Continuous inhalation of nitric oxide protects against development of pulmonary hypertension in chronically hypoxic rats.

Kouyoumdjian, C; Adnot, Serge; Levame, M; Eddahibi, Saadia; Bousbaa, Hassan; Raffestin, Bernadette

doi:10.1172/jci117372

Cited by 120 publications

(79 citation statements)

References 36 publications

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“…Nitric oxide (NO) and the natriuretic peptides attenuate vasoconstriction and vascular remodeling in hypoxia-induced pulmonary hypertension 4,5 but are difficult to administer as drugs over the long term. Their vasorelaxant and antimitogenic actions are mediated by cGMP and activation of cGMPdependent protein kinases.…”

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confidence: 99%

Sildenafil Inhibits Hypoxia-Induced Pulmonary Hypertension

Zhao

Mason²,

Morrell³

et al. 2001

Circulation

440

299

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Background-This study investigated the effect of the phosphodiesterase 5 inhibitor sildenafil on the pulmonary vascular response to hypoxia in humans and mice. Methods and Results-In a randomized, double-blind study, sildenafil 100 mg or placebo was given orally to 10 healthy volunteers 1 hour before breathing 11% O 2 for 30 minutes. Pulmonary artery pressure (PAP) was measured with an indwelling right heart catheter.

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mentioning

confidence: 99%

Sildenafil Inhibits Hypoxia-Induced Pulmonary Hypertension

Zhao

Mason²,

Morrell³

et al. 2001

Circulation

440

299

View full text Add to dashboard Cite

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“…Indeed, vasoconstrictor responses to various stimuli, such as acute hypoxia [1,2], angiotensin II [1] and endothelin-1 [3], are potentiated by inhibitors of NO synthesis. In rats exposed to chronic hypoxia, supplying NO to the pulmonary vessels by continuous inhalation attenuates muscularization of distal vessels [4]. More recently, NO has also been shown to inhibit gene expression of endothelin [5] and various growth factors, such as platelet-derived growth factor (PDGF) [5] and vascular endothelial growth factor (VEGF) [6].…”

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confidence: 99%

Induction of nitric oxide synthase activity in pulmonary arteries from normoxic and chronically hypoxic rats

Carville¹,

Adnot²,

Eddahibi³

et al. 1997

Eur Respir J

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Chronic hypoxia has recently been shown to upregulate inducible nitric oxide synthase (iNOS) gene expression in rat lung. In the present study, we questioned whether induction of NO synthesis could alter the reactivity of pulmonary arteries (PA) from chronically hypoxic (CH) rats. Dose-response curves to phenylephrine (PE) 10 -9 to 5×10 -6 M) were examined in PA rings as well as response to L-arginine analogues in isolated lungs from CH or normoxic (N) rats after various incubation times.Although maximal contraction to PE did not differ in PA from CH rats compared to N rats at time 0 (361±53 vs 506±52 mg, respectively), it was markedly decreased after prolonged incubation (149±28 vs 386±47 mg, respectively, at 4 h; p<0.001). This phenomenon persisted after endothelial-denudation, but was reversed by N G -monomethyl-L-arginine (L-NMMA) (5×10 -4 M) and prevented by actinomycin D (2×10 -6 M). In contrast, maximal contraction to PE in aorta from CH rats was similar at time 0 and 4 h. After a short incubation, PA contraction to L-NMMA was greater in CH than in N rats (96±17 vs 33±9 mg at 90 min; p<0.05), was abolished after endothelial denudation, but persisted in CH rats in the presence of calmidazolium (5×10 -4 M). At 4 h, contraction to L-NMMA was abolished in endothelium-denuded PA from N rats but only attenuated in those from CH rats. In salt solution perfused lungs, L-NMMA added 30 or 90 min after isolation did not alter baseline pressure in N rats but caused its increase in CH rats. Whereas iNOS messenger ribonucleic acid (mRNA) was detectable by reverse-transcriptase polymerase chain reaction in the PA wall of N or CH rats after 4 h of incubation, it was absent in both at the time of isolation. In contrast, there was evidence of iNOS mRNA in lungs from CH rats at the time of isolation but no signal in those from N rats.In conclusion, there is induction of nitric oxide synthase activity in pulmonary arteries from normoxic and chronically hypoxic rats after prolonged incubation, but this effect is more pronounced in pulmonary arteries from chronically hypoxic rats. Eur Respir J 1997; 10: 437-445 In recent years, there has been considerable interest in the role of nitric oxide (NO) in the normal and remodelled pulmonary circulation. Endothelium-derived NO has been shown to play an important role not only in modulating the pulmonary vascular tone but also in the control of smooth muscle proliferation associated with vascular remodelling. Indeed, vasoconstrictor responses to various stimuli, such as acute hypoxia [1,2], angiotensin II [1] and endothelin-1 [3], are potentiated by inhibitors of NO synthesis. In rats exposed to chronic hypoxia, supplying NO to the pulmonary vessels by continuous inhalation attenuates muscularization of distal vessels [4]. More recently, NO has also been shown to inhibit gene expression of endothelin [5] and various growth factors, such as platelet-derived growth factor (PDGF) [5] and vascular endothelial growth factor (VEGF) [6].In chronic hypoxic pulmonary hypertension, th...

