Department of Toxic and Narcotic Drugs, Forensic Medicine, Cairo Laboratory, Medicolegal Organization, Ministry of Justice, Cairo, Egypt; Department of Toxic and Narcotic Drugs, Forensic Medicine, Cairo Laboratory, Medicolegal Organization, Ministry of Justice, Cairo, Egypt.
Department of Pharmacology and Toxicology, Faculty of Pharmacy, Zagazig University, Zagazig 44519, Egypt.
Toxicol Appl Pharmacol. 2019 Nov 1;382:114750. doi: 10.1016/j.taap.2019.114750. Epub 2019 Sep 10.
Hepatic ischemia/reperfusion injury (H-IRI) is associated with irreversible liver damage. The current study aimed to investigate the protective effect of carvedilol against H-IRI in high-fructose high-fat diet (HFrHFD)-fed mice and the role of G protein-coupled receptor kinase 2 and 5 (GRK2 and GRK5). Mice were fed HFrHFD for 16 weeks; then mice were subjected to 30 min of ischemia followed by 1 h of reperfusion at the end of feeding period. Carvedilol (20 mg/kg, i.p.) was administered 30 min before ischemia. To explore the role of GRK2 and GRK5 in mediating carvedilol effects, paroxetine (GRK2 inhibitor, 10 mg/kg, i.p.) and amlexanox (GRK5 inhibitor, 25 mg/kg, i.p.) were administered 30 min before carvedilol administration. Liver function, histopathology and hepatic oxidative stress, as well as inflammatory and apoptotic markers were measured at the end of the experiment. In addition, adrenergic receptor downstream signals were measured in the liver. Results showed increased markers of liver injury (ALT and AST) in mice subjected to H-IRI. Moreover, liver injury was associated with slight collagen deposits as revealed by histopathology and elevated hepatic levels of oxidative stress, inflammatory and apoptotic markers. On the other hand, carvedilol protected mice against H-IRI and improved all associated pathological changes. Furthermore, pre-injection of either GRK2 or GRK5 inhibitor did not change carvedilol effects on serum ALT level and liver collagen deposits, while increased its antioxidant, anti-inflammatory and anti-apoptotic effects. In conclusion, carvedilol protects against H-IRI in HFrHFD-fed mice. GRK2 and GRK5 may not play a potential role in mediating this effect.
肝缺血/再灌注损伤（H-IRI）与不可逆性肝损伤有关。本研究旨在探讨卡维地洛对高脂高果糖饮食（HFrHFD）喂养小鼠 H-IRI 的保护作用及其与 G 蛋白偶联受体激酶 2 和 5（GRK2 和 GRK5）的关系。小鼠喂养 HFrHFD16 周；然后在喂养期末进行 30 分钟缺血，再灌注 1 小时。卡维地洛（20mg/kg，腹腔注射）在缺血前 30 分钟给予。为了探讨 GRK2 和 GRK5 在介导卡维地洛作用中的作用，给予帕罗西汀（GRK2 抑制剂，10mg/kg，腹腔注射）和氨来占诺（GRK5 抑制剂，25mg/kg，腹腔注射）在给予卡维地洛前 30 分钟。实验结束时测量肝功能、组织病理学和肝氧化应激以及炎症和凋亡标志物。此外，还测量了肝脏肾上腺素能受体下游信号。结果显示，H-IRI 小鼠的肝损伤标志物（ALT 和 AST）增加。此外，组织病理学显示肝损伤与轻微的胶原沉积有关，肝氧化应激、炎症和凋亡标志物水平升高。另一方面，卡维地洛可预防 HFrHFD 喂养小鼠的 H-IRI，并改善所有相关的病理变化。此外，预先注射 GRK2 或 GRK5 抑制剂不会改变卡维地洛对血清 ALT 水平和肝胶原沉积的影响，而增强了其抗氧化、抗炎和抗凋亡作用。总之，卡维地洛可预防 HFrHFD 喂养小鼠的 H-IRI。GRK2 和 GRK5 可能在介导这种作用中不起潜在作用。
