The anti-diabetic drug dapagliflozin induces vasodilation via activation of PKG and Kv channels.

AIM

Considering the clinical efficacy of dapagliflozin in patients with type 2 DM and the pathophysiological relevance of Kv channels for vascular reactivity. We investigate the vasodilatory effect of dapagliflozin and related mechanisms using phenylephrine (Phe)-induced contracted aortic rings.

MATERIAL AND METHODS

Arterial tone measurement was performed in aortic smooth muscle.

KEY FINDINGS

Application of dapagliflozin induced vasodilation in a concentration-dependent manner. Pre-treatment with the BK channel inhibitor paxilline, the K channel inhibitor glibenclamide, and the Kir channel inhibitor Ba did not change dapagliflozin-induced vasodilation. However, application of the Kv channels inhibitor 4-AP effectively inhibited dapagliflozin-induced vasodilation. Application of the Ca channel inhibitor nifedipine and the sarcoplasmic/endoplasmic reticulum Ca-ATPase (SERCA) pump inhibitor thapsigargin did not alter the vasodilatory effect of dapagliflozin. Moreover, the adenylyl cyclase inhibitor SQ 22536 and the protein kinase A (PKA) inhibitor KT 5720 had no effect on dapagliflozin-induced vasodilation. Although guanylyl cyclase inhibitors, NS 2028 and ODQ, did not reduce the vasodilatory effect of dapagliflozin, the protein kinase G (PKG) inhibitor KT 5823 effectively inhibited dapagliflozin-induced vasodilation. The vasodilatory effect of dapagliflozin was not affected by elimination of the endothelium. Furthermore, pretreatment with the nitric oxide synthase inhibitor L-NAME or the small-conductance Ca-activated K (SKCa) channel inhibitor apamin did not change the vasodilatory effect of dapagliflozin.

SIGNIFICANCE

We concluded that dapagliflozin induced vasodilation via the activation of Kv channels and PKG, and was independent of other K channels, Ca channels, intracellular Ca, and the endothelium.