Protective Effects Of Trimetazidin Against Acute Hypobaric Hypoxia Injury In Rats

Objectives: The aim of this study is to investigate the protective effects of trimetazidine(TMZ)against the damages of myocardial and brain tissues in rats induced by acute hypobaric hypoxia and reveal the detailed mechanisms.Methods: According to the random number table,72 female SD rats were randomly divided into 6 groups(12 rats in each group)including normal control group(C),acute hypobaric hypoxia model groups(M),different doses of TMZ treatment groups(high,medium and low doses of TMZ groups: 20 mg/kg,10 mg/kg,5 mg/mg),and positive control group(Nimodipine,N: 20 mg/kg).The low pressure oxygen tank was designed to simulate the plateau area of 7000 meters above sea level for establishing the injury model of acute hypobaric hypoxia in rats.Except for the animals in the normal control group,the rats in the other experimental groups were all exposed to hypobaric hypoxia for 12 hours.After acute exposure to hypobaric hypoxia,the morphology changes in myocardial and brain tissues in rats of each group were observed via the method of H.E staining.The brain water content of rats in each group was measured using the wet and dry weight method.The activities of lactate dehydrogenase(LDH),endothelin-1(ET-1)and sodium heart(ANP)activity were examined via the colorimetry and radioimmunoassay methods for exploring the protective effects of trimetazidine against acute hypobaric hypoxia injury.The mRNA expression levels of water channel protein-1(Aquaporin-1,AQP-1)and water channel protein-4(Aquaporin-4,AQP-4)in rat myocardial and brain tissues were determined by PR-PCR analysis.The protein expression levels of AQP-1 and AQP-4 in rat myocardial and brain tissues were determined by Western blot analysis.Results:1 H.E staining: Compared with the normal control group,there were obvious morphology changes in the rat myocardial and brain tissues in the hypobaric hypoxia model group.Compared with the hypobaric hypoxia model group,all doses of TMZ and Nimodipine can remarkably alleviate the damages of rat myocardial and brain tissues induced by acute hypobaric hypoxia.2 Brain water content: Compared with the normal control group,the brain water content of rats in the hypobaric hypoxia model group increased(P<0.01).Compared with the hypobaric hypoxia model group,all doses of TMZ and Nimodipine can significantly reduce the brain water content of rats(high dose of TMZ,P<0.01;Nimodipine,middle and low doses of TMZ,P<0.05).3 Activities of serum biomarkers: Compared with the normal control group,the contents of ANP and ET-1 in plasma(P<0.01)and the leakage of serum LDH(P<0.01)significantly increased.Compared with the hypobaric hypoxia model group,all doses of TMZ and Nimodipine can remarkably decrease the contents of ANP and ET-1(Nimodipine,high dose of TMZ P<0.01)and the release of serum LDH(Nimodipine,all doses of TMZ,P<0.01;medium and low doses of TMZ,P<0.05).4 RT-PCR analysis: Compared with the normal control group,the mRNA levels of AQP-1 and AQP-4 in the rat myocardial and brain tissues increased significantly in the hypobaric hypoxia model group(both P<0.01).Compared with the hypobaric hypoxia model group,all doses of TMZ and Nimodipine can remarkably reduce the mRNA levels of AQP-1 and AQP-4 in the rat myocardial and brain tissues(the AQP-1/4 mRNA in the cardiac tissues: Nimodipine,all doses of TMZ,P<0.01;the AQP-1 mRNA in the brain tissues: Nimodipine,high and medium doses of TMZ,P<0.01;the AQP-4 mRNA in the brain tissues: Nimodipine,all doses of TMZ,P<0.01).5 Western blot analysis: Compared with the normal control group,the protein levels of AQP-1 and AQP-4 in the rat myocardial and brain tissues increased significantly in the hypobaric hypoxia model group(both P<0.01).Compared with the hypobaric hypoxia model group,all doses of TMZ and Nimodipine can remarkably reduce the protein levels of AQP-1 and AQP-4 in the rat myocardial and brain tissues(Nimodipine,all doses of TMZ,P<0.01).Conclusions: Trimetazidine has a remarkably protective effect against the damages of myocardial and brain tissues in rats induced by acute hypobaric hypoxia.The detailed mechanism is closely associated with the improvement of vascular endothelial cell and myocardial function,the down-regulated expressions of AQP-1 and AQP-4 and the reduction of tissue edema with Trimetazidine treatment.