Endogenous endothelins and nitric oxide in hypoxic pulmonary vasoconstriction

Hubloue, Ives; Biarent, Dominique; Kafi, Sophia Abdel; Bejjani, Gilbert; Kerbaul, François; Naeije, Robert; Leeman, Marc

doi:10.1183/09031936.03.00025403a

Cited by 18 publications

(36 citation statements)

References 38 publications

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“…Such a decrease, which has also been described by others (Marshall and Metcalfe, 1989;Sato et al, 1992;Trzebski et al, 1995) may have several reasons. Inspiratory hypoxia has been shown to induce a more pronounced formation of NO in the lung, which may then lead to a systemic vasodilation resulting in a reduction of perfusion pressure (Hubloue et al, 2003). It has also been demonstrated that hypoxaemia can directly induce vasodilation in various organs (e.g.…”

Section: Discussionmentioning

confidence: 99%

Microenvironmental adaptation of experimental tumours to chronic vs acute hypoxia

et al. 2004

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This study investigated long-term microenvironmental responses (oxygenation, perfusion, metabolic status, proliferation, vascular endothelial growth factor (VEGF) expression and vascularisation) to chronic hypoxia in experimental tumours. Experiments were performed using s.c.-implanted DS-sarcomas in rats. In order to induce more pronounced tumour hypoxia, one group of animals was housed in a hypoxic atmosphere (8% O 2 ) for the whole period of tumour growth (chronic hypoxia). A second group was acutely exposed to inspiratory hypoxia for only 20 min prior to the measurements (acute hypoxia), whereas animals housed under normal atmospheric conditions served as controls. Acute hypoxia reduced the median oxygen partial pressure (pO 2 ) dramatically (1 vs 10 mmHg in controls), whereas in chronically hypoxic tumours the pO 2 was significantly improved (median pO 2 ¼ 4 mmHg), however not reaching the control level. These findings reflect the changes in tumour perfusion where acutely hypoxic tumours show a dramatic reduction of perfused tumour vessels (maybe the result of a simultaneous reduction in arterial blood pressure). In animals under chronic inspiratory hypoxia, the number of perfused vessels increased (compared to acute hypoxia), although the perfusion pattern found in control tumours was not reached. In the chronically hypoxic animals, tumour cell proliferation and tumour growth were significantly reduced, whereas no differences in VEGF expression and vascular density between these groups were observed. These results suggest that long-term adaptation of tumours to chronic hypoxia in vivo, while not affecting vascularity, does influence the functional status of the microvessels in favour of a more homogeneous perfusion.

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Section: Discussionmentioning

confidence: 99%

Microenvironmental adaptation of experimental tumours to chronic vs acute hypoxia

et al. 2004

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“…In the context of previous experiments from our laboratory studying the possible role of endothelial mediators on pulmonary vascular tone in an anesthetized (adult) dog model, these experiments were set up to investigate the effects of bosentan on pretreated lambs with L-NA at controlled flow (28).…”

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confidence: 99%

“…We started from the hypothesis demonstrated in the dog experiments, that the vasoconstrictive effects of ET are selflimited by an ET-induced synthesis of endogenous NO (28). For that purpose, we examined the effects of endogenous ET blockade on hyperoxic and hypoxic vascular tone, with and without NO synthase inhibition by L-NA in intact perinatal lambs.…”

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confidence: 99%

“…The effects of hypoxia and drugs on pulmonary vascular tone were evaluated by constructing multipoint pressure/flow plots, which has been previously demonstrated in experiments from our laboratory to be the method of preference to evaluate the functional state of the pulmonary circulation (24,28,29). This approach allows discrimination between active from passive changes of Ppa and PVR.…”

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Role of Endothelins and Nitric Oxide in the Pulmonary Circulation of Perinatal Lambs During Hyperoxia and Hypoxia

Biarent¹,

Hubloue²,

Bejjani³

et al. 2006

Pediatr Res

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Endothelins (ET) have opposite vascular effects mediated through different receptors: ET A receptors mediating vasoconstriction and ET B receptors mediating vasoconstriction as well as vasodilation. The role of ET in acute hypoxic pulmonary vasoconstriction (HPV) was studied after dual ET receptor blockade with bosentan and nitric oxide (NO) synthase inhibition with nitro-Larginine (L-NA). We started from the hypothesis that ET antagonism may inhibit HPV but, if not, would do so after NO synthase inhibition. HPV was evaluated in anesthetized lambs, with an intact pulmonary circulation, by the increase in the mean pulmonary artery pressure (Ppa) minus occluded Ppa (Ppao) gradient in response to hypoxia (inspiratory oxygen fraction of 0.1) at different levels of pulmonary flow (multipoint pressure/flow relationships). ET receptor antagonism decreased pulmonary and systemic vascular tone both in hyperoxia and hypoxia. ET antagonism had no effect on HPV. NO synthase inhibition increased pulmonary vascular tone more in hypoxia than in hyperoxia so that HPV was enhanced. After L-NA, bosentan still decreased pulmonary vascular tone in hypoxia but did not affect the magnitude of HPV. The present results suggest that ET and NO are involved in the regulation of basal pulmonary vascular tone. Furthermore, the vasodilator effect of bosentan persisted in the presence of NO synthase inhibition, suggesting a non NO-dependent vasodilator mechanism. The results from these experiments are in agreement with the idea that ET do not play a major role in HPV in the perinatal lamb, even when it is enhanced by NO synthase inhibition. (Pediatr Res 59: 131-136, 2006) E T are powerful vasoactive mediators synthesized and released by the vascular endothelium (1). Plasma levels of circulating ET-1, the predominant isoform of ET, vary with age: in the fetus and newborn infants they are higher than in neonates and infants up to 3 months of age; they then become nearly constant and similar to adult levels (2-4). ET-1 plasma levels are also elevated in newborns and children suffering from diseases associated with pulmonary hypertension (PHT) and are correlated with the severity of the disease (5-7).ET have opposite vascular effects mediated through different receptors. ET A receptors, located on vascular smooth muscle cells, mediate ET-1 vasoconstriction. ET B receptors are found on vascular smooth muscle cells, where they mediate vasoconstriction, and also on endothelial cells, where their stimulation produces vasodilation, presumably through the endothelial synthesis of NO and prostacyclin (8,9). Activation of the ET B receptor mediates pulmonary clearance of circulating ET-1 and reuptake of ET-1 by endothelial cells (8). In addition, although it is generally proposed that endothelial NO synthesis is related to ET-B receptor stimulation (8 -11), another study shows that activation of ET-A receptors also can enhance NO production in the vasculature (12). In experimental studies on the regulation of the pulmonary vascular tone in peri...

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“…NO inhibits the upregulation of cell adhesion molecules, platelet aggregation (1), and monocyte adhesion to endothelial cells (5). NO also mediates vasodilation through cGMP-dependent pathways and inhibits endothelin-1-induced vasoconstriction (12,13). For lipid-derived radicals, NO acts as a beneficial free radical scavenger, and, upon reaction with the oxygen free radical superoxide (O 2 Ϫ ⅐), the potent oxidizing and nitrating species peroxynitrite (ONOO Ϫ ) is formed.…”

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confidence: 99%