The Study On Mechanism Of Rat Hypertension Induced By Intermittent Hypoxia Of Sleep Apnea Mode

Objective:Clinical study found that obstructive sleep apnea syndrome (OSAS) is an independent risk factor of hypertension, epidemiological survey found that 40% of OSAS patients were hypertension, while 30-40% of hypertensive patients had OSAS, there were high rates coexistence between the two diseases. The reason that OSAS causes hypertension is not clear so far, clinical studies found that OSAS patients and with high sympathetic activity (SNA) compared with normal and with abnormal metabolism of vasoactive substances, so these two conditions may be closely related to the incidence of hypertension in OSAS, At the same time, different degrees OSAS patients during course of hypertension also had different results. So we observed changes in blood pressure, serum vasoactive substances, catecholamines after rats were exposed to varying degrees of intermittent hypoxia and in different time periods, in order to explore the possible mechanism of hypertension induced by CIH, and provide effective theoretical basis for clinical treatment of OSAS.Contents:1. To establish intermittent hypoxia and sustained hypoxia rat model2. The research of sympathetic nerve activity and blood pressure in rats which exposed to Sleep apnea model intermittent hypoxia3. The research of vascular endothelial function and blood pressure in rats which exposed to Sleep apnea model intermittent hypoxiaMethods:To determinate required gas flow rate and oxygen concentration of chamber in the process of establishment of model.168 male Wistar rats were randomly divided into untreated group (UD), Severe intermittent hypoxia group (IH1), moderate intermittent hypoxia group (IH2), mild intermittent hypoxia group (IH3), continuous hypoxia group (CH), sham control group (SC) and were exposed to different conditions. UD group before the experiment 8 rats and in each other group 8 rats were randomly selected to end experiment and killed in weeks 2,4,6,8, retained anticoagulated venous blood and centrigugated, then stored plasma at-80℃, systolic arterial pressure (SBP) were observed before and after experiment, plasma norepinephrine(NE), nitric monoxide (NO), endothelial nitric monoxide synthase (eNOS), endothelin-1(ET-1) were measured after experiment.results:The part one:1. According to the method which filled the chamber with nitrogen and oxygen air by cycle, we could periodically change the oxygen concentration in the chamber, at the same time, the change of oxygen concentration in the chamber altered the blood oxygen pressure and oxygen saturation of the rat in chamber. Succesfully simulated different degrees of OSAS patients sleep hypoxia.2. The blood oxygen pressure and oxygen saturation changed with the hypoxia reoxygenation period cycle, the changes of blood oxygen pressure in rat under intermittent hypoxia environment lag the changes of oxygen concentration in chamber for about 10 seconds. In SC group, blood oxygen pressure and oxygen saturation in rats were 96 mmHg-99 mmHg,97%-99%; The lowest arterial oxygen pressure of IH1, IH2, IH3 group were 35.6 mmHg,40.3 mmHg,48.8 mmHg, the lowest oxygen saturation were 60.1%,70.7%,78.8%; In CH group, the arterial oxygen pressure and oxygen saturation in rats were 37.4mmHg 39.6mmHg,64.3%-66.2%.The part two:1. There was no significant difference in the arterial systolic blood pressure (SBP) among every group rats before the experiment. With the experimental time, the SBP of rats in each IH groups increased gradually, was significantly higher than the level before the experiment and the control group (P<0.05 or P<0.01) in weeks 4, and IH3 group significantly higher than IH1 group (P<0.05). To weeks 8, the increased trend of blood pressure slowed down. The SBP of CH group and SC group was no significant difference compared with before the experiment.2. The average weight gain of rats in each IH groups and the CH group at weeks 8were lower than SC group (P<0.05), weight gain of rats in IH1 group was significantly lower than IH2 group and IH3 group (P<0.05). From weeks 6, the ratio of heart weight (THW/TBW) in IH1 group and CH group was significantly higher than the SC group (P<0.01), IH2 group higher than the SC group at weeks 8 (P<0.05).3. The plasma NE of rats in each IH groups increased gradually with experimental time, in weeks 8 significantly higher than the level of weeks 2 and the UD group (P<0.05), but increasing tendency slowed. From week 2, the plasma NE of rats in IH1 group and IH2 group rats was significantly higher than that of SC group (P<0.01), from week 2 IH3 group was significantly higher than IH1 group (P<0.05). Plasma NE of rats in CH and SC group did not change significantly with the experimental time. NE and blood pressure after the experiment was positively correlated (r=0.530, P<0.01).The part three:1. The levels of serum NO, eNOS of rats in IH groups decreased with experiment time, in weeks 8 was significantly lower than the UD group and the level of weeks 2 (P<0.01), in weeks 2,4 significantly lower than SC group and CH group (P<0.05 or P<0.01). In weeks 6,8 CH group less than the SC group (P<0.05 or P<0.01). The levels of serum NO, eNOS in each IH groups were negatively associated with hypoxia (P<0.05 or P<0.01). There was no significant difference in CH group and SC group at each time point.2. The levels of serum ET-1 in IH groups increased with the experiment time, in weeks 8 was significantly higher than the UD group and the level of weeks 2 (P<0.01), from week 2 each IH groups and CH group were significantly higher than the SC group (P<0.01). Among different degrees IH groups, in weeks 4,6 IH1 group was significantly higher than the other two groups (P<0.05). The serum ET-1 of rats in SC group and CH group at each time point was no significant difference3. ET-1 was positively correlated with blood pressure after the experiment (r=0.615, P<0.01), NO, eNOS and was negatively correlated with blood pressure after the experiment (r=-0.519. P<0.01; r=-0.548, P<0.01).conclusion:1. Intermittent hypoxia of sleep apnea rat model can simulate different degrees sleep hypoxia of OSAS patients, while building a model of continuous hypoxia as a control, to find out the difference of mechanisms between intermittent hypoxia and sustained hypoxia.2. The study found that blood pressure and sympathetic nerve activity increased in rats under the chronic intermittent hypoxia and this effect has the degree of hypoxia and hypoxia time-dependent。3. The role of chronic intermittent hypoxia can cause the damage of endothelium, which also has a low oxygen level of damage and hypoxia time-dependent.4. Enhanced sympathetic nerve activity and vascular endothelial dysfunction induced by chronic intermittent are two important ways related to elevated blood pressure.