Effects And Mechanism Of Oxidative Stress Factors On Cardiovascular System

Effects and Mechanism of Oxidative Stress Factors on Cardiovascular SystemIncrease in metal iron and hydrogen peroxide (f^Oj), or ischemia/hypoxia could produce excess of reactive oxygen species. As soon as the product of reactive oxygen species overruns that of the antioxidants, it will cause the injuries in many tissues and cells. This is called oxidative stress in pathophysiology. In recent years, more and more studies have proven that there is a close correlation between these three factors of oxidative stress and cardiovascular diseases. In the present study, we investigated the effect of these oxidative stress factors on cardiovascular system, the cooperation effect between them, and explore the possible mechanism. Meanwhile, the cardioprotection of oxidative stress preconditioning and its post-receptor mechanism were also investigated. These studies will provide the basic knowledge on this field and help finding of pharmacological methods in diagnosis and therapy.Objectives(1) To investigate the effect of iron (including hydrophilic and lipophlic forms) loading on the rat myocardium, and to explore the effect of nitric oxide (NO) on iron-induced toxicity in rat hearts;(2) To study the effect of iron on contractile function of aortic ring, and the role of hydroxyl radical and glutathione in iron-induced vascular contraction dysfunction;(3) To investigate the effects of hydrogen peroxide (H2Oa) on contractile function of myocardium and its mechanism, and the protective effect of lower concentration of H2C>2 against oxidative stress;(4) To explore enhanced injury effect of iron on the myocardium by hydrogen peroxide and the underlying mechanism;(5) To study the intracellular mechanism of hypoxic preconditioning.Methods(1) The left ventricular developed pressure (LVDP), left ventricular end diastolic pressure (LVEDP), 眃P/dtmax, heart rate and coronary flow were recorded in Langendorff perfused rat heart. The concentrations of lactate dehydrogenase (LDH) and creatine kinase (CK) in the coronary effluent, and malondialdehyde (MDA) content in the myocardium were measured.(2) Enzymatically isolated cardiomyocytes were used to determine twitch amplitude and [Ca2+]j with a video microscopic technique and a fluorometric ratio method respectively.(3) The survival rate and LDH release of cultured neonatal rat cardiomyocytes were measured.(4) Arterial vessels from rat thoracic aorta were used to record the isometric force. Vascular response induced by phenylephrine (PE) or iron was expressed as a percentage of the KCl-induced contraction.ResultsParti: Effect of iron loading on isolated rat heart and ventricular cardiomyocyte(1) Hydrophilic FeCl3 decreased the end diastolic cell length and increased thecontractile amplitude and velocity in the ventricular cardiomyocyte. In the isolated heart, it augmented the left ventricular end diastolic pressure (LVEDP) and contractile amplitude and velocity, but FeCb at 5umol/L could reduced the coronary flow. (2) Lipophilic Fe-HQ reduced the contractile amplitude, velocity and end-diastolic cell length in the cardiomyocyte. While the LVDP, 眃P/dtmax, heart rate and coronary flow showed biphasic alterations in isolated perfused rat heart. Only Fe-HQ at 5^unol/L increased the levels of LDH and CK in the coronary effluent, arrhythmia score and MDA content in the myocardium. (3) L-arginine, a NO precursor, reduced the contractile amplitude and end diastolic cell length in the cardiomyocyte, but reversibly increased LVDP, 眃P/dtmax and coronary flow in isolated perfused rat heart. (4) Pretreatment with L-arginine aggravated Fe-HQ (5^imol/L) induced decrease in contractile amplitude and velocity and end-diastolic cell length in the cardiomyocyte. LVDP, 眃P/dtmax, heart rate and coronary flow were significantly reduced, and levels of LDH and CK were increased. (5) NOS inhibitor L-NAME blocked the Fe-HQ-induced changes in contractile amplitude, velocity and end diastolic cell length of the cardiomyocyte, in...