Role of oxygen free radicals in hypertension and cardiovascular remodeling of nitric oxide-deficient rats / 中国组织工程研究

ABSTRACT

BACKGROUND: Our previous study showed that the activation of local renin-angiotensin system in heart and vessels contributed to hypertension and cardiovascular remodeling. However, whether oxygen free radical plays an important role in this process is still unclear. OBJECTIVE: To investigate the interventional effects of Ebselen, a kind of anti-oxidative drug, on rats administered by Nw-Nitro-L-arginine methyl easter (L-NAME) (L-NAME), inhibitor of nitric oxide synthase (NOS) for a long term, and probe into the role of oxygen free radicals (OFR) in hyper- tension and cardiovascular remodeling of NO-deficient rats. DESIGN: A randomized grouping and controlled animal trial. SETTING: Department of Cardiology, the Second Affiliated Hospital of Nanchang University, Institute of Cardiology, Nanchang University. MATERIALS: The experiment was completed from January 2002 to March 2003 at the Animal Experimental Lab, Institute of Cardiology, Nanchang University and the Key Molecular Medical Lab of Jiangxi Province. Twenty-four Wistar rats were divided to three groups according to the random number table method: normal control group (n=8), L-NAME group (n=8), L-NAME + Ebselen group (n=8). METHODS: ①Normal control group: The rats could eat and drink routinely, and they were administrated by skim milk ball (net weigh = 4 g) before feed every night. ② L-NAME group: The rats received L-NAME in the dose of 50 mg/kg mixed in one skim milk ball everyday before feed every night. ③ L-NAME + Ebselen group: The rats were admin istered by one skim milk ball (net weigh = 2 g) mixed with L-NAME (50 mg/kg) and one skim milk ball (net weigh = 2 g) mixed with ebselen (30 mg/kg). The systolic blood pressure (SBP) was detected before LNAME was given and at the ends of the 1st, 2nd, 4th,6th and 8th weeks respectively. The rats were killed under anesthesia at the end of the 8th week, the plasma and homogenate of myocardium of apex were taken to detect the biochemical indexes, the other heart tissues were used for the histological detections. MAIN OUTCOME MEASURE: ① Dynamic changes of blood pressure were observed. The levels of NO and malondialdehyde (MDA), activities of angiotensin-converting enzyme (ACE) and superoxide dismutase (SOD) in plasma and myocardium of apex were measured. The production of superoxide anion and the levels of angiotensin Ⅱ type 1 receptor (AT1R) protein expression in myocardium of apex were determined. ③ The pathomor- phological indexes were determined. RESULTS: All the 24 rats were involved in the analysis of results without deletion. ① SBP: At the ends of the 1st, 2nd, 4th 6th and 8th weeks, SBP elevated gradually in the L-NAME group, which were significantly higher than those in the control group at the same time (P ＜ 0.05-0.01). At the end of the 8th week, the SBP was significantly lower in the L- NAME + Ebselen group than in the L-NAME group (P ＜ 0.05). ② Bio chemical indexes in plasma and homogenate of myocardium of apex: The NO level and SOD activity in myocardial tissue were significantly lower in the L-NAME group than in the normal control group (P ＜ 0.05-0.01), but significantly higher in the L-NAME + Ebselen group than in the L- NAME group (P ＜ 0.05-0.01). The production of superoxide anion, ACE activity and level of AT1R expression were all significantly higher in the L-NAME group than in the normal control group (P ＜ 0.05), but signifi- cantly lower in the L-NAME + Ebselen group than in the L-NAME group. ③ Pathomorphological indexes: The ratio of cardiac mass to body mass, thickness of left ventricle and ratio of thickness to lumen diameter of small artery were all significantly higher in the L-NAME group and L- NAME + Ebselen group than in the normal control group (P ＜ 0.05-0.01), and the thickness of left ventricle and ratio of thickness to lumen diameter of small artery were significantly lower in the L-NAME + Ebselen group than in the L-NAME group (P ＜ 0.05) CONCLUSION: Ebselen, an anti-oxidative drug, enable to attenuate the development of hypertension and cardiovascular remodeling in NO-deficient rats. By activating renin-angiotensin system (RAS), OFR may accelerate the formation of hypertension and cardiovascular remodeling, and the increased production of OFR may contribute to the development of cardiovascular remodeling. It is indicated that RAS may play an important role in the development of hypertension and cardiovascular remodeling induced by NO-deficiency