Inhibition of Rat Cardiac Muscle Contraction and Mitochondrial Respiration by Endogenous Peroxynitrite Formation During Posthypoxic Reoxygenation

Abstract

Abstract-This study was designed to investigate the potential role of endogenous peroxynitrite (ONOO Ϫ ) formation in the inhibition of cardiac muscle contractility and mitochondrial respiration during posthypoxic reoxygenation. Isometric contraction of isolated rat left ventricular posterior papillary muscle was virtually eliminated at the end of an exposure to 15 minutes of hypoxia and remained 40Ϯ5% depressed an hour after the reintroduction of O 2 . O 2 uptake by rat left ventricular cardiac muscle, measured by a Clark-type O 2 electrode, was also inhibited by 24Ϯ2% at 10 minutes after reoxygenation. The inhibition of contractility and respiration during posthypoxic reoxygenation was markedly attenuated by the NO synthase inhibitor nitro-L-arginine, exogenous superoxide dismutase, and the ONOO Ϫ scavenger urate but not by the hydroxyl radical scavenger mannitol. Generation of ONOO Ϫ with the NO donor S-nitroso-Nacetylpenicillamine (SNAP) plus the superoxide-releasing agent pyrogallol caused an irreversible inhibition of cardiac contractile and respiratory function. Unlike ONOO Ϫ , exogenous (SNAP) and endogenous (bradykinin) sources of NO inhibited contractility in a reversible manner. Under conditions of comparable amounts of respiratory inhibition in unstimulated incubated muscle, the NO-dependent agents and the mitochondrial antagonist NaCN produced a smaller degree of suppression of contractility compared with ONOO Ϫ and posthypoxic reoxygenation. These results are consistent with a contributing role for endogenous ONOO Ϫ formation in the inhibition of cardiac muscle contractility and mitochondrial respiration during posthypoxic reoxygenation. (Circ Res. 1998;82:891-897.)

Molecular mechanisms of TNF-α-induced ceramide formation in human glioma cells:P53-mediated oxidant stress-dependent and -independent pathways

“…In U87-LXSN cells, the depletion of reduced glutathione (GSH) correlated well with the production of O 2 ÀK measured by the fluorescent dye HE, and pretreatment with Tiron prior to TNF-a significantly reduced GSH depletion (Figure 4b). The addition of an O 2 ÀK -releasing agent, pyrogallol, 22,31,32 decreased GSH levels in U-87 MG cells, although this change was prevented to a significant extent by pretreatment with Tiron (data not shown). These results indicate that p53-mediated O 2 ÀK production is responsible for GSH depletion, leading to ceramide formation through N-SMase activation during TNF-a treatment.…”

NADPH oxidase signaling and cardiac myocyte function

“…Multiple mechanisms contribute to myocardial dysfunction including altered excitation-contraction coupling, impaired myofilament calcium responsiveness, mitochondrial dysfunction and energy deficit, extracellular matrix remodeling and the loss of myocytes. A significant body of evidence implicates oxidative stress in the development of contractile dysfunction through one or more of these mechanisms [77], [78], [79], [80], [81], [82], [83] and [84], but the potential role of NADPH oxidase-derived ROS remains to be established.…”

Molecular Events in the Cardiomyopathy of Sepsis

“…The adverse effects of NO might also, in part, be related to interactions between NO and superoxide anions with subsequent production of peroxynitrite. Peroxynitrite, rather than NO per se, has been shown to impair muscle contractility during sepsis by its ability to denature proteins, perturb calcium flux, and depress mitochondrial respiration during experimental sepsis (115,116). In contrast, neutralization of peroxynitrite improved cardiac dysfunction in a rodent model of sepsis (117).…”