Loss of endothelium-dependent relaxant activity in the pulmonary circulation of rats exposed to chronic hypoxia.

Adnot, Serge; Raffestin, Bernadette; Eddahibi, Saadia; Braquet, P.; Chabrier, P

doi:10.1172/jci114965

Cited by 300 publications

(169 citation statements)

References 29 publications

(35 reference statements)

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“…19 Endothelium-dependent and -independent vasodilation was determined as dose-dependent reduction in pulmonary arterial pressure (⌬P PA ) in response to ACh and sodium nitroprusside (SNP), respectively, in lungs preconstricted with U4661951. 20 Pulmonary and systemic hemodynamics were measured in vivo in CHF and control rats as described, 8,14 and the vasorelaxant effect of inhaled nitric oxide was determined as dose-dependent reduction in P PA . Western blot analyses from whole lung homogenate and fresh lung endothelial cells (FLECs) and immunohistochemical analyses were performed as outlined in the Online Data Supplement.…”

Section: Methodsmentioning

confidence: 99%

Lung Endothelial Dysfunction in Congestive Heart Failure

Kerem

Yin

Kaestle

et al. 2010

Circulation Research

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Rationale: Congestive heart failure (CHF) frequently results in remodeling and increased tone of pulmonary resistance vessels. This adaptive response, which aggravates pulmonary hypertension and thus, promotes right ventricular failure, has been attributed to lung endothelial dysfunction. Objective: We applied real-time fluorescence imaging to identify endothelial dysfunction and underlying molecular mechanisms in an experimental model of CHF induced by supracoronary aortic banding in rats. Methods and Results: Endothelial dysfunction was evident in lungs of CHF rats as impaired endothelium-dependent vasodilation and lack of endothelial NO synthesis in response to mechanical stress, acetylcholine, or histamine. Key Words: congestive heart failure Ⅲ pulmonary hypertension Ⅲ endothelial dysfunction Ⅲ Ca 2ϩ regulation Ⅲ cytoskeletal dynamics C ongestive heart failure (CHF) is a major and growing cause of morbidity and mortality in most affluent countries, with a prevalence approaching 10 per 1000 among those older than 65 years of age. 1 Approximately 60% to 80% of patients with CHF of systolic or diastolic origin develop pulmonary hypertension owing to left heart disease (previously known as pulmonary venous hypertension). 2,3 Importantly, this form of pulmonary hypertension is not solely caused by a "passive" increase in pulmonary vascular pressures, but is frequently aggravated by a concomitant "reactive" increase in pulmonary vascular resistance (PVR). Incidence and magnitude of this "reactive" component vary from 20% to 100% and from supranormal to extreme PVR values, and seem to worsen with progressive duration and severity of the underlying heart disease. 4 -7 The "reactive" PVR increase in CHF results both from an elevated tone and extensive remodeling of lung resistance vessels. 8,9 The resulting increase in right ventricular afterload limits right ventricular output, and may ultimately cause fatal right ventricular failure. 2 The clinical relevance of this scenario is highlighted by epidemiological studies which identified reduced right ventricular ejection fraction as potent and independent predictor of mortality in CHF. 10 The results of several preclinical studies suggest that CHF may cause lung endothelial dysfunction, as indicated by an impaired endothelium-dependent relaxation of pulmonary artery segments in response to acetylcholine (ACh) in CHF rats. 11,12 Consequently, lung endothelial dysfunction has been Original

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Section: Methodsmentioning

confidence: 99%

Lung Endothelial Dysfunction in Congestive Heart Failure

Kerem

Yin

Kaestle

et al. 2010

Circulation Research

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“…As in other cardiovascular diseases, endothelial dysfunction in models of pulmonary arterial hypertension is established when pulmonary arteries exhibit a decrease in the relaxant response to acetylcholine, the reference endothelium-dependent vasodilator, acting through the activation of endothelial muscarinic receptors coupled to NO production [4,5]. In a mouse model of chronic hypoxia-induced pulmonary arterial hypertension, we have shown that the relaxant response induced by the β 2 -AR stimulation, which is also endothelium-and eNOSdependent, is preserved, whereas the relaxant response to acetylcholine is decreased [5,6].…”

Section: Introductionmentioning

confidence: 99%

Role of Gi/o-Src kinase-PI3K/Akt pathway and caveolin-1 in β2-adrenoceptor coupling to endothelial NO synthase in mouse pulmonary artery

