Effects of fosinopril,captopril and valsartan on the expressionof tissue factor in human monocytes

AIM: To investigate the effects of angiotensin-converting enzyme inhibitors (ACEI), fosinopril, captopril and angiotensin II AT₁ antagonists, valsartan on tissue factor (TF) expression on monocytes induced by lipopolysaccharide (LPS). METHODS: Mononuclear leukocytes from normal delivered female umbilical veins were incubated with bacterial LPS in presence or absence of different ACE inhibitors .At the end of incubation, the cells were disrupted by 3 freeze-thaw cycles. TF procoagulant activity was assessed by a one-stage clotting assay. RT-PCR was used to check TF mRNA expression, and GAPDH mRNA was used for parallel assay. RESULTS and CONCLUSION: The results showed that increased expression of TF mRNA induced by LPS was inhibited by fosinopril, captopril and valsartan, respectively, and the procoagualant activity of monocytes was also reduced.     

Captopril exerts myocardial protective effect in coronary microembolization rats by inhibiting oxidative stress injury and alleviating inflammatory response

AIM: To investigate the effects of captopril (CAP) on oxidative stress injury and inflammatory response induced by coronary microembolization (CME) and its related molecular mechanisms. METHODS: The rat model of CME was established by clamping the rat artery and injecting blood microemboli. The rats were divided into control group, CME group and CME+CAP group, with 6 rats in each group. The myocardial tissues of each group were collected. The changes of myocardial structure and the degree of inflammatory response were analyzed by HE staining. Cardiomyocyte apoptosis was detected by TUNEL staining. The fluorescence intensity of cleaved caspase-3 was detected by immunofluorescence obervation. The protein levels of cleaved caspase-3 and Bax were determined by Western blot. The activity of superoxide dismutase (SOD) and catalase was measured by ELISA. The production of reactive oxygen species (ROS) was detected by DHE fluorescence staining. RESULTS: CAP significantly reduced the myocardial structural changes (P<0.05), inflammatory cell infiltration (P<0.01), number of apoptotic cardiomyocytes (P<0.01), the protein levels of cleaved caspase-3 and Bax (P<0.01), and ROS production levels (P<0.01), but promoted the activity of antioxidant markers SOD and catalase (P<0.01) in the CME rats.CONCLUSION: CAP attenuates CME-induced myocardial injury by resisting oxidative stress and alleviating inflammatory response.     

Effect of captopril on AGS nude mouse model of gastric cancer

AIM: To observe the effect of captopril on the genesis and development of gastric cancer, and to explore its clinical treatment feasibility for gastric cancer. METHODS: The human gastric cancer cell line AGS was used to establish a tumor model in nude mice, and the model mice were randomly divided into 3 groups: positive control (5-fluorouracil) group, normal control (saline) group and experimental (captopril) group. After intraperitoneal injection or intragastric administration of the drugs, the tumor growth curve was determined, and the tumor tissues were also sampled to detect the expression of Ki-67, STAT3, Bax and Bcl-2 by real-time quantitative PCR and immunohistochemistry. The apoptosis was detected by TUNEL+DAPI staining. RESULTS: The tumor growth curve showed that the tumor model in the nude mice was successfully established. The tumor volumes among groups showed significantly different after 14 d growth. The increase in the tumor volume in normal control group was significantly faster than that in the other two groups, and that in positive control group was the slowest. The expression of Bax in captopril group increased, and the expression of STAT3, Ki-67 and Bcl-2 was reduced as compared with normal control group and positive control group. Compared with normal control group, the apoptotic rate increased significantly, and the protein expression of p-STAT3 and STAT3 decreased obviously in positive control group and captopril group. CONCLUSION: With better feasibility, angiotensin-converting enzyme inhibitor captopril has a significant effect on treating gastric cancer in the AGS nude mouse model by regulating the expression of STAT3, Bax, Bcl-2 and Ki-67 to accelerate the apoptosis of cancer cells, thus inhibiting tumor growth.     

