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  • Title: Pharmacodynamic of cilostazol for anti-altitude hypoxia.
    Author: Li X, Wang R, Huo Y, Zhao A, Li W, Feng S.
    Journal: Zhong Nan Da Xue Xue Bao Yi Xue Ban; 2022 Feb 28; 47(2):202-210. PubMed ID: 35545410.
    Abstract:
    OBJECTIVES: The plateau environment is characterized by low oxygen partial pressure, leading to the reduction of oxygen carrying capacity in alveoli and the reduction of available oxygen in tissues, and thus causing tissue damage. Cilostazol is a phosphodiesterase III inhibitor that has been reported to increase the oxygen release of hemoglobin (Hb) in tissues. This study aims to explore the anti-hypoxic activity of cilostazol and its anti-hypoxic effect. METHODS: A total of 40 male BALB/C mice were randomly divided into a low-dose cilostazol (6.5 mg/kg) group, a medium-dose (13 mg/kg) group, a high-dose (26 mg/kg) group, and a control group. The atmospheric airtight hypoxia experiment was used to investigate the anti-hypoxic activity of cilostazol and to screen the optimal dosage. Twenty-four male Wistar rats were randomly divided into a normoxia control group, a hypoxia model group, an acetazolamide (22.33 mg/kg) group, and a cilostazol (9 mg/kg) group. After 3 days of hypoxia in the 4 010 m high altitude, blood from the abdominal aorta was collected to determine blood gas indicators, the levels of IL-6 and TNF-α in plasma were determined by enzyme-linked immunosorbent assay, and the levels of malondialdehyde (MDA), superoxide dismutase (SOD), and glutataione (GSH) were measured. The degree of pathological damage for rat tissues was observed with HE staining. RESULTS: Compared with the control group, the survival time of mice in the low, medium, and high dose group of cilostazol was significantly prolonged, and the survival time of mice in the medium dose group was the longest, with an extension rate at 29.34%, so the medium dose was the best dose. Compared with the hypoxia model group, the P50 (oxygen partial pressure at Hb oxygen saturation of 50%) value of rats in the cilostazol group was significantly increased by 1.03%; Hb and Hct were significantly reduced by 8.46% and 8.43%, and the levels of IL-6 and TNF-α in plasma were reduced by 50.65% and 30.77%. The MDA contents in heart, brain, lung, liver, and kidney tissues were reduced by 37.12%, 29.55%, 25.00%, 39.34%, and 21.47%, respectively. The SOD activities were increased by 94.93%, 9.14%, 9.42%, 13.29%, and 20.80%, respectively. The GSH contents were increased by 95.24%, 28.62%, 28.57%, 20.80%, and 44.00%, respectively. The results of HE staining showed that compared with the hypoxia model group, cilostazol significantly improved the damage of heart, lung, and kidney tissues in rats after hypoxia. CONCLUSIONS: Cilostazol can significantly improve the oxidative stress and inflammatory reaction caused by rapid altitude hypoxia, and it has a significant protective effect on tissue damage caused by hypoxia, suggesting that it has obvious anti-hypoxic activity. 目的: 高原环境具有低氧分压的特点,氧分压降低导致肺泡携氧量降低,组织可利用氧气减少,从而引发机体组织损伤。西洛他唑是一种磷酸二酯酶III抑制剂,能够增加血红蛋白(hemoglobin,Hb)在组织中的释氧量。本研究旨在探讨西洛他唑的抗缺氧活性及在急进高原缺氧模型中的抗缺氧作用。方法: 将40只雄性BALB/C小鼠随机分为西洛他唑低(6.5 mg/kg)、中(13 mg/kg)、高剂量(26 mg/kg)组和对照组,采用常压密闭缺氧实验,考察西洛他唑的抗缺氧活性,筛选最佳给药剂量。