The SGLT2 inhibitor remogliflozin induces vasodilation in the femoral artery of rabbits via activation of a Kv channel, the SERCA pump, and the cGMP signaling pathway

This study explored the vasodilatory mechanisms of the sodium-glucose cotransporter-2 inhibitor remogliflozin using femoral arteries of rabbits. Remogliflozin dilated femoral arterial rings pre-contracted with phenylephrine in a concentration-dependent manner. Pretreatment with the Ca2+-sensitive K+ channel inhibitor (paxilline), the ATP-sensitive K+ channel inhibitor (glibenclamide), or the inwardly rectifying K+ channel inhibitor (Ba2+) did not alter the vasodilatory effect. However, vasodilation was significantly reduced by pretreatment with the voltage-dependent K+ (Kv) channel inhibitor (4-AP) and with the Kv1.5 subtype inhibitor (DPO-1) but not with Kv2.1 or Kv7 subtype inhibitor. Neither endothelium removal nor the inhibition of nitric oxide production altered the vasodilatory effect of remogliflozin. However, pretreatment with the sarcoplasmic/endoplasmic reticulum Ca2+-ATPase (SERCA) pump inhibitors thapsigargin and cyclopiazonic acid effectively reduced the remogliflozin effect, as did pretreatment with cGMP/PKG-related but not cAMP/PKA-related signaling pathway inhibitors. These results indicate that remogliflozin-mediated dilation of the femoral artery occurs via the activation of Kv channels, mainly the Kv1.5 subtype, SERCA pump, and cGMP/PKG-related signaling pathways. [Display omitted] •We investigated the remogliflozin-induced vasorelaxant effects in rabbit femoral.•Vasodilation effects of remogliflozin by activating Kv channels, SERCA pump, and cAMP/PKA signaling pathway.•Caution is required when prescribing remogliflozin in blood pressure, and diabetes mellitus patients.