Effect of captopril and betaloc on the changes in expression of MHC of left ventricle in hypertensive rats

AIM:To investigate myosin heavy chain(MHC)gene expression and the effects of captopril and betaloc at an early stage of hypertension. METHODS:Model of hypertension was made by partly narrowing two bilateral renal arteries(2K2C). The rats were divided into four groups at random. (1) control group; (2)2K2C group;(3)captopril group;(4)betaloc group.Levels of α-MHC and β-MHC mRNA were determined by dot-blot. RESULTS:α-MHC mRNA expression were gradual1y reduced in 2K2C group, while β-MHC mRNA expression were increased, and the marked changes were observed at 72h postoperation. Captopril could inhibit the changes in MHC gene expression; but betaloc could not. CONCLUSION: The expression of MHC gene has changed at an early stage of renal hypertensive rat, and renin-angiotensin system may play an important role in this change.     

Expression of TNF-α mRNA in hypertrophic myocardium by pressure overload in rats

AIM: To observe the change of TNF-α mRNA in hypertrophic cardiac myocytes induced by pressure overload in rats and the effect of captopril. METHODS: Serum and heart were collected 42 days after the cardiac hypertrophy model made by pressure overload by abdomen aorta-constriction (AC). Hypertrophic parameter and the concentration of TNF-α in serum and left ventricle were determined by ELISA. TNF-α mRNA in cardiac myocytes was determined by in situ hybridization and analyze by ELIA image analysis system. The orientation of TNF-α mRNA in cardiac myocytes was also observed. RESULTS: Left ventricle hypertrophy was observed 42 days after operation. TNF-α mRNA in AC group elevated 98% compared to sham-operated group and descended 64.14% by captopril (P<0.01), but did not descend to the normal level. The expression of TNF-α mRNA showed mostly in myocardial matrix by in situ hybridization. The level of expression was very low in sham-operation group and markedly enhanced after aorta-constriction, but it was decreased when treated by captopril. CONCLUSION: Endogenous TNF-α acts as an important adjustive factor in the pressure overload-induced cardiac hypertrophy and TNF-α mRNA increased in myocardial matrix may be activated by renin-angiotension system.     

Effects of pretreatment with captopril on the infarct size and myocardial cell apoptosis in experimental rabbits

AIM:To investigate the effects of pretreatment of captopril on the infarct size and myocardial cell apoptosis in rabbits. METHODS:Rabbits were randomly divided into sham-operated control group (SO), acute infarct group (AI) and captopril pretreatment group (CP). The rabbits of CP group were treated with captopril (25 mg·kg^-1.d^-1) for 1 week before harvest. The left circumflex branch of coronary (LCX) was ligated to develop acute ischemic model. The systolic and diastolic function of left ventricle(LV) was measured before and at 15, 30, 60 min after ligating LCX, and the blood viscosity and hematocrit before and at 60 min after ligating LCX were measured also. 6 hours later LCX ligation, the hearts were harvested for determining the infarction size, which was expressed as the ratio of infarct area to the total ischemic area, and evaluating apoptosis index expressed as the percentage of myocardial cells with TUNEL positive staining. RESULTS:1.Compared with AI group, captopril pretreatment significantly reduced the infarction size (16.60%±0.94% vs 36.24%±1.94%, P＜0.05), and improved the LV function and viscosity of blood. 2. Apoptosis of myocardial cell was found in the myocardium surrounding to the infarction area, however, the apoptosis index of CP group was significantly lower than that of AI group (26.30%±0.71% vs 42.44%±2.32%,P＜0.05).CONCLUSION:Apoptosis of myocardial cell exists in the area surrounding the infarction. Captopril pretreatment can reduce infarction size and myocardial apoptosis index, and improve the LV function as well as blood viscosity in this acute ischemic model.     

