Experimental Studies On Anti-hypoxia And Prevention And Treatment Of Hypoxic Pulmonary Hypertension With Administration Of ViTA

Aim: Hypoxia is a common pathologic process. Exposure to hypoxia induces hypoxic pulmonary hypertension (HPH), which subsequently increases the workload of right ventricle and is the key step in the development of right ventricle hypertrophy and high altitude heart disease. The underlying mechanisms of HPH are not completely understood, although studies have substantially contributed to the current understanding of several areas. So there are no effective and satisfactory strategies on prevention and treatment of HPH. The disturbances of energy metabolism, augmentation of reactive oxygen species (ROS), imbalance of cellular Ca2+ homeostasis and impairment of NO pathway are the basic biochemical processes, which promote each other and form vicious cycles in hypoxic cellular injury. We assumed strategies on promoting NO production, scavenging of ROS, mitigating Ca2+ overload would enhance cell protection and have effect on prevention of HPH. Vitamin C is the strongest antioxidant, which is able to scavenge 100% oxygen-derived free radicals; Taurine has the ability to adjust cell Ca2+-balance; L-Arginine serves as NO precursor to improve NO production. Therefore, we investigated Vitamin C, Taurine and L-Arginine, and their combinations (ViTA for ab.) on prevention of HPH and cytoprotection of pulmonary smooth muscle cells exposed to hypoxia, expecting that the combinations of the above drugs are more powerful for protecting hypoxic cell damage, and on the prevention and treatment of HPH and hypoxic right ventricle hypertrophy.Method:1. Male Wistar rats had been divided into three groups: Hypoxia 2 weeks, Hypoxia 4 weeks and plain control (PC). Hypoxia 2 weeks and Hypoxia 4 weeks group had divided into eight subgroups further: hypoxia control (H), Vitamin C (V), Taurine (T), L-Arginine (L), Vitamin C +Taurine (TV), Taurine + L-Arginine (TL), Vitamin C + L-Arginine (VL) and Taurine + Vitamin C + L-Arginine (TVL), the therapy groups were given corresponding drugs every day orally. After exposed (12 hours ever day) 2 and 4 weeks in hypobaric chamber at simulated high altitude of 5000 meters, mean pulmonary artery pressure andhemodynamic indexes of heart were measured; blood plasma, pulmonary tissue and the heart were taken at a simulated altitude of 4000 meters. Activity of lactate dehydrogenase (LDH), content of maleic dialdehyde (MDA) in blood plasma, NO production in pulmonary tissue homogenate and index of right ventricle hypertrophy were determined.2. Pulmonary arterial smooth muscle cells (PASM) were culture from rat pulmonary artery. The cells were then sub cultured and divided into b four groups: normoxic and hypoxic 12, 24, 48 hour groups. The cells of hypoxic groups were cultured in a 5% COa incubator and 2% 62. Cell vitality was measure by MTT method. Effects of the above drugs and their combinations on cytoprotection of cells exposed to hypoxia were studied.Results:1. Effects of drugs on cytoprotection and prevention of HPH on hypoxic model in ratMean pulmonary artery pressure: The rats of 2H and 4H groups developed remarkable HPH. The average of pulmonary artery pressure (MAP) was significantly higher than that of plain group, with an elevation of about 25 mmHg (P<0.01). Each group with drugs administered emolliated the elevation of MAP caused by hypoxia, of which the effect TVL is the most powerful in the control of MAP, with about 8.8 mmHg lower than that of hypoxic group without drugs administered (P<0.01). There were no statistic differences among other groups (P<0.05). MAP in each hypoxic 4-week group with drug treated is significant lower than that of 4 H group (P0.01?), but among treated groups, there were no remarkable differences. Right ventricle weight index: the index of 2H and 4H was significant higher than that of PC (PO.01), with 1.56- and 1.63- folds of higher respectively. The value of each therapy group was about 20% lower than that of each corresponding H group (P<0.01). Among treated groups, there were no statistic differences. Lactate dehydrogenase: the activities of LDH of...