| Objective:To investigate the effects and mechanisms of Valsartan/hydrochlorothiazide folic acid tablets on hypertension in rats with hyperhomocysteinemia, and provide experimental basis for the further development and clinical application of Valsartan /hydrochlorothiazide folic acid tablets.Methods:170 SD rats, male and female combination,12 were randomly selected as the control group, the rest were copied to renal hypertensive rats model by two-kidney and one-clip (2K1C) surgery,4 to 6 weeks after the operation, measurement of blood pressure, according to blood pressure level (systolic blood pressure,140 mmHg or higher) the rats were randomly divided into 7 groups:model group, valerian hydrochlorothiazide 1 (8+1.25 mg/kg), valerian hydrochlorothiazide 2 group (16+2.5 mg/kg), folic acid group (0.08 mg/kg), valerian hydrochlorothiazide folic acid 1 (8 +1.25+0.04 mg/kg), valerian hydrochlorothiazide folic acid 2 group (8+1.25+0.08 mg/kg), valerian hydrochlorothiazide folic acid 3 group (16+2.5+0.08 mg/kg),12-15 rats of each group. The rats in control group were giving distilled water, others were received 0.5% methionine solution, they were all treated by intragastric administration, 1 times a day. Observe the general conditions of the rats, determine the weight once two weeks, according to the weight adjusting dosage, for 26 consecutive weeks. Blood pressure of each rat was measured successively before and after drug delivery at different time. Four weeks after treatment, rat orbital blood, the level of plasma Homocysteine (Hcy) were measured. In administration of last week, collection of 24h rat urine, the urine volume was recorded, The rat urine creatinine (Ucr),urinary mAlb, and β2-MG were measured. After the last administration, the rats were fasted without water 12 h, the next day, anesthetized with 3.0% chloral hydrate, draw blood from abdominal aortic, determination of serum creatinine (Scr), blood urea nitrogen (BUN), and creatinine clearance (Ccr) were calculated, the concentrations of Hey, thromboxane B2(TXB2),6-ket-prostaglandin F1α(6-K-PGF1α), endothelin (ET), nitric oxide (NO), malondialdehyde(MDA), and the activity of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) in serum were detected. Fixed the right kidney tissue, heart of each rat and brain tissue by 10% neutral folmalin and embedded in paraffin and cut into slices, tissue were stained by HE observating the pathological change.Results:l.The impact on the body weight of rats.Body weight of rats in each group on the rise, after 14 weeks to stabilize, there was no significant difference in body weight between the rats of the same sex.2.The impact on blood pressure, plasma Hey levels of rats.Compared with the normal group, systolic blood pressure and plasma Hey level were significantly elevated (P<0.01) in model group, Compared with the model group, the blood pressure decreased significantly in valerian hydrochlorothiazide groups and valerian hydrochlorothiazide folic acid groups. Compared with the scorresponding valerian hydrochlorothiazide group, the blood pressure were decreased further more in valerian hydrochlorothiazide folic acid group, but no significant difference. The plasma Hcy level was Decreased significantly (P<0.01) in folic acid group and valerian hydrochlorothiazide folic groups, the level was lower than that of folic acid group, but there was no significant difference.3.The impact on renal functionof rats.Compared with the normal group, the Scr, BUN, β2-MG, mAlb was significantly higher, the Ucr, Ccr was significantly lower in model group, Compared with the model group, the Scr, BUN, β2-MG, mAlb was significantly lower, the Ucr, Ccr was significantly higher in valerian hydrochlorothiazide groups. The Scr, BUN, β2-MG, mAlb have a downward in Folic acid grouptrend, Ucr, Ccr tended to increase, but there was no significant difference. Compared with the scorresponding valerian hydrochlorothiazide group, the mAlb were decreased significantly, the Ucr, Ccr was markedly higher in valerian hydrochlorothiazide folic acid 2and 3 group.the Ucr, Ccr has upward trend, mAlb, β2-MG has declined in valerian hydrochlorothiazide folic acid 1 group, but there was no significant difference. Effectively improve renal function.4. The impact on the level of oxidative stress of rats.Compared with the model group, activity of SOD and GSH-Px were significantly increased, MDA significantly decreased in valerian hydrochlorothiazide groups, the MDA significantly decreased in folic acid group;Compared with the scorresponding valerian hydrochlorothiazide group, activity of SOD were increased further more and MDA further decline in valerian hydrochlorothiazide folic acid groups (P<0.05). Oxidative stress level has been effectively controlled.5. The impact on endothelial and coagulation status of rats.Compared with the normal group,6-K-PGF1α, NO reduced markedly, TXB2, ET increased remarkably in the model group. Compared with the model group,6-K-PGF1α, NO increased remarkably, TXB2, ET reduced markedly in valerian hydrochlorothiazide groups,6-K-PGF1α increased significantly, TXB2 decreased, NO on upward trend, ET on downward trend in folic acid group, but there was no significant difference. Compared with the scorresponding valerian hydrochlorothiazide group,6-K-PGF1α, NO increased remarkably, ET reduced markedly, TXB2 on downward trends in valerian hydrochlorothiazide folic acid 2 and 3 group; 6-K-PGF1α, NO on upward trend, ET, TXB2 on downward trend in valerian hydrochlorothiazide folic acid 1 group, but the difference was not statistically significant. Endothelial and coagulation status improved.6. The impact on heart, kidney and brain histopathology of rats.Compared with the normal group, glomerular volume increased significantly, the number of cells increased, GBM irregular thickening, of the small arteries arteriosclerosis, inflammatory cell infiltration. Cardiomyocytes thicker and longer, nuclei hypertrophy, fibers break, the heart wall thickening, myocardial fibrosis in the model. Compared with the model group, GBM were lower, mesangial matrix were decreased, ventricular wall thickness were alleviated in valerian hydrochlorothiazide groups; mesangial cell proliferation were lower, part of the rat cardiomyocytes hypertrophy, myocardial fibrosis mitigated in folic acid group; Compared with the valerian hydrochlorothiazide, glomerular and tubular structures become normal. There were no obvious thickening and hypertrophy of myocardial cell, no significant muscle fiber thickening, nuclear morphology were normal. In each drug treatment groups, the brain pathology have no significant change.Illustrate as the experiment progresses, significantly brain tissue damage does not appear in hypertension rats with hyperhomocysteinemia. After combination therapy, the heart and kidney pathology improved in hypertension rats with hyperhomocysteinemia, the degree of target organ damage mitigation.Conclusion:Valsartan/hydrochlorothiazide folic acid tablets on hypertension in rats with hyperhomocysteinemia have significant antihypertensive effect, Can reduce homocysteine level, significantly improve the heart, kidney pathology, reduce the degree of target organ damage, superior to valsartan/hydrochlorothiazide, folic acid alone. Its mechanism may be related to antioxidant effect, improving endothelial cell function, coagulation status. |
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