Temporal variation in endotoxin‐induced vascular hyporeactivity in a rat mesenteric artery organ culture model

O’Brien, Alastair; Wilson, Andrew J.; Sibbald, Robert; Singer, Mervyn; Clapp, Lucie H.

doi:10.1038/sj.bjp.0704079

Cited by 30 publications

(30 citation statements)

References 47 publications

(99 reference statements)

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“…These findings from the pulmonary vasculature are consistent with reports demonstrating endotoxin-induced hyporeactivity to α-1 adrenergic agonists in other vessel beds and species [5,15,43], including humans [44]. These reactions have been reported both after in vitro and in vivo application of endotoxin and have been suggested to involve the actions of NO and an increased action of soluble guanylate cyclase.…”

Section: Discussionsupporting

confidence: 81%

“…Endotoxin has been shown to induce major vasomotor disturbances involving effects on responses to both vasoconstrictive and vasodilating substances in various animal models and vascular beds [15,16,17,18,19]. Many of these substances in the vascular wall are also highly involved in the pathophysiology of sepsis, but their integrated action in the pulmonary vasculature during endotoxaemia, and ALI, is not fully elucidated.…”

Section: Introductionmentioning

confidence: 99%

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Endotoxin Induces Differentiated Contractile Responses in Porcine Pulmonary Arteries and Veins

et al. 2010

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Background/Aims: Sepsis-induced lung injury is characterized by pulmonary hypertension, edema and deteriorated gas exchange. As in vivo studies have indicated that bacterial endotoxin predominantly induces a pulmonary venous constriction, we aimed to investigate effects of endotoxin on isolated porcine pulmonary vessels. Methods: Pulmonary arteries and veins were examined using in vitro isometric force recordings. Endothelin-receptor protein expression and distribution were analyzed by Western blot and immunohistochemistry. Freshly isolated preparations and vessels incubated (24 h) with/without endotoxin (10 µg·ml^–1) were compared. The contractile responses to phenylephrine, UK14.304, U46619, PGF₂_α, endothelin-1 (ET-1) and sarafotoxin were recorded, as well as the relaxation in response to acetylcholine, isoproterenol and nitroprusside. Results: In freshly isolated vessels, phenylephrine-induced contractions had a 5-times larger amplitude in arteries than in veins. The amplitude of the contractions in response to sarafotoxin was nearly 2 times larger in veins than in arteries, but there was no difference in responses to ET-1. Endotoxin markedly reduced phenylephrine-induced contractions in both arteries and veins, whereas the responses to ET-1 and sarafotoxin were augmented in veins only. No apparent changes in ET receptor expression or distribution were detected with Western blot or immunohistochemistry. Conclusion: Endotoxin differentially and selectively alters the contractile responses of porcine pulmonary vessels in vitro, towards a situation where the α-1 adrenergic responses of arteries are attenuated and the ET responses of veins are augmented. In situations with high adrenergic activity and high circulating ET levels, such as sepsis, these results may provide a mechanism contributing to pulmonary hypertension and edema formation.

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Section: Discussionsupporting

confidence: 81%

Section: Introductionmentioning

confidence: 99%

Endotoxin Induces Differentiated Contractile Responses in Porcine Pulmonary Arteries and Veins

et al. 2010

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“…Data collected from clinical studies and various endotoxemia models suggest that this phenomenon is related to the activation of the nuclear factor (NF)-B pathway, enabling the expression of several specific genes involved in the pathogenesis of septic shock leading to the production of cytokines, adhesion molecules, cyclooxygenase-2 (COX-2), and inducible nitric oxide synthase (iNOS) (33,34). The induction of iNOS along with an overproduction of NO has also been shown to play a major role in endotoxemia-induced vascular hyporeactivity in several experimental models (31,38) as well as in small vessels in patients with septic shock (37).…”

mentioning

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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“…Interestingly, in contrast to the pronounced impairment of contractions to methoxamine, contractions to U46619 in the aortae were unaffected by LPS infusion at either 2 or 24 h. Similarly, U46619-induced contractions were reported to be largely maintained in rat mesenteric arteries in an in vitro model of endotoxemia, whereas those to phenylephrine were attenuated (O'Brien et al, 2001;Wylam et al, 2001). In rats rendered tolerant to lethal doses of endotoxin by repeated sublethal doses of endotoxin, the pressor response to phenylephrine was attenuated, but a higher peak response to U46619 was observed compared with controls (Coffee et al, 1991), although in the same model, the sensitivity of the response to U46619 in isolated aortic rings was reduced (Temple et al, 2001).…”

Section: Downloaded Frommentioning

confidence: 86%

Effects of in Vivo Lipopolysaccharide Infusion on Vasoconstrictor Function of Rat Isolated Mesentery, Kidney, and Aorta

Farmer

Roberts²,

Gardiner³

et al. 2003

J Pharmacol Exp Ther

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Continuous infusion of lipopolysaccharide (LPS) into conscious rats elicits regionally selective cardiovascular disturbances. The aim of the present study was to assess contractile function in different vascular preparations (renal, mesenteric, and thoracic aorta) taken from rats infused with LPS for 2 or 24 h. Sustained responses to continuous infusion of methoxamine but not to KCl were reduced in the aorta (at 2 and 24 h LPS) and mesentery (at 24 h LPS) but not in the renal vascular bed. In contrast, transient responses to bolus doses of methoxamine were unchanged in the mesentery. In Ca 2ϩ -imaging experiments with fura-2, challenge with a single concentration of methoxamine (10 M, which showed an impaired contractile response at 24 h LPS) induced a rise in intracellular Ca 2ϩ in the mesenteric artery that was not different from the control. Furthermore, in the aorta, the contractile response to caffeine was attenuated only in the 2 h LPS group. These results show that there is regional heterogeneity in in vitro vascular responsiveness in preparations taken from LPS-infused rats. Thus, in mesenteric beds and aortae, but not renal beds, there is hypocontractility to methoxamine that is not due to a generalized inability of the smooth muscle to contract, which is evident with sustained but not transient application of agonist (mesentery) and which, in late endotoxemia (24 h LPS), does not appear to involve abnormalities in Ca 2ϩ mobilization or entry.

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Temporal variation in endotoxin‐induced vascular hyporeactivity in a rat mesenteric artery organ culture model

Cited by 30 publications

References 47 publications

Endotoxin Induces Differentiated Contractile Responses in Porcine Pulmonary Arteries and Veins

Endotoxin Induces Differentiated Contractile Responses in Porcine Pulmonary Arteries and Veins

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

Effects of in Vivo Lipopolysaccharide Infusion on Vasoconstrictor Function of Rat Isolated Mesentery, Kidney, and Aorta

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