toxin-ii-(anemonia-sulcata) and Ventricular-Dysfunction--Left

Reactive oxygen species (ROS) and intracellular Ca(2+) overload play key roles in myocardial ischemia-reperfusion (IR) injury but the relationships among ROS, Ca(2+) overload and LV mechanical dysfunction remain unclear. We tested the hypothesis that H(2)O(2) impairs LV function by causing Ca(2+) overload by increasing late sodium current (I(Na)), similar to Sea Anemone Toxin II (ATX-II). Diastolic and systolic Ca(2+) concentrations (d[Ca(2+)](i) and s[Ca(2+)](i)) were measured by indo-1 fluorescence simultaneously with LV work in isolated working rat hearts. H(2)O(2) (100 microM, 30 min) increased d[Ca(2+)](i) and s[Ca(2+)](i). LV work increased transiently then declined to 32% of baseline before recovering to 70%. ATX-II (12 nM, 30 min) caused greater increases in d[Ca(2+)](i) and s[Ca(2+)](i). LV work increased transiently before declining gradually to 17%. Ouabain (80 microM) exerted similar effects to ATX-II. Late I(Na) inhibitors, lidocaine (10 microM) or R56865 (2 microM), reduced effects of ATX-II on [Ca(2+)](i) and LV function, but did not alter effects of H(2)O(2). The antioxidant, N-(2-mercaptopropionyl)glycine (MPG, 1 mM) prevented H(2)O(2)-induced LV dysfunction, but did not alter [Ca(2+)](i). Paradoxically, further increases in [Ca(2+)](i) by ATX-II or ouabain, given 10 min after H(2)O(2), improved function. The failure of late I(Na) inhibitors to prevent H(2)O(2)-induced LV dysfunction, and the ability of MPG to prevent H(2)O(2)-induced LV dysfunction independent of changes in [Ca(2+)](i) indicate that impaired contractility is not due to Ca(2+) overload. The ability of further increases in [Ca(2+)](i) to reverse H(2)O(2)-induced LV dysfunction suggests that Ca(2+) desensitization is the predominant mechanism of ROS-induced contractile dysfunction.

Topics: Animals; Anti-Arrhythmia Agents; Benzothiazoles; Calcium; Calcium Channel Blockers; Cardiotonic Agents; Cnidarian Venoms; Hydrogen Peroxide; Ion Transport; Lidocaine; Male; Myocardial Reperfusion Injury; Myocardium; Organ Culture Techniques; Ouabain; Oxidants; Piperidines; Rats; Rats, Sprague-Dawley; Ventricular Dysfunction, Left