependent K⁺ (Kv) channel inhibitor 4-aminopyridine (3 mM) reduced the vasorelaxant effect. Specifically, the vasorelaxant response to ipragliflozin was significantly attenuated by pretreatment with the Kv7.X channel inhibitors linopirdine (10 μM) and XE991 (10 μM), the sarcoplasmic/endoplasmic reticulum Ca²⁺-ATPase (SERCA) pump inhibitors thapsigargin (1 μM) and cyclopiazonic acid (10 μM), and the cAMP/protein kinase A (PKA)-associated signaling pathway inhibitors SQ22536 (50 μM) and KT5720 (1 μM). Neither the cGMP/protein kinase G (PKG)-associated signaling pathway nor the endothelium was involved in ipragliflozin-induced vasorelaxation. We conclude that ipragliflozin induced vasorelaxation of rabbit femoral arteries by activating Kv channels (principally the Kv7.X channel), the SERCA pump, and the cAMP/PKA-associated signaling pathway independent of other K⁺ (ATP-sensitive K⁺, inwardly rectifying K⁺, and Ca²⁺-sensitive K⁺) channels, cGMP/PKG-associated signaling, and the endothelium.

Keywords: Femoral artery; Ipragliflozin; Kv channel; SERCA pump; Vasorelaxation.