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The Anti-Diabetic Drug Dapagliflozin Induces Vasodilation via Activation of PKG and Kv Channels

Hongliang Li, Sung Eun Shin, Mi Seon Seo, Jin Ryeol An, Il-Whan Choi, Won-Kyo Jung, Amy L Firth, Dae-Sung Lee, Mi-Jin Yim, Grace Choi, Jeong Min Lee, Sung Hun Na, Won Sun Park

Life Sci. 2018 Mar 15;197:46-55.

PMID: 29409796

Abstract:

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 BKCa channel inhibitor paxilline, the KATP channel inhibitor glibenclamide, and the Kir channel inhibitor Ba2+ did not change dapagliflozin-induced vasodilation. However, application of the Kv channels inhibitor 4-AP effectively inhibited dapagliflozin-induced vasodilation. Application of the Ca2+ channel inhibitor nifedipine and the sarcoplasmic/endoplasmic reticulum Ca2+-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 Ca2+-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, Ca2+ channels, intracellular Ca2+, and the endothelium.

Chemicals Related in the Paper:

Catalog Number Product Name Structure CAS Number Price
AP126643376-A KT 5823 KT 5823 126643-37-6 Price
AP204326432 NS 2028 NS 2028 204326-43-2 Price
IAR42415609 PKG Inhibitor PKG Inhibitor Price
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