| ObjectiveHypertension is one of the major diseases that endanger human life. The ultimate goal of the treatment is protecting the target organs effectively and reducing the mortality rate and disability rate. Although the efficiency of antihypertensive by Western medicine is fast, there may be many adverse reactions. Moreover, the effect of protecting the target organs by Western medicine is not good. Traditional Chinese medicine (TCM) has characteristics of multi-channel, multi-link and multi-target in treating hypertension and its price is relatively low. In addition, it has little or no adverse reaction. Therefore, the development of proprietary Chinese medicines is of great significance in developing TCM resources and promoting modernization of TCM, especially for the pharmacological research on the active ingredients and mechanism of action.The primary purpose of this paper is to do a pharmacological research on the Xuechangning sugar free granule based on previous studies. Xuechangning sugar free granule is a new proprietary Chinese medicine that has been developed according to my instructor's clinical prescription named "regulating the function of liver and kidney while removing phlegm and blood stasis". We discuss its Anti-hypertension mechanism from different aspects such as left ventricular remodeling, vascular remodeling and vascular endothelial function, to provide some new ideas in the prevention and treatment of hypertension in clinical practices.Methods1. Xuechangning sugar free granule Radix rehmanniae preparata25g,carapax et plastrum testudins3g, radix salviae miltiorrhizae15g, fructus trichosanthis12g, radix notoginseng5g, ramulus uncariae cum uncis12g. Raw-material medicine mixed according to recipe portion after a second dry(Break carapax et plastrum testudins into pieces, fore-decoct30min, and ramulus uncariae cum uncis post-decoct for5min). Add distilled water to soak overnight at air temperature, reflux extraction. Then mixed and concentrated all filtrate, to prepare the extract (containing raw medicine1g per ml), refrigerated ready to use.2. The animals and groupsThe animals used in this experiment are two kinds of rat models:the spontaneously hypertensive rats (SHR) model and "two kidney-one clip" renal hypertensive rats (RHR) model.(1) RHR are divided into five groups according to the random number table:Sham operation group, Model group, High-dosage of Xuechangnin group, Low-dosage of Xuechangnin group, Losartan group (n=10).(2) SHR are divided into four groups according to the random number table:Model group, High-dosage of Xuechangnin group, Low-dosage of Xuechangnin group, Losartan group (n=10). In addition, there is a control group of10normal SD rats.3. Administration method(1) The model rats started administration from the first five weeks after model establishment. The dose of medicine was clinical equivalent dose. High-dosage of Xuechangnin group was supplied with20g raw medicine/kg/d; Low-dosage of Xuechangnin group was supplied with lOg raw medicine/kg/d; losartan group was supplied with30mg/kg/d, administration volumes were all1ml/100g. The sham operation group and model group were both supplied with1ml/100g distilled water. Administered once AM per day for five continuous weeks. During the experiment, the rats in each group were supplied with standard feed and with free access to water.(2) SHR was administrated at the tenth week. The way of delivery and feeding was the same as the corresponding groups of RHR, and the control group was same with the sham group.4. Research contentsThe research includes five parts:①The improvement and evaluation in method of renal hypertensive model rats;②The effects of Xuechangning on blood pressure and the contents of NO and AngⅡ in serum of two model rats;③The effects of Xuechangning on the morphology in target organs of two model rats, such as heart, kidney and aorta. We observed morphological changes of the heart, aorta and kidney by light microscope and observed the ultrastructure of the aorta and kidney by electron microscopy. Meanwhile, we measured the left ventricular mass and artery intima-media wall thickness;④The protein production of bFGF and OPN in the aortic tissue of two model rats were detected by immunohistochemical, while the mRNA expression of bFGF and OPN were detected by RT-PCR;⑤The protein production of ACE2in the myocardial tissue of two model rats were detected by immunohistochemical, while the mRNA expression of AT1R AT2R and ACE2were detected by RT-PCR.Results1. Compared with sham operation group, systolic blood pressure of model group began to increase on the3rd day after building the models, and then significantly increased on the7th day. And hypertension has been initially formed on the14th day; there were significant differences compared with sham operation group (P<0.05).2. In the RHR model, the antihypertensive effect on high-dosage of Xuechangnin group was equal to