Chronic hypoxia impairs soluble guanylyl cyclase-mediated pulmonary arterial relaxation in the rat

Crawley, David; Zhao, Lan; Giembycz, M. A.; Liu, Shufang; Barnes, Peter J.; Winter, R. J. D.; Evans, Timothy W.

doi:10.1152/ajplung.1992.263.3.l325

Cited by 40 publications

(48 citation statements)

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“…Many observations in animals (30,31) and patients (32)(33)(34) support the view that endothelial dysfunction or injury contributes to different forms of pulmonary hypertension, including hypoxic pulmonary hypertension. Endothelial dysfunction associated with decreased NO production is likely to play a role in the development of pulmonary hypertension as vasoconstrictive stimuli are no longer counterbalanced by the vasorelaxant NO.…”

Section: Discussionmentioning

confidence: 89%

Adenoviral-mediated transfer of the human endothelial nitric oxide synthase gene reduces acute hypoxic pulmonary vasoconstriction in rats.

Janssens¹,

Bloch²,

Zhang³

et al. 1996

J. Clin. Invest.

143

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Nitric oxide (NO), a vasodilator involved in the regulation of pulmonary vascular tone, is synthesized by a family of enzymes, nitric oxide synthases (NOS). To investigate whether adenoviral-mediated overexpression of constitutive endothelial NOS (ceNOS) would attenuate hypoxic pulmonary vasoconstriction, we aerosolized 3 ϫ 10 9 plaque forming units of a recombinant adenovirus containing the ceNOS gene (AdCMVceNOS) into rat lungs. Four days after infection, transgene expression was confirmed using immunoblot techniques. Diffuse ceNOS immunostaining was detected in alveoli and medium-sized and small pulmonary vessels of AdCMVceNOS-transduced lungs. AdCMVceNOStransduction was associated with an 86% increase in [ 3 H]arginine to [ 3 H]citrulline conversion and a rise in pulmonary cGMP levels from 7 Ϯ 1 to 59 Ϯ 9 pmol/mg protein in lungs from AdCMVceNOS versus control rats, ( P Ͻ 0.05). During acute hypoxia (FIO 2 ϭ 0.10) for 25 min, mean pulmonary artery pressure (PAP) increased significantly from 17 Ϯ 1 to 27 Ϯ 1 mmHg in rats aerosolized with saline ( n ϭ 4) and from 18 Ϯ 1 to 28 Ϯ 1 mmHg in rats given an adenoviral vector expressing a nuclear-targeted ␤ -galactosidase gene (AdCMV ␤ gal, n ϭ 8). In contrast, in AdCMVceNOS-transduced rats ( n ϭ 8) the hypoxia-induced increase in PAP was significantly attenuated (18 Ϯ 1 to 23 Ϯ 2 mmHg). Systemic blood pressure was not affected by aerosol gene transfer. Thus, adenoviral-mediated ceNOS gene transfer to rat lungs increases ceNOS expression and activity, and reduces acute hypoxic pulmonary vasoconstriction. Aerosolized recombinant adenovirus overexpressing vasodilatory proteins can act as a selective pulmonary vasodilator and may hold promise as a future therapeutic strategy for pulmonary hypertension. ( J. Clin. Invest. 1996. 98:317-324.)

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Section: Discussionmentioning

confidence: 89%

Adenoviral-mediated transfer of the human endothelial nitric oxide synthase gene reduces acute hypoxic pulmonary vasoconstriction in rats.

Janssens¹,

Bloch²,

Zhang³

et al. 1996

J. Clin. Invest.

143

View full text Add to dashboard Cite

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“…There may also be a discrepancy between expression and function of sGC, as investigations in pulmonary arteries from chronic hypoxic rats demonstrated impaired vasorelaxation in response to acetylcholine and sodium nitroprusside [41]. In in vitro studies on purified sGC in haem-containing and haem-free preparations were investigated.…”

Section: Discussionmentioning

confidence: 99%

Expression and function of soluble guanylate cyclase in pulmonary arterial hypertension