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“…In these cases, the simultaneous administration of a low concentration of NO could reduce the need for higher levels of oxygen flow volume. In addition, NO has been shown to modulate the pulmonary vascular tone by acting as a protective mechanism against pulmonary vasoconstriction and preventing pulmonary vascular remodelling in rats exposed to chronic hypoxia [20].…”

Section: Discussionmentioning

confidence: 99%

The effect of low-dose inhalation of nitric oxide in patients with pulmonary fibrosis

Yoshida¹,

Taguchi²,

Gabazza³

et al. 1997

Eur Respir J

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The aim of this study was to determine whether low-dose inhalation of nitric oxide (NO) improves pulmonary haemodynamics and gas exchange in patients with stable idiopathic pulmonary fibrosis (IPF).The investigation included 10 IPF patients breathing spontaneously. Haemodynamic and blood gas parameters were measured under the following conditions: 1) breathing room air; 2) during inhalation of 2 parts per million (ppm) NO with room air; 3) whilst breathing O 2 alone (1 L·min -1 ); and 4) during combined inhalation of 2 ppm NO and O 2 (1 L·min -1 ).During inhalation of 2 ppm NO with room air the mean pulmonary arterial pressure (Ppa 25±3 vs 30±4 mmHg) and the pulmonary vascular resistance (PVR 529±80 vs 699±110 dyn·s·cm -5 ) were significantly (p<0.01) lower than levels measured whilst breathing room air alone. These findings suggest that the combined use of nitric oxide and oxygen might constitute an alternative therapeutic approach for treating idiopathic pulmonary fibrosis patients with pulmonary hypertension. However, further studies must first be carried out to demonstrate the beneficial effect of oxygen therapy on pulmonary haemodynamics and prognosis in patients with idiopathic pulmonary fibrosis and to rule out the potential toxicity of inhaled nitric oxide, particularly when used in combination with oxygen. Eur Respir J 1997; 10: 2051-2054. Idiopathic pulmonary fibrosis (IPF) is characterized by progressive inflammatory and fibrotic processes of the lung [1][2][3]. The beneficial effect of long-term oxygen therapy (LTOT) has not been demonstrated in IPF patients: however, LTOT is commonly prescribed to patients with advanced IPF associated with hypoxaemia and pulmonary hypertension [4][5][6][7]. Inhaled nitric oxide (NO) has been shown to selectively and acutely vasodilate pulmonary vessels in various hypertensive lung diseases [8][9][10][11]. Inhaled NO has been shown to be more effective than inhaled oxygen (O 2 ) in decreasing the mean pulmonary artery pressure (Ppa) in disorders associated with chronic pulmonary hypertension [12]. Moreover, inhaled NO improves arterial oxygenation in patients with the acute respiratory distress syndrome (ARDS) undergoing O 2 therapy [13].This effect of inhaled NO has also been demonstrated in cases of pulmonary fibrosis during acute exacerbation undergoing O 2 therapy [14,15]. CHANNICK et al. [14] first reported that inhalation of 40 parts per million (ppm) NO is effective for improving pulmonary haemodynamics and arterial oxygenation. However, NO concentrations lower than 10 ppm have been shown to be sufficient for improving pulmonary hypertension and gas exchange in ARDS patients [16]. In fact, we have previously reported that 2 ppm NO improved pulmonary hypertension and arterial oxygenation in a patient with IPF undergoing acute exacerbation [15].However, the effect of inhaled NO in clinically stable IPF patients spontaneously breathing room air has not yet been reported. The combined inhalation of NO and O 2 has been reported to be effective for impro...

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Continuous inhalation of nitric oxide protects against development of pulmonary hypertension in chronically hypoxic rats.

Cited by 120 publications

References 36 publications

Sildenafil Inhibits Hypoxia-Induced Pulmonary Hypertension

Sildenafil Inhibits Hypoxia-Induced Pulmonary Hypertension

Induction of nitric oxide synthase activity in pulmonary arteries from normoxic and chronically hypoxic rats

The effect of low-dose inhalation of nitric oxide in patients with pulmonary fibrosis

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