Distribution of Nos Isoforms in a Porcine Endotoxin Shock Model

Doursout, Marie–Françoise; Oguchi, Takeshi; Fischer, Uwe; Liang, Yangyan; Chelly, Brice; Hartley, Craig J.; Chelly, Jacques E.

doi:10.1097/shk.0b013e3181598b77

Cited by 23 publications

(7 citation statements)

References 32 publications

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“…Similar to our results, a stable blood pressure profile of eNOS −/− mice has been described during endotoxemia [7]. Following LPS infusion, a markedly increased myocardial eNOS activity has been demonstrated leading to a decrease in blood pressure after 30 min [10]. Concurrent with stable blood pressure and systemic vascular resistance, NOS3 −/− mice exhibited preserved LVDP, +d P /d t max and −d P /d t min while cardiac function was impaired in septic WT mice already at 6 h after sepsis induction.…”

Section: Discussionsupporting

confidence: 89%

Endothelial NOS (NOS3) impairs myocardial function in developing sepsis

et al. 2013

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Endothelial nitric oxide synthase (NOS)3-derived nitric oxide (NO) modulates inotropic response and diastolic interval for optimal cardiac performance under non-inflammatory conditions. In sepsis, excessive NO production plays a key role in severe hypotension and myocardial dysfunction. We aimed to determine the role of NOS3 on myocardial performance, NO production, and time course of sepsis development. NOS3−/− and C57BL/6 wildtype mice were rendered septic by cecum ligation and puncture (CLP). Cardiac function was analyzed by serial echocardiography, in vivo pressure and isolated heart measurements. Cardiac output (CO) increased to 160 % of baseline at 10 h after sepsis induction followed by a decline to 63 % of baseline after 18 h in wildtype mice. CO was unaltered in septic NOS3−/− mice. Despite the hyperdynamic state, cardiac function and mean arterial pressure were impaired in septic wildtype as early as 6 h post CLP. At 12 h, cardiac function in septic wildtype was refractory to catecholamines in vivo and respective isolated hearts showed impaired pressure development and limited coronary flow reserve. Hemodynamics remained stable in NOS3−/− mice leading to significant survival benefit. Unselective NOS inhibition in septic NOS3−/− mice diminished this survival benefit. Plasma NOx- and local myocardial NOx- and NO levels (via NO spin trapping) demonstrated enhanced NOx- and bioactive NO levels in septic wildtype as compared to NOS3−/− mice. Significant contribution by inducible NOS (NOS2) during this early phase of sepsis was excluded. Our data suggest that NOS3 relevantly contributes to bioactive NO pool in developing sepsis resulting in impaired cardiac contractility.Electronic supplementary materialThe online version of this article (doi:10.1007/s00395-013-0330-8) contains supplementary material, which is available to authorized users.

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Section: Discussionsupporting

confidence: 89%

Endothelial NOS (NOS3) impairs myocardial function in developing sepsis

et al. 2013

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“…For example, iNOS was frequently reported to inhibit the growth of parasites in vitro and in vivo especially in mice. However, despite the observation that nitric oxide is involved in the pathophysiological processes during septic shock and LPS response in pigs [ 37 , 38 ] and that iNOS is upregulated in the central nervous system of swine following infection with pseudorabies [ 39 ], iNOS is not an essential part of the innate immune response in pigs [ 40 ].…”

Section: Discussionmentioning

confidence: 99%

Experimental PorcineToxoplasma gondiiInfection as a Representative Model for Human Toxoplasmosis

Nau

Eller

Wenning

et al. 2017

Mediators of Inflammation

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Porcine infections are currently not the state-of-the-art model to study human diseases. Nevertheless, the course of human and porcine toxoplasmosis is much more comparable than that of human and murine toxoplasmosis. For example, severity of infection, transplacental transmission, and interferon-gamma-induced antiparasitic effector mechanisms are similar in pigs and humans. In addition, the severe immunosuppression during acute infection described in mice does not occur in the experimentally infected ones. Thus, we hypothesise that porcine Toxoplasma gondii infection data are more representative for human toxoplasmosis. We therefore suggest that the animal model chosen must be critically evaluated for its assignability to human diseases.

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“…Phosphorylated eNOS, via the Akt/phosphatidylinositol 3-kinase pathway, is known to regulate enzyme activity (11). Endotoxin challenge involves eNOS activity in its early phase and induces a later increase in iNOS expression (8,10) that can exert a negative feedback on eNOS expression during endotoxemia (6,23). It is well documented that LPS impairs endothelium-dependent relaxation to ACh as well as flow, leading to endothelial dysfunction in both resistance and conductance arteries (6,22).…”

Section: Discussionmentioning

confidence: 99%

Recombinant human activated protein C improves endotoxemia-induced endothelial dysfunction: a blood-free model in isolated mouse arteries

Sennoun¹,

Baron-Menguy²,

Burban³

et al. 2009

American Journal of Physiology-Heart and Circulatory Physiology

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Recombinant human activated protein C (rhAPC) is one of the treatment panels for improving vascular dysfunction in septic patients. In a previous study, we reported that rhAPC treatment in rat endotoxemia improved vascular reactivity, although the mechanisms involved are still under debate. In the present study, we hypothesized that rhAPC may improve arterial dysfunction through its nonanticoagulant properties. Ten hours after injection of LPS in mice (50 mg/kg ip), aortic rings and mesenteric arteries were isolated and incubated with or without rhAPC for 12 h. Aortic rings were mounted in a myograph, after which arterial contractility and endothelium-dependent relaxation were measured in the presence or absence of nitric oxide synthase or cyclooxygenase inhibitors. Flow (shear stress)-mediated dilation with or without the above inhibitors was also measured in mesenteric resistance arteries. Protein expression was assessed by Western blotting. Lipopolysaccharide (LPS) reduced aortic contractility to KCl and phenylephrine as well as dilation to acetylcholine. LPS also reduced flow-mediated dilation in mesenteric arteries. In rhAPC-treated aorta and mesenteric arteries, contractility and endothelial responsiveness to vasodilator drug and shear stress were improved. rhAPC treatment also improved LPS-induced endothelial dysfunction; this effect was associated with an increase in the phosphorylated form of endothelial nitric oxide synthase and protein kinase B as well as cyclooxygenase vasodilatory pathways, thus suggesting that these pathways, together with the decrease in nuclear factor-κB activation and inducible nitric oxide synthase expression in the vascular wall, are implicated in the endothelial effect of rhAPC. In conclusion, ex vivo application of rhAPC improves arterial contractility and endothelial dysfunction resulting from endotoxemia in mice. This finding provides important insights into the mechanism underlying rhAPC-induced improvements on arterial dysfunction during septic shock.

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Distribution of Nos Isoforms in a Porcine Endotoxin Shock Model

Cited by 23 publications

References 32 publications

Endothelial NOS (NOS3) impairs myocardial function in developing sepsis

Endothelial NOS (NOS3) impairs myocardial function in developing sepsis

Experimental PorcineToxoplasma gondiiInfection as a Representative Model for Human Toxoplasmosis

Recombinant human activated protein C improves endotoxemia-induced endothelial dysfunction: a blood-free model in isolated mouse arteries

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