Schermuly

Jp²,

Pullamsetti³

et al. 2008

Eur Respir J

218

168

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Alterations of the nitric oxide receptor, soluble guanylate cyclase (sGC) may contribute to the pathophysiology of pulmonary arterial hypertension (PAH). In the present study, the expression of sGC in explanted lung tissue of PAH patients was studied and the effects of the sGC stimulator BAY 63-2521 on enzyme activity, and haemodynamics and vascular remodelling were investigated in two independent animal models of PAH.Strong upregulation of sGC in pulmonary arterial vessels in the idiopathic PAH lungs compared with healthy donor lungs was demonstrated by immunohistochemistry. Upregulation of sGC was detected, similarly to humans, in the structurally remodelled smooth muscle layer in chronic hypoxic mouse lungs and lungs from monocrotaline (MCT)-injected rats. BAY 63-2521 is a novel, orally available compound that directly stimulates sGC and sensitises it to its physiological stimulator, nitric oxide. Chronic treatment of hypoxic mice and MCT-injected rats, with fully established PAH, with BAY 63-2521 (10 mg?kg) partially reversed the PAH, the right heart hypertrophy and the structural remodelling of the lung vasculature.Upregulation of soluble guanylate cyclase in pulmonary arterial smooth muscle cells was noted in human idiopathic pulmonary arterial hypertension lungs and lungs from animal models of pulmonary arterial hypertension. Stimulation of soluble guanylate cyclase reversed right heart hypertrophy and structural lung vascular remodelling. Soluble guanylate cyclase may thus offer a new target for therapeutic intervention in pulmonary arterial hypertension.KEYWORDS: BAY 63-2521, cardiovascular diseases, nitric oxide, pharmacology, pulmonary arterial hypertension, smooth muscle P ulmonary arterial hypertension (PAH) is a disabling disease, with high mortality, characterised by sustained elevation in pulmonary arterial pressure (Ppa) and pulmonary vascular remodelling due to proliferation and migration of pulmonary artery smooth muscle cells (PASMCs) [1]. Imbalance of vasodilatory and vasoconstrictive mediators has been implicated in these changes. Reduced urinary excretion of prostaglandin (PG)I 2 and augmented excretion of thromboxane metabolites were found in patients with idiopathic PAH (IPAH) [2], and immunohistological studies have shown reduced expression of PGI 2 synthase in the pulmonary vessels originating from those patients [3]. Another important mediator in the regulation of vascular tone is nitric oxide (NO), which is synthesised by NO synthases. Local NO production from endothelium and epithelium regulates pulmonary perfusion, depending on alveolar ventilation to assure optimised ventilation/perfusion distribution [4][5][6]. In patients with IPAH, it has been reported that the expression of endothelial NO synthase is downregulated [7], while other reports show an upregulation in plexiform lesions of IPAH patients [8]. However, little is known about the expression and regulation of soluble guanylate cyclase (sGC) which operates as a receptor for NO. Typically, sGC is found as a hetero...

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“…Vascular remodeling and neomuscularization after chronic hypoxia might have resulted in irreversible restriction of the vascular bed, and thus, nonresponsiveness to inhaled NO. This might be in part due to reduced activity of soluble guanylate cyclase, an NO receptor which has been reported to be decreased in isolated pulmonary artery segments obtained from rats that breathed at low oxygen tensions for 7 d (25).…”

Section: Discussionmentioning

confidence: 99%

Sustained pulmonary hypertension and right ventricular hypertrophy after chronic hypoxia in mice with congenital deficiency of nitric oxide synthase 3.

Steudel

Scherrer‐Crosbie²,

Bloch³

et al. 1998

J. Clin. Invest.

213

133

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Chronic hypoxia induces pulmonary hypertension and right ventricular (RV) hypertrophy. Nitric oxide (NO) has been proposed to modulate the pulmonary vascular response to hypoxia. We investigated the effects of congenital deficiency of endothelial NO synthase (NOS3) on the pulmonary vascular responses to breathing 11% oxygen for 3-6 wk. After 3 wk of hypoxia, RV systolic pressure was greater in NOS3-deficient than in wild-type mice (35 Ϯ 2 vs 28 Ϯ 1 mmHg, x Ϯ SE, P Ͻ 0.001). Pulmonary artery pressure (P PA ) and incremental total pulmonary vascular resistance (R PI ) were greater in NOS3-deficient than in wild-type mice (P PA 22 Ϯ 1 vs 19 Ϯ 1 mmHg, P Ͻ 0.05 and R PI 92 Ϯ 11 vs 55 Ϯ 5 mmHg·min·gram·ml Ϫ 1 , P Ͻ 0.05). Morphometry revealed that the proportion of muscularized small pulmonary vessels was almost fourfold greater in NOS3-deficient mice than in wild-type mice. After 6 wk of hypoxia, the increase of RV free wall thickness, measured by transesophageal echocardiography, and of RV weight/body weight ratio were more marked in NOS3-deficient mice than in wildtype mice (RV wall thickness 0.67 Ϯ 0.05 vs 0.48 Ϯ 0.02 mm, P Ͻ 0.01 and RV weight/body weight ratio 2.1 Ϯ 0.2 vs 1.6 Ϯ 0.1 mg·gram Ϫ 1 , P Ͻ 0.05). RV hypertrophy produced by chronic hypoxia was prevented by breathing 20 parts per million NO in both genotypes of mice. These results suggest that congenital NOS3 deficiency enhances hypoxic pulmonary vascular remodeling and hypertension, and RV hypertrophy, and that NO production by NOS3 is vital to counterbalance pulmonary vasoconstriction caused by chronic hypoxic stress. (

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Chronic hypoxia impairs soluble guanylyl cyclase-mediated pulmonary arterial relaxation in the rat

Cited by 40 publications

References 0 publications

Adenoviral-mediated transfer of the human endothelial nitric oxide synthase gene reduces acute hypoxic pulmonary vasoconstriction in rats.

Adenoviral-mediated transfer of the human endothelial nitric oxide synthase gene reduces acute hypoxic pulmonary vasoconstriction in rats.

Expression and function of soluble guanylate cyclase in pulmonary arterial hypertension

Sustained pulmonary hypertension and right ventricular hypertrophy after chronic hypoxia in mice with congenital deficiency of nitric oxide synthase 3.

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