Effects of remimazolam regulating the Nrf2/GPX4 pathway on circulatory function in septic shock rats

doi:10.11958/20241809

Abstract

Abstract:

Objective To investigate the effect and mechanism of remimazolam on circulatory function in septic shock rats. Methods Seventy-two SPF grade rats were randomly divided into the control group, the model group, the dexamethasone group, the low and high dose remimazolam groups and the high-dose remimazolam+Nrf2 inhibitor (ML385) group, with 12 rats in each group. The septic shock rat model was established by intravenous infusion of 10 mg/kg lipopolysaccharide (LPS). After 6 hours of modeling, the mean arterial pressure (MAP) and heart rate (HR) of rats were measured. Enzyme linked immunosorbent assay (ELISA) method was applied to measure serum levels of lactic acid (Lac), tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, IL-6, nitric oxide (NO), and endothelin-1 (ET-1). Hematoxylin-eosin (HE) staining was applied to observe morphological changes in vascular tissue. TUNEL staining was applied to observe the apoptosis of vascular endothelial cells. DHE fluorescent probe was used to detect the level of ROS in vascular tissue. The colorimetric method was applied to detect the contents of MDA and the activity of SOD in vascular tissue. Western blot assay was applied to detect the protein expression of nuclear factor E2-related factor 2 (Nrf2) and glutathione peroxidase 4 (GPX4) in vascular tissue. Results Compared with the control group, MAP, SOD activity in vascular tissue, Nrf2 and GPX4 protein levels were lower in the model group, while HR, serum Lac, NO, ET-1, TNF-α, IL-1β, IL-6 levels, endothelial cell apoptosis rate, ROS level in vascular tissue and MDA content were higher (P<0.05). Compared with the model group, MAP, SOD activity in vascular tissue, Nrf2 and GPX4 protein levels were higher in the dexamethasone group and in the low and high dose remimazolam groups, while HR, serum Lac, NO, ET-1, TNF-α, IL-1β, IL-6 levels, endothelial cell apoptosis rate, ROS level in vascular tissue and MDA content were lower (P<0.05). Nrf2 inhibitor ML385 greatly reduced the protective effect of remimazolam on septic shock rats (P<0.05). Conclusion Remimazolam may improve circulatory function in septic shock rats by activating the Nrf2/GPX4 pathway, inhibiting inflammatory response and oxidative stress, reducing endothelial cell damage.

Key words: shock, septic, endothelial cells, remimazolam, nuclear factor E2 related factor 2, glutathione peroxidase 4

CLC Number:

R631

Figures/Tables 9

References 26

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组别	MAP/mmHg	HR/（次/min）	Lac/（mmol/L）
对照组	98.17±2.41	317.50±12.65	1.86±0.31
模型组	47.00±3.16^a	490.42±18.43^a	4.90±0.57^a
地塞米松组	85.42±2.64^b	336.92±17.30^b	2.39±0.36^b
瑞马唑仑低剂量组	69.00±2.49^bc	444.58±13.28^bc	4.11±0.51^bc
瑞马唑仑高剂量组	83.67±4.08^bd	347.42±14.58^bd	2.52±0.40^bd
瑞马唑仑高剂量+ML385组	55.50±4.30^e	470.50±13.60^e	4.60±0.54^e
F	213.415^＊＊	150.423^＊＊	47.693^＊＊

组别	MAP/mmHg	HR/（次/min）	Lac/（mmol/L）
对照组	98.17±2.41	317.50±12.65	1.86±0.31
模型组	47.00±3.16^a	490.42±18.43^a	4.90±0.57^a
地塞米松组	85.42±2.64^b	336.92±17.30^b	2.39±0.36^b
瑞马唑仑低剂量组	69.00±2.49^bc	444.58±13.28^bc	4.11±0.51^bc
瑞马唑仑高剂量组	83.67±4.08^bd	347.42±14.58^bd	2.52±0.40^bd
瑞马唑仑高剂量+ML385组	55.50±4.30^e	470.50±13.60^e	4.60±0.54^e
F	213.415^＊＊	150.423^＊＊	47.693^＊＊

组别	NO/（μmol/L）	ET-1/（ng/L）
对照组	14.27±2.31	5.52±1.03
模型组	56.30±4.24^a	18.44±1.99^a
地塞米松组	24.15±3.08^b	8.39±1.17^b
瑞马唑仑低剂量组	39.42±3.76^bc	13.69±1.52^bc
瑞马唑仑高剂量组	26.93±3.25^bd	9.02±1.31^bd
瑞马唑仑高剂量+ML385组	48.60±4.10^e	15.74±1.68^e
F	123.114^＊＊	66.340^＊＊

组别	NO/（μmol/L）	ET-1/（ng/L）
对照组	14.27±2.31	5.52±1.03
模型组	56.30±4.24^a	18.44±1.99^a
地塞米松组	24.15±3.08^b	8.39±1.17^b
瑞马唑仑低剂量组	39.42±3.76^bc	13.69±1.52^bc
瑞马唑仑高剂量组	26.93±3.25^bd	9.02±1.31^bd
瑞马唑仑高剂量+ML385组	48.60±4.10^e	15.74±1.68^e
F	123.114^＊＊	66.340^＊＊

组别	TNF-α/（ng/L）	IL-1β/（ng/L）	IL-6/（ng/L）
对照组	45.60±5.72	22.48±4.19	27.75±5.21
模型组	149.44±9.83^a	97.30±8.06^a	126.49±10.30^a
地塞米松组	66.32±6.40^b	38.65±5.25^b	44.38±6.45^b
瑞马唑仑低剂量组	101.25±9.29^bc	77.24±7.13^bc	89.20±9.10^bc
瑞马唑仑高剂量组	70.41±7.35^bd	42.18±6.22^bd	50.69±7.28^bd
瑞马唑仑高剂量+ML385组	120.23±9.64^e	85.67±7.90^e	107.83±9.92^e
F	133.122^＊＊	124.447^＊＊	135.321^＊＊