The sodium-glucose cotransporter 2 inhibitor tofogliflozin induces vasodilation of rabbit femoral artery by activating Kv channels, the SERCA pump, and the sGC/cGMP pathway

초록

Tofogliflozin is a sodium-glucose cotransporter 2 inhibitor widely used to treat type 2 diabetes mellitus, but it also exhibits cardio-protective effects. This study investigated the vasodilatory action of tofogliflozin using rabbit femoral artery rings pre-contracted with phenylephrine (1 mu M). The results showed the concentration-dependent induction of vasodilation by tofogliflozin, a response that remained unchanged following endothelial removal, pretreatment with the nitric oxide synthase inhibitor L-NAME (100 mu M), or the inhibition of low- and intermediate-conductance Ca2+-activated K+ channels using apamin (1 mu M) in combination with TRAM-34 (1 mu M). Furthermore, pretreatment with the voltage-dependent K+ (Kv) channel inhibitor 4-AP (3 mM) reduced the vasodilatory effects of tofogliflozin whereas pretreatment with the ATP-sensitive K+ channel inhibitor glibenclamide (10 mu M) or the large-conductance Ca2+-activated K+ channel inhibitor paxilline (1 mu M) did not. Notably, our findings indicated that Kv7.X, rather than Kv1.5 or Kv2.1, is the primary Kv subtype involved in tofogliflozininduced vasodilation. The vasodilatory effects of tofogliflozin were also significantly inhibited in femoral arterial rings pretreated with the sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) pump inhibitors thapsigargin (1 mu M) and cyclopiazonic acid (10 mu M). Tofogliflozin-induced vasodilation was unaltered in arterial rings exposed to the adenylyl cyclase inhibitor SQ 22536 (50 mu M), the protein kinase A (PKA) inhibitor KT 5720 (1 mu M), and the protein kinase G inhibitor KT 5823 (1 mu M) whereas it was effectively reduced by the soluble guanylyl cyclase (sGC) inhibitor ODQ (10 mu M). These findings suggest that tofogliflozin-induced vasodilation is mediated by the activation of the SERCA pump, the sGC/cGMP pathway, and Kv channels.

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