Comparison of Some Pharmacokinetic Parameters of 5 Angiotensin-Converting Enzyme Inhibitors in Normal Beagles

This study was designed to determine the degree of inhibition of the angiotensin-converting enzyme (ACE) in 5 normal dogs given single doses of conventionally used ACE inhibitors (ACEis). In addition the time required for that inhibition to return to 50% of the difference between maximum and zero (control values) was measured as an estimate of duration of action. The 5 ACEis (with dosages given in parentheses) were bena/april (0.5 mg/kg), captopril (2.0 mg/kg), enalapril (0.5 mg/kg), lisinopril (0.5 mg/kg), and ramipril (0.25 mg/kg). Blood samples for ACE activities were obtained before dosing and at 1.5, 3.0, 6.0, 12.0, and 24.0 hours after dosing. All ACEis except captopril decreased ACE activities to approximately 25% of control by the 1.5-to 3.0-hour sample, and ACE activities returned to 50% of the difference by the 12-hour sample. The value of ACE activity returned to normal by 24 hours for benazapril, whereas values for ACE activity remained below normal for enalapril, lisinopril, and ramipril at 24 hours. For captopril, however, ACE levels decreased to approximately 80% of control by the 1.5-hour recording, and returned to levels not different from control by the 3-hour recording. Based upon this study performed on normal dogs given a single dose, no pharmacokinctic advantage or disadvantage is apparent for any ACEi except captopril, which, at the dosage used, decreased ACE levels to a much lesser degree and shorter time.     

The protective effects of angiotensin Ⅱ receptor blocker irbesartan on kidney function in diabetic rats

AIM: To investigate the effects and mechanisms of irbesartan, one of the angiotensin Ⅱreceptor blockers, on kidney function in diabetic rats. METHODS: Forty adult male Wistar rats were randomly divided into four groups: control group, diabetes group, irbesartan group and captopril group. At the end of 12 weeks, the rats were sacrificed. Urine volume, body weight, kidney weight/body weight, plasma, glucose, glycosylated hemoglobin (HbA₁c), urinary β₂-microglobulin (β₂-MG) excretion, urinary albumin excretion rate (UAR), creatinine clearance (Ccr) were measured. Nitric oxide (NO) and endothelin-1 (ET-1) levels in plasma, urinary and renal tissues were determined. RESULTS: Urine volume, kidney weight/body weight, plasma glucose, HbA1C, UAR, Ccr, urinary β₂-MG excretion, NO and ET-1 levels of urinary, blood and renal tissue in diabetic rats were significantly higher than those of normal controls ( P<0.01). UAR, Ccr, urinary β₂-MG excretion, ET-1 and NO levels of urinary and renal tissue in rats of irbesartan and captopril groups were significantly lower than those of DM rats ( P<0.01). There were positive relationships among the levels of plasma, urinary, renal tissue ET-1, NO and UAR, Ccr and urinary β₂-MG excretion. CONCLUSION: Irbesartan could prevent from the injury of renal function in STZ-induced diabetic rats. And it maybe one of the most importan mechanisms that irbesartan could reduce the NO and ET-1 levels in STZ-induced diabetic rats.     

卡托普利对肉鸡肺动脉高压和腹水发病率的影响

探讨了卡托普利对肉鸡腹水发病率的影响。结果表明,在28、36和44日龄卡托普利可明显降低肺动脉压(P<0.05);对红细胞压积没有明显作用;腹水发病率卡托普利组低于低温组6个百分点。证实卡托普利对肉鸡腹水发病率具有一定作用。     

Effects of captopril on expression of calcineurin and NF-κB p65 in the heart of hypertensive rats

AIM: To study the effect of captopril on calcineurin and NF-κB p65 in the signal transduction pathway of the cardiovascular remodeling in hypertensive rats. METHODS: Using a animal model of hypertension induced by abdominal aortic banding, the rats were treated with captopril for 10 weeks. The blood pressure was observed with a tail cuff method. The heart weight and heart weight/body weight were measured. The expression of calcineurin and NF-κB p65 were studied by using immunohistochemistry. RESULTS: After treated with captopril, the blood pressure of the model rats was decreased (P<0.01), the heart weight or heart weight/body weight were also decreased (P<0.01). The calcineurin and NF-κB p65 protein overexpression was down-regulated, NF-κB-positive area and area percentage were reduced in the heart of hypertensive rats (P<0.01，P<0.01). CONCLUSION: Captopril reverses the cardiovascular remodeling by affecting the overexpression of calcineurin and NF-κB p65 involved in the cardiovascular remodeling in hypertensive rats.