Department of Pharmaceutical Sciences, College of Pharmacy, Mercer University, 3001 Mercer University Drive, Atlanta, GA 30341, USA.
Int J Mol Sci. 2021 Oct 7;22(19):10842. doi: 10.3390/ijms221910842.
The antidiabetic drug empagliflozin is reported to produce a range of cardiovascular effects, including a reduction in systemic blood pressure. However, whether empagliflozin directly modulates the contractility of resistance-size mesenteric arteries remains unclear. Here, we sought to investigate if empagliflozin could relax resistance-size rat mesenteric arteries and the associated underlying molecular mechanisms. We found that acute empagliflozin application produces a concentration-dependent vasodilation in myogenic, depolarized and phenylephrine (PE)-preconstricted mesenteric arteries. Selective inhibition of smooth muscle cell voltage-gated K channels K1.5 and K7 abolished empagliflozin-induced vasodilation. In contrast, pharmacological inhibition of large-conductance Ca-activated K (BK) channels and ATP-sensitive (K) channels did not abolish vasodilation. Inhibition of the vasodilatory signaling axis involving endothelial nitric oxide (NO), smooth muscle cell soluble guanylyl cyclase (sGC) and protein kinase G (PKG) did not abolish empagliflozin-evoked vasodilation. Inhibition of the endothelium-derived vasodilatory molecule prostacyclin (PGI) had no effect on the vasodilation. Consistently, empagliflozin-evoked vasodilation remained unaltered by endothelium denudation. Overall, our data suggest that empagliflozin stimulates smooth muscle cell K channels K1.5 and K7, resulting in vasodilation in resistance-size mesenteric arteries. This study demonstrates for the first time a novel mechanism whereby empagliflozin regulates arterial contractility, resulting in vasodilation. Due to known antihypertensive properties, treatment with empagliflozin may complement conventional antihypertensive therapy.
抗糖尿病药物恩格列净据报道可产生一系列心血管效应，包括降低全身血压。然而，恩格列净是否直接调节阻力型肠系膜动脉的收缩性尚不清楚。在这里，我们试图研究恩格列净是否可以松弛阻力型大鼠肠系膜动脉，以及相关的潜在分子机制。我们发现，急性恩格列净应用可使肌源性、去极化和苯肾上腺素（PE）预收缩的肠系膜动脉产生浓度依赖性的血管舒张。选择性抑制平滑肌细胞电压门控 K 通道 K1.5 和 K7 可消除恩格列净诱导的血管舒张。相比之下，药理学抑制大电导钙激活的 K（BK）通道和 ATP 敏感性（K）通道并不能消除血管舒张。抑制涉及内皮一氧化氮（NO）、平滑肌细胞可溶性鸟苷酸环化酶（sGC）和蛋白激酶 G（PKG）的血管舒张信号轴并不能消除恩格列净引起的血管舒张。抑制内皮衍生的血管舒张分子前列环素（PGI）对血管舒张没有影响。一致地，恩格列净引起的血管舒张在去除内皮后仍未改变。总的来说，我们的数据表明，恩格列净刺激平滑肌细胞 K 通道 K1.5 和 K7，导致阻力型肠系膜动脉的血管舒张。这项研究首次证明了恩格列净调节动脉收缩性从而导致血管舒张的新机制。由于具有已知的降压特性，恩格列净的治疗可能补充传统的降压治疗。