Banquet

Delannoy

Agouni

et al. 2011

Cellular Signalling

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“…An increased propensity to PHT in the newborn period, compared with other stages of life, is predominantly related to two factors: a failure in the physiological fall in pulmonary vascular resistance required for a successful transition to postnatal life, and the rapid development of anatomical changes in the heart and pulmonary vasculature (23), known collectively as vascular remodeling. Evidence suggests that abnormally decreased pulmonary arterial relaxation is an early functional feature of PHT that directly contributes to the subsequent anatomical changes of remodeling (1). Together, these changes lead to narrowing of the vessel lumen, exaggerated responses to constrictors (3,14), and reduced compliance, all of which are believed to contribute to a chronic and progressive form of PHT that is refractory to current therapies (13).…”

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confidence: 99%

Contribution of xanthine oxidase-derived superoxide to chronic hypoxic pulmonary hypertension in neonatal rats

Jankov¹,

Kantores²,

Pan³

et al. 2008

American Journal of Physiology-Lung Cellular and Molecular Phys

117

105

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Jankov RP, Kantores C, Pan J, Belik J. Contribution of xanthine oxidase-derived superoxide to chronic hypoxic pulmonary hypertension in neonatal rats. Am J Physiol Lung Cell Mol Physiol 294: L233-L245, 2008. First published December 14, 2007 doi:10.1152/ajplung.00166.2007.-Xanthine oxidase (XO)-derived reactive oxygen species (ROS) formation contributes to experimental chronic hypoxic pulmonary hypertension in adults, but its role in neonatal pulmonary hypertension has received little attention. In rats chronically exposed to hypoxia (13% O2) for 14 days from birth, we examined the effects of ROS scavengers (U74389G 10 mg ⅐ kg Ϫ1 ⅐ day Ϫ1 or Tempol 100 mg ⅐ kg Ϫ1 ⅐ day Ϫ1 ip) or a XO inhibitor, Allopurinol (50 mg ⅐ kg Ϫ1 ⅐ day Ϫ1 ip). Both ROS scavengers limited oxidative stress in the lung and attenuated hypoxia-induced vascular remodeling, confirming a critical role for ROS in this model. However, both interventions also significantly inhibited somatic growth and normal cellular proliferation in distal air spaces. Hypoxiaexposed pups had evidence of increased serum and lung XO activity, increased vascular XO-derived superoxide production, and vascular nitrotyrosine formation. These changes were all prevented by treatment with Allopurinol, which also attenuated hypoxia-induced vascular remodeling and partially reversed inhibited endothelium-dependent arterial relaxation, without affecting normal growth and proliferation. Collectively, our findings suggest that XO-derived superoxide induces endothelial dysfunction, thus impairing pulmonary arterial relaxation, and contributes to vascular remodeling in hypoxia-exposed neonatal rats. Due to the potential for adverse effects on normal growth, targeting XO may represent a superior "antioxidant" strategy to ROS scavengers for neonates with pulmonary hypertension.antioxidants; allopurinol; U74389G; Tempol; 8-isoprostane PULMONARY HYPERTENSION (PHT) is a common condition of the critically ill neonate (12,18,52,64,65). An increased propensity to PHT in the newborn period, compared with other stages of life, is predominantly related to two factors: a failure in the physiological fall in pulmonary vascular resistance required for a successful transition to postnatal life, and the rapid development of anatomical changes in the heart and pulmonary vasculature (23), known collectively as vascular remodeling. Evidence suggests that abnormally decreased pulmonary arterial relaxation is an early functional feature of PHT that directly contributes to the subsequent anatomical changes of remodeling (1). Together, these changes lead to narrowing of the vessel lumen, exaggerated responses to constrictors (3,14), and reduced compliance, all of which are believed to contribute to a chronic and progressive form of PHT that is refractory to current therapies (13).A major pathological role for increased generation of reactive oxygen species (ROS) in the pathogenesis of experimental PHT is evidenced by antioxidant intervention studies performed in fetal lambs (24, 39), in hyperoxia-exp...

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Loss of endothelium-dependent relaxant activity in the pulmonary circulation of rats exposed to chronic hypoxia.

Cited by 300 publications

References 29 publications

Lung Endothelial Dysfunction in Congestive Heart Failure

Lung Endothelial Dysfunction in Congestive Heart Failure

Role of Gi/o-Src kinase-PI3K/Akt pathway and caveolin-1 in β2-adrenoceptor coupling to endothelial NO synthase in mouse pulmonary artery

Contribution of xanthine oxidase-derived superoxide to chronic hypoxic pulmonary hypertension in neonatal rats

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