Empagliflozin Relaxes Resistance Mesenteric Arteries by Stimulating Multiple Smooth Muscle Cell Voltage-Gated K+ (KV) Channels.

Ahasanul Hasan,Raquibul Hasan

doi:10.3390/ijms221910842

Abstract

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 KV1.5 and KV7 abolished empagliflozin-induced vasodilation. In contrast, pharmacological inhibition of large-conductance Ca2+-activated K+ (BKCa) channels and ATP-sensitive (KATP) 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 (PGI2) 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 KV channels KV1.5 and KV7, 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.

Highlights

Type 2 diabetes (T2D) and hypertension are two major and independent risk factors for the development of cardiovascular diseases including heart disease, stroke, peripheral arterial disease and chronic kidney disease [1]
We demonstrated for the first time that empagliflozin stimulates vasodilation in resistance arteries such as the small mesenteric arteries
Our data demonstrate that empagliflozin-evoked vasodilation does not depend on endothelial signaling; rather, it depends on the activation of arterial smooth muscle cell KV 1.5 and KV 7 ion channels

Summary

Introduction

Type 2 diabetes (T2D) and hypertension are two major and independent risk factors for the development of cardiovascular diseases including heart disease, stroke, peripheral arterial disease and chronic kidney disease [1]. Hypertension and T2D often coexist, which multiplies the risk of adverse cardiovascular events in affected individuals [1,2]. Clinical studies suggest that there is considerable residual risk for cardiovascular events in the hypertensive-diabetic group despite standard pharmacologic treatment and lifestyle modifications [4]. There is a growing interest among clinicians with respect to management strategies for blood pressure lowering in this high-risk group that complement conventional antihypertensive therapy. This is based on a number of rigorous clinical trials that have shown that new hypoglycemic agents such as SGLT2

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Conclusion