| Objective: The development of medical science, make people realize that oxygen free radical damage and endothelial dysfunction have close relationship with hypertension occurrence, development and prognosis. In the physiological conditions,there is a balance with the generatian and cleaning of reactive oxygen species (ROS), so,they have no effect on organism .The level of ROS accommodated by endogenous oxidativeresistance system, superoxide dismutase(SOD)is one of the important antioxidase.In the state of hypertention, ROS increases,meanwhile SOD decreses. moreover,excessive ROS can attack unsaturated fatty acid in biological membrane, cause lipid peroxidation,produce lipid peroxidation product, Such as malonaldehyde(MDA),so MDA increses。lipid peroxidationproduct enlarge the effet of ROS by chain reactive amplification, thus,The content of MDA often can reflect the lipid peroxidation and oxidatie stress level。Nitric oxide(NO)and Endothelin(ET) are two vascontracting and vasrelaxing factors produced and released from vascular endothelial cell ,they have contrary biological effects.. Normally, they constantly released into the near vascular smooth muscle, adjust the vascular vasomotion state, In order to maintain the stability of the blood pressure and the perfusion of the organization. Hypertension pations often have endothelial injury , it can cause inflammatory cell adhesion, activation and devour reaction, therefore free radicals produced a lot. Oxygen free radicals can damage the endothelial cells, inactivate NO. Also can inhibit endothelialcell synthesis and release NO, cause the synthesis and release of NO relativly shortage, ET increasing。 Oxygen free radical damage and then the formation of endothelial dysfunction play an important role for hypertension and its complications. Therefore,hypertension patients should actively control of blood pressure, attention also should be paid to oxygen free radical scavenging, lipid peroxidation reducing and endothelial function Improving。For the past few years, Some foreign and domestic large clinical trials proved that the Statin drugs(HMG-COA reductase inhibitor) not only have the strong lipid-lowering role, but aslo played a role of antiinflammatory ,anti-oxidation, immunomodulatory, endothelial protecting, anti-thrombosis, stability of patches, protection of cardiac structure and function, etc.This experimentis wanted to observe the relationship of oxygen free radical damage and endothelial dysfunction occurs with hypertension through testing the changes of Superoxide dismutase (SOD), Malonaldehyde(MDA), Nitric oxide(NO), endothelin(ET) and SODmRNA from myocardial structure and blood of spontaneously hypertensive rats(SHR) after application of different doses of Rosuvastatin, so as to investigate its influence and possible mechanism to hypertension oxidatie stress and endothelial function. Namely, Whether Rosuvastatin can play a role of antioxidant and endothelial protection and whether it has ralationship with its dose,and then provide the basis for clinical treatment .Methods: In this study, eight Wistar-Kyoto rats(WKY)were designated as normal control group(group N), and thirty-two SHR rats were randomly divided into four groups, which were designated as rosuvastatin 3.125mg/(kg.d)group (group T1), rosuvastatin 6.25 mg/ (kg.d) group (group T2), rosuvastatin 12.5 mg/(kg.d)group (group T3)and SHR control group (group H).There were eight male rats, which were clean, aged 9-10 weeks and body weight 240-260g in each group. There were no statistically difference in weight and SHR division between the groups(p>0.05). After two week's free-running period in natural light-dark cycles, they were housed at 22±2℃and free access to food and water. The blood pressure was measured by means of a noninvasive tail-cuff method before and after the four weeks treatment. SHR in group T1 were treated with rosuvastatin3.125mg/(kg.d), group T2 with rosuvastatin 6.25 mg/(kg.d), group T3 with rosuvastatin 12.5 mg(/kg.d). And the control groups which were group N and H were given the same volume of tap water. Each group was maintained in its respective feeding scheme for 4 weeks before the experiment. Animal experiments were conducted in accordance with guidelines of Hebei Geriatric Institute.For the determination of levels of SOD, MDA, NO and ET in rats myocardial tissue and blood, rats were sacrificed by operating on chest, and the levels of SOD, MDA, No from blood and myocardial tissue were measured by colorimetry,the level of ET from blood was measured by radioimmunoassay method, the level of ET from myocardial tissue was measured by Immunohistochemical method, SODmRNA was measured by PCR . All numerical data were presented with mean±standard deviation( x±s). SPSS11.5 statistics analysis software was used. Test of normality and homogeneity test for variance were performed firstly, then one-way analysis of variance was carried out, LSD-t test was used to compare differences among groups. P<0.05 was thought of statistical significance.Results: 1 The activity of SOD form blood was significantly lower in group H(160.24±1.75)than that in group N(188.80±1.11)(p<0.05)and that in group T1(170.02±2.58),group T2(179.37±1.01), group T3(187.19±0.49)(p<0.05). There were significantly difference among the treated groups(p<0.05).2 The level of MDA from blood was significantly higher in group H(8.35±0.09)than that in group N(6.23±0.06)(p<0.05)and that in group T1(7.78±0.08), group T2(7.21±0.07), group T3(6.82±0.11)(p<0.05). There were significantly difference among the treated groups(p<0.05).3 The level of NO from blood was significantly lower in group H(25.36±0.66)than that in group N(46.52±0.68)(p<0.05)and that in group T1(31.47±0.44), group T2(35.47±0.43), group T3(41.28±0.52)(p<0.05). There were significantly difference among the treated groups(p<0.05). 