Long-term effects of oxypurinol on oxidative modification of actin and myocardial contractility in mice with heart failure / 上海交通大学学报（医学版）

ABSTRACT

Objective To investigate the long-term effects of xanthine oxidase inhibitor,oxypurinol on myocardial contractility of post-ischemic heart failure in mice,and explore the underlying mechanism. Methods One hundred and twenty SV120 mice were randomly assigned into myocardial infarction control group,sham operation group and Oxy treatment group.Post-ischemic heart failure were induced by left anterior descending coronary artery ligation in myocardial infarction control group and Oxy treatment group,and mice in Oxy treatment group and sham operation group were orally administered with 0.5 mmol/L Oxy each day.Nine to eleven months after treatment,echocardiography was performed in all groups.Trabeculae from the right ventricle of mice were dissected for assessment of changes in excitation-contraction coupling.Sarcomere length was measured by laser diffraction.Intracellular free Ca~(2+) concentration([Ca~(2+)]_I)was detected with fluorescent dye Fura-2,which was microinjected iontophoretically into cells. Steady-state force-[Ca~(2+)]_I was achieved by addition of ryanodine and increasing the stimulus frequency to induce tetanization,and the relationship between myocardial contractility and intracellular Ca~(2+) transients was analysed.Besides,Western blotting was performed to determine the oxidation of myofilament proteins. Results Long-term oral administration of oxypurinol significantly improved myocardial contraction function and reduced ventricular wall thickness.Programming of excitation-contraction coupling was significantly improved,and maximal Ca~(2+) activated force(F_(max))in steady-state wag also significantly increased.Western blotting revealed the oxidative modification of actin in mice of Oxy treatment group was significantly inhibited compared with that of myocardial infarction control group. Conclusion Long-term treatment with Oxy improves the cardiac contraction function and boosts the cardiac force dramatically in post-ischemia heart failure.The increase in contraction is the result of increased myofilament Ca~(2+) responsiveness.Thus,antioxidant oxypurinol,by preventing oxidative damage to contractile proteins,can augment contraction with little changes in[Ca~(2+)]_I,represents new class of inotropic agents with advantages of reducing Ca~(2+) overload,and offers new promises in management of heart failure in the future.