Effects of endotoxin on human myocardial contractility involvement of nitric oxide and peroxynitrite

Flesch, Markus; Kilter, Heiko; Cremers, Bodo; Laufs, Ulrich; Südkamp, Michael; Ortmann, Monika; Müller, Frank; Böhm, Michael

doi:10.1016/s0735-1097(98)00660-3

Cited by 69 publications

(44 citation statements)

References 33 publications

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“…This may be important in humans with cardiac diseases, such as congestive heart failure or inflammatory heart disease, that are associated with pathological NO generation through increased NOS expression in cardiac myocytes. 25,26 In addition, the cardio-adaptive effects of high NO levels may also relate to the inhibition of mitochondrial oxygen consumption and glucose uptake in cardiac myocytes. 27 The similar positive inotropic effect of NE, as well as the similar antiadrenergic effect of ACh, in WT and TG hearts suggests that receptor-effector coupling was unaffected by NO and that the cellular effects of NO mainly relate to the desensitization of the myofilaments.…”

Section: Discussionmentioning

confidence: 99%

Myocardial Contractile Function and Heart Rate in Mice With Myocyte-Specific Overexpression of Endothelial Nitric Oxide Synthase

et al. 2001

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Background-The major source of nitric oxide (NO) in the heart is the constitutive form of NO synthases (eNOS, NOS III) that is expressed in vascular endothelium and cardiac myocytes. NO mediates endothelium-dependent vasodilation and may modulate cardiac function. We examined the role of NO in hearts from transgenic (TG) mice overexpressing eNOS exclusively in cardiac myocytes. Methods and Results-Three independent TG lines with varying levels of NOS activity were selected, and the hearts were isolated and retrogradely perfused at constant flow. We found that NO is positively inotropic in spontaneously beating hearts from wild-type (WT) mice, whereas hearts overexpressing eNOS had reduced basal contractility that was partially reversed by NOS blockade. Heart rate was not altered. Acetylcholine (10 to 1000 nmol/L) increased contractility in unstimulated hearts and decreased contractility after ␤-adrenergic stimulation with norepinephrine, and these responses were identical in WT and TG hearts. Finally, resting systolic intracellular calcium (Ca

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Section: Discussionmentioning

confidence: 99%

Myocardial Contractile Function and Heart Rate in Mice With Myocyte-Specific Overexpression of Endothelial Nitric Oxide Synthase

et al. 2001

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“…The role of peroxynitrite in activating AR in the ischemic heart is not surprising. Despite being considered a harmful byproduct of the reaction between NO and superoxide causing tissue injury under a variety of pathological conditions (51) such as heart failure (52), sudden cardiac death (53), and the depression of myocardial contractility due to endotoxin (54) or overproduction of cytokines (35), emerging evidence suggests the possibility that at low levels peroxynitrite could have a signaling role. For instance, stimulation of sarco/endoplasmic reticulum Ca 2ϩ -ATPase by NO during arterial relaxation has recently been shown to be mediated by peroxynitrite-induced glutathiolation (55).…”

Section: Figure 5 Inhibition Of Ar Exacerbates Ischemic Injurymentioning

confidence: 99%

Role of Nitric Oxide in Regulating Aldose Reductase Activation in the Ischemic Heart

