EUROPEAN JOURNAL OF PHARMACOLOGY
·
2025
·
IF 4.7
Jie Yan,Xiaowen Zhang,Lifeng Feng,Shengzheng Zhang,Han Wei,Wencong Tian,Qiwen Li,Jing Li,Liang Yang,Jie Liu,Yang Xu,Jianlin Cui,Shan Ren,Zhi Qi,Yang Gao
Hypertension is a primary risk factor for cardiovascular disease. Recently, Ertugliflozin (Ertu), a new sodium-glucose cotransporter-2 (SGLT2) inhibitor, though primarily approved by the FDA as an antidiabetic agent, has been reported to lower blood pressure. However, whether Ertu directly regulates the contractility of arteries remains unknown. Here, we examined Ertu's effects on vascular function and underlying molecular mechanisms. Isometric tension of arteries was recorded using a multi-wire myograph system. In rat mesenteric arteries, Ertu acutely relaxed vessels constricted by phenylephrine (PE) and high K + (KPSS), while pretreatment with Ertu inhibited PE- and KPSS- induced vascular constriction. Similar outcomes were observed in the mouse thoracic aorta. Notably, these vasodilatory effects of Ertu are mediated by vascular smooth muscle cells (VSMCs) rather than endothelial cells. Mechanistically, we found that Ertu activated AMP-activated protein kinase (AMPK) signaling pathway in VSMCs and rat thoracic aorta tissues by decreasing ATP levels and the ATP/ADP ratio. Using the AMPK inhibitor Compound C, we observed that Ertu-induced vasodilation was abolished. Furthermore, we found that Compound C reversed Ertu-mediated reductions in cytosolic calcium concentration ([Ca 2+ ]i) and mitochondrial fission, which were accompanied by diminished mitochondrial membrane potential in VSMCs. In conclusion, this study demonstrates for the first time that Ertu inhibits AMPK-mediated mitochondrial fission in VSMCs, leading to vasorelaxation, suggesting its potential as a therapeutic agent for hypertension.
研究领域:
药理学
·
心血管生物学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
PHYSIOLOGY & BEHAVIOR
·
2023
·
IF 2.9
Bo Pang,Lu-Lu Zhang,Bin Li,Feng-Xian Sun,Zhi-Da Wang
An antidiabetic agent sodium glucose co-transporter 2 (SGLT2) inhibitor ertugliflozin has been revealed to bind to catalytic anionic site of acetylcholinesterase (AChE), which is considered to be associated with the cognitive decline in neurodegenerative diseases, such as Alzheimer's disease (AD). The aim of the present study was thus to probe the effect of ertugliflozin on AD. Intracerebroventricular injection of streptozotocin (STZ/i.c.v) (3 mg/kg) was done bilaterally in male Wistar rats at 7–8 weeks of age. Two treatment doses (5 mg/kg and 10 mg/kg) of ertugliflozin were given intragastrically to STZ/i.c.v-induced rats for 20 days daily for behavioral assessment. Biochemical estimations of cholinergic activity, neuronal apoptosis, mitochondrial function and synaptic plasticity were performed. Behavioral results with ertugliflozin treatment revealed attenuation of cognitive deficit. Ertugliflozin also inhibited hippocampal AChE activity, downregulated pro-apoptotic marker expression, as well as mitigated mitochondrial dysfunction and synaptic damage in STZ/i.c.v rats. Importantly, we found that the hyperphosphorylation of tau in the hippocampus of STZ/i.c.v rats was decreased after oral administration of ertugliflozin, which was accompanied by decreased Phospho.IRS-1 Ser307 /Total.IRS-1 ratio and increased Phospho.Akt Ser473 /Total.Akt and Phospho.GSK3β Ser9 /Total.GSK3β ratios. Our results indicated that treatment with ertugliflozin reversed AD pathology, which may be associated with inhibition of insulin signaling disruption-induced tau hyperphosphorylation.
研究领域:
神经科学
·
药理学
·
神经退行性疾病
·
认知障碍
✓ 已验证
产品关联
DOI
PubMed
高影响因子
PLoS One
·
2026
·Vol. 21
·期 6
·e0350400
·
IF 2.8
Xin Zhou,Yanru Deng,Caihui Guo,Ying Li,Yuhao Fu,Zhi Wang,Zhanjun Dong
Background
Patients with type 2 diabetes mellitus (T2DM) usually accompany with the occurrence of high blood pressure, necessitating a combination of treatments. This includes sodium-glucose co-transporter 2(SGLT2) inhibitors like empagliflozin, ertugliflozin, and henagliflozin, and antihypertensives like telmisartan. Both classes interact with transporters like P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), with telmisartan further inhibiting several, including organic anion transporting poly-peptide (OATP) 1B1/1B3.
Objective
Despite their common use, pharmacokinetic interactions between these drugs remain underexplored. This study aims to investigate the potential pharmacokinetic interaction between three specific SGLT2 inhibitors and telmisartan.
Methods
Rats were divided into twelve groups, with six rats per group, and received different combinations of empagliflozin, ertugliflozin, henagliflozin, and telmisartan. Drug concentrations were measured using ultra-performance liquid chromatography-tandem mass spectrometry, and mRNA expressions through quantitative reverse transcription polymerase chain reaction (RT-qPCR).
Results
Our study manifested that telmisartan increased the plasma concentration-time curves (AUC 0-t and AUC 0–∞ ) and the maximum plasma concentrations (C max ) of empagliflozin, whereas the apparent clearance (CL z/F ) and apparent volume of distribution (V z ) significantly decreased(all p ＜ 0.05). Similarly, telmisartan increased the AUC 0-t , AUC 0-∞ and C max of henagliflozin and decreased the CL z/F (all p ＜ 0.05). When coadministered with ertugliflozin or henagliflozin, the AUC 0-t and AUC 0–∞ of telmisartan decreased significantly and the CL z/F increased significantly(all p ＜ 0.05). Furthermore, PCR results demonstrated that telmisartan decreased the expression of BCRP expression in liver, intestines and kidney, P-gp expression in the intestines and kidney and OATP1B2 expression in liver tissue.
Conclusions
Our findings highlight the importance of these drug interactions, which could inform dose adjustments to enhance safety in patients with T2DM and hypertension.
✓ 已验证
DOI
PubMed
高影响因子
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