the effect of the losartan group after fifth week's treatment; they are both better than the low-dosage of Xuechangnin group. Meanwhile, the blood pressure of losartan group is lower than high-dosage of Xuechangnin group in each of the other time points. In addition high-dosage of Xuechangnin group is better than the low-dosage of Xuechangnin group in reducing serum AngⅡ content. Meanwhile, losartan group increased serum AngⅡ content. High-dosage of Xuechangnin group was equal to losartan group in increasing serum NO content; they are both better than the low-dosage of Xuechangnin group; In the SHR model, the antihypertensive effect on high-dosage of Xuechangnin group is equal to losartan group after fifth weeks treatment, are both better than the low-dosage of Xuechangnin group. Meanwhile, the blood pressure of losartan group is lower than high-dosage of Xuechangnin group in each of the other time points. High-dosage of Xuechangnin group is best in reducing serum AngⅡcontent. In addition, high-dosage of Xuechangnin group has a significant effect on increasing serum NO, bettei than low-dosage of Xuechangnin group and losartan group.3. We obtained consistent results in the two models:the role of reducing LVMI, MT, and VFC and inhibiting morphological change of the heart and aorta are considerable in high-dosage of Xuechangnin group and losartan group, and both better than the low-dosage of Xuechangnin group; In addition, high-dosage of Xuechangnin group and low-dosage of Xuechangnin group had a certain protective effect on the kidney, While losartan group had a relatively poor protective effect on the kidney.4. The result suggests that RHR groups are consistent with that of SHR groups in reducing the protein production of bFGF and OPN and their mRNA expression in the aortic tissue. We found that high-dosage of Xuechangnin group is superior to low-dosage of Xuechangnin group and losartan group. While the role of the losartan group is unstable, sometimes equal to the high-dosage of Xuechangnin group, sometimes equal to the low-dosage of Xuechangnin group.5. The result shows that RHR groups are equal to that of SHR groups in increasing protein production of ACE2and AT2RmRNA expression in the myocardial tissue. We found that the effects are considerable in high-dosage of Xuechangnin group and losartan group, they are both better than low-dosage of Xuechangnin group and close to the normal control group; while the role of reducing ATlRmRNA expression in Losartan group is better than high-dosage of Xuechangnin group and low-dosage of Xuechangnin group; Besides, the results show that RHR groups are equal to that of SHR groups in ACE2mRNA expression. In the RHR model, we found that high-dosage of Xuechangnin group and losartan group both can increase ACE2mRNA expression of the myocardial tissue, but the losartan group is better; in the SHR model, we found that high-dosage of Xuechangnin group can increase ACE2mRNA expression of the myocardial tissue significantly, and is better than the losartan group and the low-dosage of Xuechangnin group, while the latter two effects are relatively poor.Conclusion1. Xuechangning has a significant effect on reducing blood pressure of the two models. The blood pressure of rats showed a slow but continued decreasing tendency in the whole period of experiment. Although the effect of antihypertensive is not as good as losartan, it shows advantages of TCM in reducing the blood pressure slowly, steadily and continuously;2. Xuechangning can reduce the contents of Angll in serum of two model rats, while increase the contents of NO in serum of two model rats. So it can improve the endothelial function; 3. Xuechangning can reduce LVMI, increase protein production of ACE2and expression of ACE2mRNA and AT2RmRNA in the myocardial tissue, while reducing the expression of ATlRmRNA. Morphological observation of myocardial tissue showed that Xuechangning can significantly improve morphological features of the heart of the two models. It is illustrated that Xuechangning can improved ventricular remodeling significantly, thus inhibiting the damage of this target organ;4. Xuechangning can significantly reduce Mt and VFC in thoracic aorta wall of RHR and SHR, reduce the protein production of bFGF and OPN and their mRNA expression in the aortic tissue, and significantly improve morphological manifestations of the aorta. It is illustrated that Xuechangning can improved arterial vascular remodeling obviously, thus inhibiting the damage of this target organ;5. Xuechangning can significantly improve the kidney morphologic features of the two models, thus inhibiting the damage of this target organ;6. Generally speaking, we obtained consistent results in the two models: the high-dosage of Xuechangnin group excels the low one. The effect on protecting the target organ of Xuechangning is superior to that of losartan.
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