4 The level of ET-1 from blood was significantly higher in group H(89.83±0.96)than that in group N(64.10±0.41)(p<0.05)and that in group T1(81.28±0.57), group T2(76.28±0.52), group T3(70.63±0.60)(p<0.05). There were significantly difference among the treated groups(p<0.05).5 The activity of SOD form myocardial tissue was significantly lower in group H(90.72±3.86)than that in group N(132.61±3.29)(p<0.05)and that in group T1(99.13±4.54), group T2(108.83±4.12), group T3(125.71±3.79)(p<0.05). There were significantly difference among the treated groups(p<0.05).6 The level of MDA form myocardial tissue was significantly higher in group H(2.37±0.21) than that in group N(1.59±0.20)(p<0.05)and that in group T1(2.06±0.15), group T2(1.82±0.19), group T3(1.67±0.15)(p<0.05). There were significantly difference among the treated groups(p<0.05).7 The level of NO form myocardial tissue was significantly lower in group H(0.47±0.06)than that in group N(0.72±0.06) (p<0.05)and that in group T1(0.52±0.05), group T2(0.61±0.02), group T3(0.71±0.05)(p<0.05). There were significantly difference among the treated groups(p<0.05).8 It was shown that ET-1 antibody mainly existed in cytoplasm of myocardial tissue of rats according to immunohistochemical technique. The level of ET-1 was significantly higher in group H(7.69±0.18) than that in group N(1.61±0.06)(p<0.05) and that in group T1(4.74±0.13), group T2(4.04±0.20), group T3(3.54±0.17)(p<0.05). There were significantly difference among the treated groups(p<0.05).9 The result of Polymerase Chain Reaction show that the expression of SODmRNA was significantly lower in group H(0.58±0.04) than that in group N(0.77±0.06)(p<0.05)and that in group T1(0.91±0.03), group T2(1.11±0.02), group T3 (1.33±0.02)(p<0.05). There were significantly difference and the expression of SODmRNA was gradually increasing among the treated groups (p<0.05).10 Systolic blood pressure(SBP) of group H(148.45±5.33)was significantly higher than that of group N (108.07±2.11)before the treatment with rosuvastatin. SBP of group T1,group T2,group T3 were (145.43±5.48),(143.22±4.90)and(148.82±5.82), higher than that of normal control group(p<0.05), but there were not significantly difference among the groups of SHR, as well as in each other group. After the four week treatment with rosuvastatin, SBP of group H,group N,group T1,group T2,group T3 were(109.23±2.41),(152.88±3.59),(143.15±5.13),(140.70±4.72),(143.63±6.06) ,compared to the SBP of before rosuvastatin i ntervention:There was a modest decrease in the SBP of group H and group N ,but there was no significant statistically difference (p>0.05);the SBP of group T1,group T2,group T3 all decreased ,but the decreas of group T1 has no significant statistically difference(p>0.05),and the decreas of group T2,group T3 has significant statistically difference(p<0.05).Conclusions: 1 In this experiment,we tested the index of oxidative stress and vascular endothelial dysfunction of SHR rats. The results showed that the level of oxidative stress is enhanced and the vascular endothelial dysfunction is impaired in SHR rats. Vascular endothelial dysfunction was concerning to peroxide increased, antioxidant activity weakened, and oxidative stress enhanced, which suggested that endothelial dysfunction caused by oxidative stress response was at least in part involved in the occurrence and development of hypertension. 2 Rosuvastatin significantly decrease the ET, MDA levels and increase the NO, SOD levels in the myocardial tissue of SHR rats, which suggestes that rosuvastatin could improve endothelial function in patients with hypertension. This effect may be related to reducing reactive oxygen species in vivo by rosuvastatin.3. The Expression of mRNA increased after rosuvastatin intervention,it showed that the inducement of SOD occurred at the level of genetic transcription and translation .generally speaking,the promoter of SOD gene was not completiy open,when induced by drug,SOD gene promoter opened completly,thus the expression increased,So the activity of SOD enhanced.4. Rosuvastatin could lower blood pressure in SHR rats,the mechanism was it can reduce reactive oxygen species and improve endothelial function.5. Different doses of rosuvastatin may have different effects, which suggest that its pharmacological effects are dose-dependent. |
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