将24只雄性Wistar大鼠随机分为常氧对照组、缺氧模型组、乙酰唑胺(22.33 mg/kg)组和西洛他唑(9 mg/kg)组,急进4 010 m高原缺氧3 d后,采集腹主动脉血测定血气指标,用酶联免疫吸附法测定血浆中白细胞介素6(interleukin-6,IL-6)、肿瘤坏死因子-α(tumor necrosis factor-α,TNF-α)的水平,测定主要组织的丙二醛(malondialdehyde,MDA)含量、超氧化物歧化酶(superoxide dismutase,SOD)活力、谷胱甘肽(glutataione,GSH)含量,HE染色观察大鼠组织病理损伤程度。结果: 与对照组相比,西洛他唑低、中、高剂量组小鼠存活时间均显著延长,其中中剂量组存活时间最长,延长率最高(29.34%),中剂量为最佳给药剂量。与缺氧模型组相比,西洛他唑组大鼠Hb氧饱和度为50%时的氧分压(P50)升高1.03%,Hb含量、红细胞比容分别降低8.46%、8.43%;血浆中IL-6、TNF-α水平分别降低50.65%、30.77%;心肌、脑、肺、肝、肾组织中MDA含量分别降低37.12%、29.55%、25.00%、39.34%、21.47%,SOD活力分别升高94.93%、9.14%、9.42%、13.29%、20.80%,GSH含量分别升高95.24%、28.62%、28.57%、20.80%、44.00%。HE染色结果提示西洛他唑组大鼠缺氧后心肌、肺、肾组织损伤较缺氧模型组明显改善。结论: 西洛他唑对急进高原缺氧所致的氧化应激和炎症反应有明显的改善作用,对缺氧所致的组织损伤有明显的保护作用,提示其具有明显的抗缺氧活性。. OBJECTIVE: The plateau environment is characterized by low oxygen partial pressure, leading to the reduction of oxygen carrying capacity in alveoli and the reduction of available oxygen in tissues, and thus causing tissue damage. Cilostazol is a phosphodiesterase III inhibitor that has been reported to increase the oxygen release of hemoglobin (Hb) in tissues. This study aims to explore the anti-hypoxic activity of cilostazol and its anti-hypoxic effect. METHODS: A total of 40 male BALB/C mice were randomly divided into a low-dose cilostazol (6.5 mg/kg) group, a medium-dose (13 mg/kg) group, a high-dose (26 mg/kg) group, and a control group. The atmospheric airtight hypoxia experiment was used to investigate the anti-hypoxic activity of cilostazol and to screen the optimal dosage. Twenty-four male Wistar rats were randomly divided into a normoxia control group, a hypoxia model group, an acetazolamide (22.33 mg/kg) group, and a cilostazol (9 mg/kg) group. After 3 days of hypoxia in the 4 010 m high altitude, blood from the abdominal aorta was collected to determine blood gas indicators, the levels of IL-6 and TNF-α in plasma were determined by enzyme-linked immunosorbent assay, and the levels of malondialdehyde (MDA), superoxide dismutase (SOD), and glutataione (GSH) were measured. The degree of pathological damage for rat tissues was observed with HE staining. RESULTS: Compared with the control group, the survival time of mice in the low, medium, and high dose group of cilostazol was significantly prolonged, and the survival time of mice in the medium dose group was the longest, with an extension rate at 29.34%, so the medium dose was the best dose. Compared with the hypoxia model group, the P50 (oxygen partial pressure at Hb oxygen saturation of 50%) value of rats in the cilostazol group was significantly increased by 1.03%; Hb and Hct were significantly reduced by 8.46% and 8.43%, and the levels of IL-6 and TNF-α in plasma were reduced by 50.65% and 30.77%. The MDA contents in heart, brain, lung, liver, and kidney tissues were reduced by 37.12%, 29.55%, 25.00%, 39.34%, and 21.47%, respectively. The SOD activities were increased by 94.93%, 9.14%, 9.42%, 13.29%, and 20.80%, respectively. The GSH contents were increased by 95.24%, 28.62%, 28.57%, 20.80%, and 44.00%, respectively. The results of HE staining showed that compared with the hypoxia model group, cilostazol significantly improved the damage of heart, lung, and kidney tissues in rats after hypoxia. CONCLUSION: Cilostazol can significantly improve the oxidative stress and inflammatory reaction caused by rapid altitude hypoxia, and it has a significant protective effect on tissue damage caused by hypoxia, suggesting that it has obvious anti-hypoxic activity.
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