| Hypoxia, cold and other special environmental factors in plateau area seriouslyaffect the military operation capacity of the troops stationed in the high altitude, reducethe mobility and combat effectiveness of troops. Modern high-tech war demand troopsrapid mobility and remote deployment, under this context, the influence of specificenvironmental factors and army's special operations factors are intertwined, so thishazard military operational capability and health of the combatants more seriously.Acute mountain sickness is the clinical syndrome more often appeared when the armywho rapidly entered the plateau and after arrived in plateau, if not treated in time, it maybe consequential high altitude cerebral edema and high altitude pulmonary edema, thusthreaten the life.Plateau hypoxia can affect the body's physiological function, such as nerve,circulation, breathing, digestion, endocrine and immune and etc, is the initial factor ofvarious altitude sickness. In1962, the self-defense counterattack war in China-Indianborder, Non-combat downsizing is2.38times than combat downsizing caused byenvironmental factors, which accounts for the first was hypoxic. In2010, earthquakerelief operations in Yushu showed that how quickly and effectively to improve hypoxiatolerance, prevent and mitigate acute mountain sickness is an important medicalproblem being solved. A mass of researches indicate that drug administration is morerealistic when people quickly enter the plateau beside comprehensive training service,acclimatization, simulated high altitude hypoxic acclimatization and appropriatelyclimbing strategies. Since the1990s, acetazolamide is the only drug approved by FDA in U.S.A for this indication. SUA is a new carbon anhydride enzyme target-basedinhibitor synthesized and owned intellectual property rights by our institute, through theearly pharmacodynamics study, we have initially identified that SUA can improvehypoxia tolerance of small animals, compared with the positive control acetazolamide,SUA have the better ability to resist hypoxia.The article first took epidemiological survey of acute mountain sickness of whorapidly entered the plateau for earthquake relief, and then analyzed the incidence ofAMS and its main influencing factors. Based on the classic model of acute hypoxicinjury, further defined the role of SUA in improving the hypoxia tolerance, anddiscussed its possible mechanism.Ⅰ.Epidemiological survey of acute mountain sickness among poeple rapidlyacutely ascended to plateau for earthquake reliefBy using the method of cluster sampling to investigate the incidence of AMS of the691officers who rapidly entered Yushu for earthquake relief,and then use the Republicof China national military standard---GJB1098-91The diagnosis and principles ofacute mountain sickness to diagnose the AMS.The incidence of AMS of the army who rapidly entered Yushu for earthquake reliefwas35.8percent. Univariate analysis showed that former resident altitude,transport,upper respiratory tract infection and the history of stationed in the plateau wereassociated with the incidence of AMS. Multivariate analysis showed that air transportand upper respiratory tract infection were the independent risk factors of AMS. The riskof occurrence of AMS through the way of air was24.4times than way of road, the riskof AMS who suffered from upper respiratory tract infection was77.4times than the onewho didn't.Ⅱ. The pharmacodynamics study of the carbon anhydride enzyme target-basedinhibitors---SUA in the role of improving hypoxia tolerance1. Effect of SUA on the survival time of mice in normobaric hypoxiaThe Kunming mice were randomly divided into17groups (n=10):normal controlgroup, eight doses of Carbonic anhydrase groups [3.125,6.25,12.5,25,50,100,200,400mg/(kg·d)]and eight doses of SUA groups[3.125,6.25,12.5,25,50,100,200,400mg/(kg·d)]；Fed the mice five days and then placed them into the oxygen deficit bottlesto measure the survival time in the condition of hypoxia.In improving the endurance of mice in the condition of airtight hypoxia, the survival time of the SUA groups[6.25mg/(kg·d),12.5mg/(kg·d),25mg/(kg·d),50mg/(kg·d),100mg/(kg·d),200mg/(kg·d) and400mg/(kg·d)]were (27.38±4.63,29.53±4.43,29.67±7.28,31.55±6.34,32.45±6.65,36.81±7.24and35.41±4.20) min, compared with the normal control group(22.90±3.19) min, the survival time significantly prolonged (P<0.05or P<0.01);Compared with the same dose of Carbonic anhydrase groups (24.54±3.17,22.70±3.04,22.67±2.99,23.93±0.96,27.87±5.06,30.79±5.12and35.14±6.46) min, the survivaltime significantly prolonged; The minimum effective dose of SUA and Carbonicanhydrase were6.25and100mg/(kg·d), the potency of SUA is16times the carbonicanhydrase.2. Effect of SUA on the survival time of mice in the condition of decompressionhypoxiaThe male Kunming mice were randomly divided into5groups (n=10): normalcontrol group, acetazolamide [100mg/(kg·d)] and SUA groups[25,50,100mg/(kg·d)]；Fed the mice five days and then put them in the ladder cage, placed in Low-pressurechamber to measure the survival time in the condition of decompression and hypoxia.In improving the endurance of mice in the condition of decompression hypoxia, themiddle and high doses of the SUA group's survival time of mice were(24.82±3.92,28.27±5.89)min, significantly longer than control groups [(21.96±2.51)min,P＜0.05]；compared with the acetazolamide group(23.11±3.71)min, the survival time of SUAgroup[100mg/(kg·d)] significantly was prolonged.