Dapagliflozin Stimulates Smooth Muscle Cell Voltage -Gated Kr Channels K,7 to Induce Vasodilation in Resistance Mesenteric Arteries

The antidiabetic drug dapagliflozin is a sodium-glucose cotransporter-2 (SGLT2) inhibitor that, in addition to glucose reduction, lowers systemic blood pressure and adverse cardiovascular events. Here, we sought to investigate if dapagliflozin dilates resistance mesenteric arteries that control peripheral vascular resistance and blood pressure. We performed pressurized arterial myography on freshly isolated, ex-vivo preparation of resistance-size mesenteric arteries from Sprague Dawley rats to examine if dapagliflozin can regulate arterial contractility. To assess the role of endothelial signaling, endothelium was denuded by slow passage of air bubbles through the vessel lumen. We also used different pharmacological modulators of major endothelium- and smooth muscle-specific vasodilatory pathways. Our pressure myography data showed that dapagliflozin application produced a concentration-dependent vasodilation in phenylephrine (PE)-constricted rat mesenteric arteries. Non-selective inhibition of K channels and selective inhibition of smooth muscle cell voltage-gated K channels K 7 significantly abolished dapagliflozin-induced vasorelaxation. Inhibition of other major K isoforms such as K 1.3, K 1.5 channels as well as large-conductance Ca -activated K (BK ) channels, ATP-sensitive (K ) channels did not abolish vasodilation. Dapagliflozin-evoked mesenteric artery vasodilation remained unaltered upon pharmacological inhibition of endothelial cell to smooth muscle signaling axis involving nitric oxide (NO), soluble guanylyl cyclase (sGC) and protein kinase G (PKG), as well as the inhibition of endothelium-derived prostacyclin (PGI ). Consistent with pharmacological inhibition, endothelium denudation had no effect on dapagliflozin-induced vasodilation. Overall, our data suggests that dapagliflozin selectively stimulates arterial smooth muscle cells K 7 channels, leading to vasodilation in resistance mesenteric arteries. These findings are significant as it uncovers a direct vasodilatory action of dapagliflozin in resistance mesenteric arteries, which may lower systemic blood pressure.