H(2)O(2)-induced left ventricular dysfunction in isolated working rat hearts is independent of calcium accumulation.
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.
Wang
Lianguo
L
Department of Pharmacology and Cardiovascular Research Group, University of Alberta, Edmonton, AB, Canada.
Lopaschuk
Gary D
GD
Clanachan
Alexander S
AS
D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D052160:Benzothiazoles / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002316:Cardiotonic Agents / Q000494:pharmacology; D003064:Cnidarian Venoms / Q000494:pharmacology; D006861:Hydrogen Peroxide / Q000494:pharmacology*; D017136:Ion Transport / Q000187:drug effects; D008012:Lidocaine / Q000494:pharmacology; D008297:Male; D015428:Myocardial Reperfusion Injury / Q000378:metabolism / Q000503:physiopathology; D009206:Myocardium / Q000378:metabolism*; D009924:Organ Culture Techniques; D010042:Ouabain / Q000494:pharmacology; D016877:Oxidants / Q000494:pharmacology*; D010880:Piperidines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018487:Ventricular Dysfunction, Left / Q000139:chemically induced* / Q000378:metabolism* / Q000503:physiopathology
D000889:Anti-Arrhythmia Agents; D052160:Benzothiazoles; D002121:Calcium Channel Blockers; D002316:Cardiotonic Agents; D003064:Cnidarian Venoms; D016877:Oxidants; D010880:Piperidines; D010042:Ouabain; C028800:toxin II (Anemonia sulcata); C054551:R 56865; D008012:Lidocaine; D006861:Hydrogen Peroxide; D002118:Calcium