Reactive oxygen species (ROS) enhance myocardial ischemia-reperfusion (I/R) injury. Ischemic preconditioning (PC) provides potent cardioprotective effects in I/R. However, it has not been elucidated whether PC diminishes ROS stress in I/R and whether PC protects the myocardium from ROS stress transmurally and homogeneously. Isolated rabbit hearts perfused with Krebs-Henseleit buffer underwent 30 min of ischemia and 60 min of reperfusion. Hemodynamic changes and myocardial damage extent were analyzed in four groups. The control group underwent I/R alone. The H2O2 group underwent I/R with H2O2 infusion (50 microM) in the first minute of reperfusion to enhance oxidative stress. The PC and H2O2+PC groups underwent 5 min of PC before control and H2O2 protocols, respectively. Extracted myocardial DNA was analyzed for 8-hydroxydeoxyguanosine (8-OHdG), an indicator of oxidative DNA damage, with the use of the HPLC-electrochemical detection method. Glutathione peroxidase (GPX) activity and the reduced form of GSH were measured by spectrophotometric assays. The myocardial infarct size was significantly reduced in the PC group (19 +/- 2%) compared with the control group (37 +/- 4%; P < 0.05), particularly in the subendocardium. H2O2 transmurally increased the infarct size by 59 +/- 4% (P < 0.05), which was significantly diminished in the H2O2+PC group (31 +/- 4%; P < 0.01). The GSH levels, but not GPX activity, were well preserved transmurally in protocols with PC. The 8-OHdG levels were significantly decreased in PC and were significantly enhanced in H2O2 (P < 0.01). These changes in oxidative DNA damage were effectively diminished by PC. In conclusion, PC enhanced the scavenging activity of GSH against ROS transmurally, reduced myocardial damage, particularly in the subendocardium, and diminished the transmural difference in myocardial infarct size.

Magnesium administration has an infarct size limiting effect independent of its effects on myocardial oxygen consumption and incidence of arrhythmia in rabbits. The infarct size limiting effect of magnesium is attributable, at least in part, to augmentation of adenosine mechanism.

Reactive oxygen species (ROS) enhance myocardial ischemia-reperfusion (I/R

nervous activation is a crucial compensatory mechanism in heart failure. However, excess catecholamine may induce cardiac dysfunction and ␤-adrenergic desensitization. Although magnesium is known to be a cardioprotective agent, its beneficial effects on acute cardiac dysfunction remain to be elucidated. We examined the effects of magnesium on left ventricular (LV) dysfunction induced by a large dose of isoproterenol in dogs. Sixteen anesthetized dogs underwent a continuous infusion of isoproterenol (1 g ⅐ kg Ϫ1 ⅐ min Ϫ1 ) with or without a magnesium infusion (1 mg ⅐ kg Ϫ1 ⅐ min Ϫ1 ). The dose response to small doses of isoproterenol (0.025-0.2 g ⅐ kg Ϫ1 ⅐ min Ϫ1 ) was tested hourly. A large dose of isoproterenol decreased LV systolic function, increased the time constant of LV isovolumic relaxation, and suppressed the dose response to small doses of isoproterenol in a time-dependent manner. Magnesium significantly attenuated isoproterenol-induced LV systolic and diastolic dysfunction and preserved the dose response to isoproterenol. Serum-ionized calcium significantly decreased with a large dose of isoproterenol but was fully maintained at baseline level with magnesium. A large dose of isoproterenol increased serum lipid peroxide levels and serological markers of myocardial damage, which were significantly suppressed by magnesium. In conclusion, magnesium significantly attenuated excess isoproterenol-induced acute cardiac dysfunction and ␤-adrenergic desensitization. calcium overload; free radical; dog, left ventricular; tau SYMPATHETIC ACTIVATION IS a crucial compensatory mechanism in heart failure, and serum catecholamine levels are an indicator of the clinical severity (8). However, excess catecholamine may actually induce cardiac cell injury, leading to cardiac dysfunction (34). This is one of the rationales for the clinical beneficial effects of ␤-adrenergic receptor blockade on the prognosis and cardiac function in chronic heart failure (7, 13, 27, 32). Excess isoproterenol (ISO), a selective ␤-adrenergic receptor agonist, induces myocardial necrosis and apoptosis, interstitial fibrosis, and left ventricular (LV) hypertrophy and dysfunction (14, 36). The mechanism of cardiac dysfunction induced by excess ISO may be attributed to calcium overload (19) and free radical generation (37). Moreover, excess ISO induces ␤-adrenergic desensitization (18), one of the hallmarks of heart failure, which potentially exacerbates cardiac dysfunction.Magnesium is known as a cardioprotective factor in the treatment of hypertension, ischemic heart disease, and chronic heart failure (2, 21, 38, 43). In experiments on cardiac ischemia-reperfusion, magnesium has been reported to reduce myocardial calcium overload (44), free radical generation (11), and myocardial infarct size (26). High magnesium levels have been reported to suppress ␤-adrenergic desensitization (9). However, the beneficial effects of magnesium in acute heart failure remain to be elucidated.The goal of the present study was to investigate whether magnesium prev...

Nitric oxide (NO) inhalation therapy has been widely used in several diseases with pulmonary hypertension. However, application of NO inhalation therapy remains controversial in heart failure. Cardiovascular effects of inhaled NO (iNO) were evaluated in dogs before and after induction of heart failure with and without infusion of vasoactive agents. iNO did not affect the baseline left ventricular (LV) function or the response to isoproterenol in control conditions or heart failure induced by procainamide. Pulmonary vascular resistance was significantly decreased by iNO in heart failure with infusion of vasoactive agents. Unexpectedly, LV end-diastolic pressure was significantly elevated by iNO in heart failure in the presence of infusion of vasoactive agents independent of their types; either the vasodilating agents of acetylcholine and nitroglycerin or the vasoconstricting agents of norepinephrine and angiotensin-II. The end-diastolic LV dimension and wall stress were also significantly increased by iNO, however, those at end systole were not affected. These results suggested that NO inhalation therapy reduced pulmonary vascular resistance, whereas in the presence of additional stress of vasoactive agents, it increased LV preload and end-diastolic wall stress in heart failure.