Hasan Ahasanul, Menon Sreelakshmi N, Zerin Farzana, Hasan Raquibul
Department of Pharmaceutical Sciences, College of Pharmacy, Mercer University, Atlanta, GA, United States.
Heliyon. 2022 May 20;8(5):e09503. doi: 10.1016/j.heliyon.2022.e09503. eCollection 2022 May.
Dapagliflozin is a sodium-glucose cotransporter 2 (SGLT2) inhibitor that, in addition to glucose reduction, lowers systemic blood pressure. Here, we investigated if dapagliflozin could directly relax small mesenteric arteries that control peripheral vascular resistance and blood pressure, and the underlying molecular mechanism. We used pressurized arterial myography, pharmacological inhibition and Western blotting to investigate the direct effect of dapagliflozin on the contractility of freshly isolated, resistance-size rat mesenteric arteries. Our pressure myography data unveiled that dapagliflozin relaxed small mesenteric arteries in a concentration-dependent manner. Non-selective inhibition of K channels and selective inhibition of smooth muscle cell voltage-gated K channels K7 attenuated dapagliflozin-induced vasorelaxation. Inhibition of other major K isoforms such as K1.3, K1.5 channels as well as large-conductance Ca-activated K (BK) channels, ATP-sensitive (K) channels did not abolish vasodilation. Dapagliflozin-evoked vasodilation remained unaltered by pharmacological inhibition of endothelium-derived nitric oxide (NO) signaling, prostacyclin (PGI), as well as by endothelium denudation. Our Western blotting data revealed that SGLT2 protein is expressed in rat mesenteric arteries. However, non-selective inhibition of SGLTs did not induce vasodilation, demonstrating that the vasodilatory action is independent of SGLT2 inhibition. Overall, our data suggests that dapagliflozin directly and selectively stimulates arterial smooth muscle cells K7 channels, leading to vasodilation in resistance-size mesenteric arteries. These findings are significant as it uncovers for the first time a direct vasodilatory action of dapagliflozin in resistance mesenteric arteries, which may lower systemic blood pressure.
达格列净是一种钠-葡萄糖协同转运蛋白2（SGLT2）抑制剂，除了降低血糖外，还能降低全身血压。在此，我们研究了达格列净是否能直接舒张控制外周血管阻力和血压的肠系膜小动脉及其潜在的分子机制。我们使用压力动脉肌动描记法、药理学抑制和蛋白质印迹法来研究达格列净对新鲜分离的、具有阻力大小的大鼠肠系膜动脉收缩性的直接影响。我们的压力肌动描记法数据表明，达格列净以浓度依赖性方式舒张肠系膜小动脉。非选择性抑制钾通道和选择性抑制平滑肌细胞电压门控钾通道K7可减弱达格列净诱导的血管舒张。抑制其他主要的钾亚型，如K1.3、K1.5通道以及大电导钙激活钾（BK）通道、ATP敏感性（K）通道，并不会消除血管舒张作用。达格列净诱发的血管舒张不受内皮源性一氧化氮（NO）信号传导、前列环素（PGI）的药理学抑制以及内皮剥脱的影响。我们的蛋白质印迹数据显示，SGLT2蛋白在大鼠肠系膜动脉中表达。然而，非选择性抑制SGLT并不会诱导血管舒张，这表明血管舒张作用独立于SGLT2抑制。总体而言，我们的数据表明，达格列净直接且选择性地刺激动脉平滑肌细胞的K7通道，导致具有阻力大小的肠系膜动脉血管舒张。这些发现意义重大，因为它首次揭示了达格列净在阻力性肠系膜动脉中的直接血管舒张作用，这可能会降低全身血压。
