Effects of Inhaled Nitric Oxide and Oxygen in High-Altitude Pulmonary Edema

Anand, Inder; Prasad, B. Aravinda; Chugh, Sumeet S.; Rao, Kamini; Cornfield, David N.; Milla, Carlos; Singh, Navneet; Singh, Surjit; Selvamurthy, W.

doi:10.1161/01.cir.98.22.2441

Cited by 85 publications

(46 citation statements)

References 12 publications

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“…A resting P pa of . 25 Several studies have shown a prevalence of HAPH between 5 and 18% in the population living at o3,200 m on the Altiplano in South America [7,8]. WU and GE [9] reported that in the Qinghai Province of China HAPH is more common in children than adults and the enhanced incidence of HAPH with increasing altitude is more pronounced in children than adults.…”

Section: Epidemiologymentioning

confidence: 99%

High-altitude pulmonary hypertension

Xq¹,

Jing²

2009

European Respiratory Review

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High-altitude pulmonary hypertension (HAPH) is a specific disease affecting populations that live at high elevations. The prevalence of HAPH among those residing at high altitudes needs to be further defined. Whereas reduction in nitric oxide production may be one mechanism for the development of HAPH, the roles of endothelin-1 and prostaglandin I 2 pathways in the pathogenesis of HAPH deserve further study.Although some studies have suggested that genetic factors contribute to the pathogenesis of HAPH, data published to date are insufficient for the identification of a significant number of gene polymorphims in HAPH.The clinical presentation of HAPH is nonspecific. Exertional dyspnoea is the most common symptom and signs related to right heart failure are common in late stages of HAPH. Echocardiography is the most useful screening tool and right heart catheterisation is the gold standard for the diagnosis of HAPH. The ideal management for HAPH is migration to lower altitudes. Phosphodiesterase 5 is an attractive drug target for the treatment of HAPH.In addition, acetazolamide is a promising therapeutic agent for high-altitude pulmonary hypertension. To date, no evidence has confirmed whether endothelin-receptor antagonists have efficacy in the treatment of high-altitude pulmonary hypertension.KEYWORDS: High-altitude pulmonary hypertension, hypoxia-inducible factor-1, nitric oxide, phosphodiesterase inhibitors, pulmonary vasoconstriction, right heart catheterisation H igh-altitude pulmonary hypertension (HAPH) due to chronic exposure to high altitude is a designated subset of pulmonary hypertension (PH) according to the third clinical classification of PH, which was approved during a conference in 2003 in Venice, Italy [1].It is estimated that more than 140 million people live 2,500 m above sea level, and the number of temporary visitors to mountains is close to 40 million [2,3]. Due to the substantial population exposed to the effects of high altitude, HAPH has become a public health problem in mountainous regions throughout the world. There are three specific locations where high-altitude studies have recently been performed: 1) the Himalayas of Asia; 2) the Andes of South America; and 3) the Rocky Mountains of North America. The present review will focus on the epidemiology, pathophysiology, pathogenesis, clinical characteristics and treatment of HAPH. DEFINITIONHAPH is a clinical syndrome seen in adults and children residing in high-altitude regions. As chronic mountain syndrome (CMS) is characterised by severe hypoxaemia, excessive polycythaemia and marked PH [4], HAPH is regarded as an important subset of CMS. However, the definition and diagnostic criteria of HAPH remain somewhat vague. According to the 2003 conference on PH, HAPH is classified in the third group of PH (table 1) [1]. Thus, right heart catheterisation is required to establish the diagnosis of HAPH (PH is defined by a mean pulmonary artery pressure (P pa) of .25 mmHg at rest or .30 mmHg with exercise) [5]. EPIDEMIOLOGYAlthough HAP...

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Section: Epidemiologymentioning

confidence: 99%

High-altitude pulmonary hypertension

Xq¹,

Jing²

2009

European Respiratory Review

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“…2,3 For example, individuals with pulmonary hypertension demonstrate reduced levels of pulmonary arterial endothelial NO synthase (eNOS) expression 3 and benefit clinically from inhalation NO therapy. 4,5 Indeed, mutant mice lacking the eNOS gene or newborn lambs treated with the eNOS inhibitor N -monomethyl-Larginine (LNMA) developed progressive elevation of pulmonary arterial pressures and resistance. 6,7 We have previously shown that HMG-CoA reductase inhibitors or statins increase eNOS expression by cholesterol-independent mechanism involving inhibition of Rho geranylgeranylation.…”

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confidence: 99%

Rho-Kinase Mediates Hypoxia-Induced Downregulation of Endothelial Nitric Oxide Synthase

et al. 2002

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Background-Hypoxia-induced pulmonary hypertension is a major cause of morbidity and mortality. Hypoxia induces pulmonary vasoconstriction, in part, by decreasing endothelial nitric oxide synthase (eNOS) expression. The mechanism by which hypoxia decreases eNOS expression is not known but may involve Rho-kinase-induced actin cytoskeletal changes in vascular endothelial cells. Methods and Results-To determine whether hypoxia regulates eNOS expression through Rho-kinase, we exposed human saphenous and pulmonary artery endothelial cells to hypoxia (3% O 2 ) with and without a Rho-kinase inhibitor, hydroxyfasudil (0.1 to 100 mol/L), for various durations (0 to 48 hours). Hypoxia increased Rho-kinase expression and activity by 50% and 74%, decreased eNOS mRNA and protein expression by 66Ϯ3% and 57Ϯ5%, and inhibited eNOS activity by 48Ϯ9%. All of these effects of hypoxia on eNOS were reversed by cotreatment with hydroxyfasudil. Furthermore, inhibition of Rho by Clostridium botulinum C3 transferase or Rho-kinase by overexpression of dominant-negative Rho-kinase reversed hypoxia-induced decrease in eNOS expression. Indeed, disruption of the actin cytoskeleton, the downstream target of Rho-kinase, by cytochalasin D also upregulated eNOS expression. Hypoxia reduced eNOS mRNA half-life from 22Ϯ2 to 13Ϯ2 hours, which was reversed by cotreatment with hydroxyfasudil. However, neither hypoxia nor hydroxyfasudil had any effects on eNOS gene transcription. Conclusions-These

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“…3 Treatment with inhaled NO improves pulmonary hypertension, arterial oxygenation, and pulmonary edema in patients with HAPE. 7,8 Thus, it is plausible that genetic variants that affect the production of NO may also affect susceptibility to HAPE.…”

Section: See P 826mentioning

confidence: 99%