Ⅲ.The mechanism study of the new carbon anhydride enzyme target-basedinhibitors---SUA in the role of improving hypoxia tolerance1. Effect of SUA on the activity of carbonic anhydraseⅡof the miceThe male Kunming mice were randomly divided into11groups (n=8): normalcontrol group, five Carbonic anhydrase groups[12.5,25,50,100and200mg/(kg·d)] andfive SUA groups [12.5,25,50,100and200mg/(kg·d)]；Removed kidney and brain afterfed the mice five days, and then used microplate reader to measure the activity ofcarbonic anhydraseⅡ of the homogenate.Compared with the normal control group, SUA[25,50,100and200mg/(kg·d)]dosegroups can inhibit the activity of carbonic anhydraseⅡin renal (CAⅡ)(P<0.05, P<0.01); SUA[100and200mg/(kg·d)] dose groups significantly inhibited the activity ofcarbonic anhydraseⅡ(CAⅡ) in brain (P <0.05).2. Effect of SUA on urine volume and urine ions in the ratsThe adult Wistar rats were randomly divided into control group and low, mediumand high doses of SUA groups[40,80and160mg/(kg·d)]. After five days continuousadministration, in the condition of the water load,we used the metabolic cage tocollecte urine for six hours, determined the urine's output and used the atomicabsorption photometric to determine the concentration of the Na+, K+in the urine, usedsilver nitrate titration to determine the concentration of the Cl﹣.The medium and highdoses of SUA groups significantly increased urine volume of the rats, compared withthe control group, the differences was significant(P＜0.05,P＜0.01);Compared with thecontrol group, the output of Na+and Cl﹣increased significantly in the medium andhigh doses of SUA groups (P＜0.05,P＜0.01), however the output of K+reducedsignificantly.Ⅳ.The new carbon anhydride enzyme target-based inhibitors---SUA protectsbrain inurry induced by acute hypoxia1. Effect of SUA on the behaviors in open-field test of rats in hypobaric hypoxiaThe adult Wistar rats were randomly divided into normoxic control group,hypoxicgroup and SUA groups[40,80and160mg/(kg·d)]. Exposure them to hypoxic at8000msimulated altitude for12hours, then put all groups in open-field test box(100cm×100cm×50cm), detect the effect on the self-exploratory behavior in acutehypoxia.Compared with the control group, the latency of the hypoxic group's rats inopen-field test box prolonged, times of crossing, rearing and modification were reduced.Compared with the hypoxic group, the behavior of SUA group[40mg/(kg·d)] wassimilar, the behaviors in open-field test of SUA groups[80and160mg/(kg·d)]significantly improved.2. Effect of SUA on the histopathological change of the cerebral cortex induced byhypoxia We did the hematoxylin-eosin staining dyed, acetic acid uranium and folic acid leaddouble dyed, then used light microscopy to observe histopathological change of thecerebral cortex, observed the influence of SUA on brain damage caused by hypoxia.Anatomy observation visible：the gyrus became wide and flat, sulcal becamenarrow and shallow, the cerebral cortex oedema, Ventricle became narrow caused bypressure. We use light microscope to observe major change of the cerebral cortex:nerve cells and perivascular gap obviously widened of the hypoxic group, there wereittle effusion between perivascular clearance. Blood capillary dilate congestion and glialcells oedema, cell swelling the increase in size, cell membrane not clear, pale cytoplasmdyed. SUA treatment group was still visible that glial cells and capillaries's around washalo, but the degree gradually reduced. These results suggested that the rats's cerebralcortex appeared obvious pathological changes of the acute hypoxia model, prophylacticto use SUA can significantly reduced the damage of the cerebral cortex.3. The influence of SUA on the change of cerebral cortex's water content caused byhypoxiaBy using the method of wet weight and dry weight, took each group's righthemisphere cortex, placed in the weighing bottle which had already weighed to weighthe wet eight. Then put it in the110℃thermostatic drying oven for24hours tillconstant weight (the difference of the twice weigh≤0.2mg), weighed the dry eightand then used the Elliot formula to calculate the percentage of water content:water content(%)=(wet weight-dry weight)/wet weight×100%Compared with the normoxic control group, the water content of cerebral cortex ofhypoxic group significantly prolonged(P＜0.01),it illustrated that12hours later in thecondition of Acute hypoxia, the mice appeared obvious brain edema. Compared withthe hypoxic group, after preventive giving SUA,the water content of three dose SUA[40,80,160mg/(kg·d)] groups significantly prolonged(P＜0.01),and close to the normallevel.Conclusion:1. Yushu relief actions shows that large-scale radical plateau will cause higherincidence of acute mountain sickness. air transport and upper respiratory tract infectionwere the main influence factors of AMS's incidence of who rapidly entered the plateau for earthquake relief, so we should prevent in advance and take drug intervention.2. Prophylactic to use SUA for five days, above the doses of6.25(mg·kg-1·d-1)canextend the survival time of mice in the condition of acute hypoxia exposure, thedose-effect relationship is significant, SUA worked better than Acetazolamide, and it is16times than Acetazolamide.3. SUA can significantly inhibit the activity renal carbonic anhydrase Ⅱ (CA Ⅱ),promote the excretion of bicarbonate from urine, thus cause mild metabolic acidosis,and help to reduce the inhibition of pulmonary ventilation caused by respiratoryalkalosis, which arise from excessive ventilation. In addition, SUA can significantlyinhibit the activity of the brain carbonic anhydraseⅡ (CA Ⅱ), this may reduce theformation of cerebrospinal fluid which is related with acute high altitude sickness.4. SUA has a significant diuretic effect, which mechanism is relevant with thecarbonic anhydrase inhibited in the kidney.5. SUA can significantly reduced the cerebral cortex's edema level of the rat in thecondition of acute hypoxia, improve brain function in the special environment ofaltitude acute hypoxia. Its mechanism is relevant with SUA inhibit the generation ofoxygen free radical and improve the activities of antioxidant enzymes. |
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