Beneficial effect of the mitochondrial ATP‑sensitive potassium channel‑specific opener nicorandil on the collapsed lung via inhibition of apoptosis in clinical thoracic surgery

Wang,Chunguang; Wu,Zhengwen; Li,Zhiqin; Wang,Zhichun; Ke,Honggang; Huang,Xinchong

doi:10.3892/mmr.2023.12948

Beneficial effect of the mitochondrial ATP‑sensitive potassium channel‑specific opener nicorandil on the collapsed lung via inhibition of apoptosis in clinical thoracic surgery

Authors:
- Chunguang Wang
- Zhengwen Wu
- Zhiqin Li
- Zhichun Wang
- Honggang Ke
- Xinchong Huang
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Affiliations: Department of Anesthesiology, Affiliated Hospital of Nantong University, Nantong, Jiangsu 226001, P.R. China, Department of Anesthesiology, Yangzhou Hongquan Hospital, Yangzhou, Jiangsu 225200, P.R. China, Department of Anesthesiology, Xiamen University Hospital Affiliated of Xiamen University, Xiamen, Fujian 361005, P.R. China, Department of Anesthesiology, Shuyang Hospital Affiliated of Xuzhou Medical University, Suqian, Jiangsu 223600, P.R. China, Department of Cardiothoracic Surgery, Affiliated Hospital of Nantong University, Nantong, Jiangsu 226001, P.R. China
Published online on: February 1, 2023 https://doi.org/10.3892/mmr.2023.12948
Article Number: 61

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Abstract

With the use of thoracoscopic surgery technology, one‑lung ventilation (OLV) is becoming more crucial as a basic requirement for enhanced recovery after surgery; however, it can lead to severe pulmonary injury, which is an issue for anesthesiologists. Therefore, it is important to protect pulmonary function during thoracic surgery anesthesia, particularly to protect the function of the collapsed lung. Our previous study on rabbits reported that nicorandil, a US Food and Drug Administration‑approved mitochondrial ATP‑sensitive potassium channel‑specific opener, can protect against lung injury in the collapsed lung. Therefore, the beneficial effect of nicorandil on OLV‑induced pulmonary injury in clinical thoracic surgery was further evaluated in the present study. Nicorandil was infused at 2 mg/h for 2 h from induction to 1 h after OLV in the nicorandil group. Trends in arterial oxygen desaturation (SaO₂), arterial partial pressure for oxygen (PaO₂) and the lung microstructure were assessed. ELISA was used to assess the levels of TNF‑α and malondialdehyde (MDA), and the activity of superoxide dismutase (SOD). A TUNEL assay was performed to evaluate apoptosis. Western blotting was used to analyze the relative expression levels of signaling proteins associated with apoptosis. Western blotting was performed to evaluate the protein expression levels of hypoxia‑inducible factor 1α (HIF‑1α), PI3K, Akt and NF‑κB, and reverse transcription‑quantitative PCR was used to detect HIF‑1α mRNA expression levels in the lungs of patients infused with nicorandil and nitroglycerin. Nicorandil treatment was associated with higher SaO₂ and PaO₂ compared with nitroglycerin treatment in OLV. The levels of MDA and TNF‑α in the operated lung of the nicorandil group were significantly lower compared with those in the control group. In addition, nicorandil was associated with higher SOD activity compared with nitroglycerin. The nicorandil‑treated lung, similar to the sham group, exhibited improved microstructure and less apoptosis in the experimental group. The protein expression levels of PI3K, phosphorylated Akt and HIF‑1α were significantly increased, whereas NF‑κB was significantly decreased in the nicorandil‑treated lung compared with the control group. Overall, nicorandil demonstrated beneficial effects by decreasing apoptosis in the operated lung, which was collapsed and then re‑expanded during OLV in thoracic surgery anesthesia. Nicorandil may serve a vital role by decreasing the overloading of calcium in mitochondria, shutting off the mitochondrial membrane permeability transition pore, reducing the release of cytochrome c, simultaneously triggering activation of the PI3K/Akt signaling pathway around the cell membrane, downregulating NF‑κB, upregulating HIF‑1α, and then reducing Bax/Bcl‑2, caspase‑3 and apoptosis. The trial registration was ChiCTR‑IOR‑17014061 (registered on December 20, 2017).

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