Kaiserová

Tang

Srivastava

et al. 2008

Journal of Biological Chemistry

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Aldose reductase (AR) catalyzes the reduction of several aldehydes ranging from lipid peroxidation products to glucose. The activity of AR is increased in the ischemic heart due to oxidation of its cysteine residues, but the underlying mechanisms remain unclear. To examine signaling mechanisms regulating AR activation, we studied the role of nitric oxide (NO). Treatment with the NO synthase (NOS) inhibitor, N-nitro-L-arginine methyl ester prevented ischemia-induced AR activation and myocardial sorbitol accumulation in rat hearts subjected to global ischemia ex vivo or coronary ligation in situ, whereas inhibition of inducible NOS and neuronal NOS had no effect. Activation of AR in the ischemic heart was abolished by pretreatment with peroxynitrite scavengers hesperetin or 5, 10, 15, 20-tetrakis-[4-sulfonatophenyl]-porphyrinato-iron [III]. Site-directed mutagenesis and electrospray ionization mass spectrometry analyses showed that Cys-298 of AR was readily oxidized to sulfenic acid by peroxynitrite. Treatment with bradykinin and insulin led to a phosphatidylinositol 3-kinase (PI3K)-dependent increase in the phosphorylation of endothelial NOS at Ser-1177 and, even in the absence of ischemia, was sufficient in activating AR. Activation of AR by bradykinin and insulin was reversed upon reduction with dithiothreitol or by inhibiting NOS or PI3K. Treatment with AR inhibitors sorbinil or tolrestat reduced post-ischemic recovery in the rat hearts subjected to global ischemia and increased the infarct size when given before ischemia or upon reperfusion. These results suggest that AR is a cardioprotective protein and that its activation in the ischemic heart is due to peroxynitrite-mediated oxidation of Cys-298 to sulfenic acid via the PI3K/Akt/endothelial NOS pathway.Aldose reductase (AR 2 ; EC 1.1.1.21) is a member of the aldoketo reductase (AKR) superfamily (AKR1B1). It catalyzes the reduction of a broad spectrum of substrates that range from simple aromatic aldehydes and steroid carbonyls to aldo-keto sugars (1, 2). The wide substrate specificity of AR suggests that the enzyme may be involved in detoxification of endogenous and xenobiotic aldehydes. Our studies show that AR displays highest catalytic efficiency with aldehydes derived from phospholipid oxidation (3). Both free aldehydes, such as 4-hydroxytrans-2-nonenal, and phospholipid-bound aldehydes, such as 1-palmitoyl-2-oxo-valeroyl-phosphatidylcholine, are high affinity substrates of the enzyme (4, 5). In addition, AR is also capable of catalyzing the reduction of glutathione conjugates of unsaturated aldehydes (6, 7). In case of short-chain aldehydes such as acrolein or crotonaldehyde, catalytic efficiency of AR is severalfold higher with the glutathione conjugate than with the parent aldehyde (7). Consistent with its antioxidant role, AR is up-regulated under conditions of oxidative stress (2), such as vascular inflammation (8), heart failure (9), and ischemic preconditioning in rabbit (10) and rat (11) hearts. Nevertheless, the functional significance of AR u...

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“…30,31 iNOS expression has been reported in cardiac myocytes from various human heart failure phenotypes. 6,32,33 In fact, there is a significant correlation between heart failure severity and NO production.…”

Section: No and Human Heart Failurementioning

confidence: 99%

Expression of Inducible Nitric Oxide Synthase Depresses β-Adrenergic–Stimulated Calcium Release From the Sarcoplasmic Reticulum in Intact Ventricular Myocytes

2001

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Background-␤-Adrenergic hyporesponsiveness in many cardiomyopathies is linked to expression of inducible nitric oxide synthase (iNOS) and increased production of NO. The purpose of this study was to examine whether iNOS expression alters the function of the sarcoplasmic reticulum (SR) Ca 2ϩ release channel (ryanodine receptor, RyR) during ␤-adrenergic stimulation. Methods and Results-Expression of iNOS was induced by lipopolysaccharide (LPS) injection (10 mg/kg) 6 hours before rat myocyte isolation. Confocal microscopy (fluo-3) was used to measure Ca 2ϩ spark frequency (CaSpF, reflecting resting RyR openings) and Ca 2ϩ transients. CaSpF was greatly increased by the adenylate cyclase activator forskolin (100 nmol/L) in normal myocytes (iNOS not expressed), but this effect was suppressed (by 77%) in LPS myocytes (iNOS expressed). When NO production by iNOS was inhibited by aminoguanidine (1 mmol/L), there was a further increase in the forskolin-induced CaSpF in LPS myocytes (to levels similar to the forskolin-stimulated CaSpF in normal myocytes). This effect was also seen in myocytes isolated from a failing human heart. There was no effect of aminoguanidine on forskolin-stimulated CaSpF in normal myocytes. ODQ (10 mol/L), an inhibitor of NO stimulation of guanylate cyclase, did not restore the forskolin-induced rise in CaSpF in LPS myocytes. Aminoguanidine also increased twitch Ca 2ϩ transient amplitude in LPS myocytes after forskolin application (independent of changes in SR Ca 2ϩ load). Conclusions-iNOS/NO depresses ␤-adrenergic-stimulated RyR function through a cGMP-independent pathway (eg, NO-and/or peroxynitrite-dependent redox modification). This mechanism limits ␤-adrenergic responsiveness and may be an important signaling pathway in cardiomyopathies, including human heart failure.

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Effects of endotoxin on human myocardial contractility involvement of nitric oxide and peroxynitrite

Cited by 69 publications

References 33 publications

Myocardial Contractile Function and Heart Rate in Mice With Myocyte-Specific Overexpression of Endothelial Nitric Oxide Synthase

Myocardial Contractile Function and Heart Rate in Mice With Myocyte-Specific Overexpression of Endothelial Nitric Oxide Synthase

Role of Nitric Oxide in Regulating Aldose Reductase Activation in the Ischemic Heart

Expression of Inducible Nitric Oxide Synthase Depresses β-Adrenergic–Stimulated Calcium Release From the Sarcoplasmic Reticulum in Intact Ventricular Myocytes

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