Metformin Restores Intermediate-Conductance Calcium-Activated K⁺Channel– and Small-Conductance Calcium-Activated K⁺Channel–Mediated Vasodilatation Impaired by Advanced Glycation End Products in Rat Mesenteric Artery

Abstract

The present study was designed to investigate the effect of metformin on the impairment of intermediate-conductance and small-conductance Ca 21-activated potassium channels (IK Ca and SK Ca )-mediated relaxation in diabetes and the underlying mechanism. The endothelial vasodilatation function of mesenteric arteries was assessed with the use of wire myography. Expression levels of IK Ca and SK Ca and phosphorylated Thr 172 of AMPactivated protein kinase (AMPK) were measured using Western blot technology. The channel activity was observed using a whole-cell patch voltage clamp. Reactive oxygen species (ROS) were measured using dihydroethidium and 29,79-dichlorofluorescein diacetate. Metformin restored the impairment of IK Ca -and SK Camediated vasodilatation in mesenteric arteries from streptozotocininduced type 2 diabetic rats and that from normal rats incubated with advanced glycation end products (AGEs) for 3 hours. In cultured human umbilical vein endothelial cells (HUVECs), 1 mM metformin reversed AGE-induced increase of ROS and attenuated AGEand H 2 O 2 -induced downregulation of IK Ca and SK Ca after longterm incubation (.24 hours). Short-term treatment (3 hours) with 1 mM metformin reversed the decrease of IK Ca and SK Ca currents induced by AGE incubation for 3 hours without changing the channel expression or the AMPK activation in HUVECs. These results are the first to demonstrate that metformin restored IK Ca -and SK Ca -mediated vasodilatation impaired by AGEs in rat mesenteric artery, in which the upregulation of channel activity and protein expression is likely involved.

KCa channel activation normalizes endothelial function in Type 2 Diabetic resistance arteries by improving intracellular Ca2+ mobilization

“…It is further noteworthy that the vasodilatory effects of SKA-31 and related KCa activators have been reported in multiple arterial beds and species, despite expected differences in endothelial cell phenotype and function in vessels from different regions of the vasculature [22][23][24]26,29,39,49,50]. Although not apparent in our study, increases or decreases in endothelial KCa channel expression/activity have been reported in other rodent models of T2D [56][57][58], which may relate to differences in animal phenotype (e.g. lean vs. obese), age, genetic alterations, vascular bed, etc.…”

Effect of Oxidative Stress on the Estrogen-NOS-NO-KCa Channel Pathway in Uteroplacental Dysfunction: Its Implication in Pregnancy Complications

“…The reduced expression of SK3 and IK1 (K Ca 3.1) in the placenta, umbilical vessels, and HUVECs was also associated with the upregulation of NOX2 or NOX4 and heightened oxidative stress in preeclamptic pregnancy [113, 187, 188]. The contributing role of ROS to the downregulation of SK Ca and IK Ca channels was substantiated based on the following findings: (1) restoration of channel expression by antioxidants such as apocynin, tempol, and tiron and (2) simulation of the downregulation by oxidants such as superoxide generated by exogenous X/XO mixture and H 2 O 2 [113, 188, 189].…”

Metformin restores electrophysiology of small conductance calcium-activated potassium channels in the atrium of GK diabetic rats

“…GK rats in the metformin-treated group (Met) ( n = 6) received intragastric administration of metformin (300 mg/kg/day) since 12 weeks of age for three months, while an equal volume of citric acid buffer was intragastrically administrated daily to the rats in the GK and Con groups ( n = 6 each group). This high dose of metformin was chosen because that long-term treatment with high-dose metformin could alleviate vascular dysfunction and rescue SK channel-mediated vasodilation in diabetic rats [ 14 , 15 ]. At the end of three-month metformin treatment, electrocardiogram (ECG) was performed on all rats to monitor the cardiac electrical activity.…”