Inhaled nitric oxide versus aerosolized iloprost for the treatment of pulmonary hypertension with left heart disease*

Yin, Ning; Kaestle, Stephanie M.; Yin, Jun; Hentschel, Thomas; Pries, Axel R.; Kuppe, Hermann; Kuebler, Wolfgang M.

doi:10.1097/ccm.0b013e3181962ce6

Cited by 37 publications

(35 citation statements)

References 29 publications

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“…Although evidence supports a role of pulmonary VSMC phenotypic switch in the pathogenesis PH, an imbalance between pulmonary vasoconstrictors such as ET-1 and vasodilators such as NO and PGI 2 has also been implicated in PH (19,26,33,34,38,64), and vasodilators are a major component of the current therapy for PH (10,47,71,80). However, a large number of patients do not respond to vasodilators, possibly because of excessive pulmonary vascular remodeling.…”

Section: Discussionmentioning

confidence: 99%

“…Endothelial dysfunction, excessive pulmonary vascular smooth muscle cell (VSMC) proliferation, hypertrophy, and migration, as well as various degrees of pulmonary vasoconstriction and inflammation, are major components of the pathobiology of PH and therefore represent important targets for current and emerging therapies (9,13). Vasodilator therapies such as prostacyclin (PGI 2 ), endothelin (ET-1) receptor antagonists, and phosphodiesterase-5 (PDE-5) inhibitors, either separate or in combination, are variably successful in slowing PH progression and prolonging survival (10,47,51,71,80). Also, it is increasingly appreciated that alternative approaches such as antiproliferative, proapoptotic, or immunomodulatory therapies hold promise in further improving the outcome of PH (5,18,36,52,54,64,77).…”

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confidence: 99%

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Improved pulmonary vascular reactivity and decreased hypertrophic remodeling during nonhypercapnic acidosis in experimental pulmonary hypertension

Christou

Reslan

Mam

et al. 2012

American Journal of Physiology-Lung Cellular and Molecular Phys

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Christou H, Reslan OM, Mam V, Tanbe AF, Vitali SH, Touma M, Arons E, Mitsialis SA, Kourembanas S, Khalil RA. Improved pulmonary vascular reactivity and decreased hypertrophic remodeling during nonhypercapnic acidosis in experimental pulmonary hypertension. Am J Physiol Lung Cell Mol Physiol 302: L875-L890, 2012. First published January 27, 2012; doi:10.1152/ajplung.00293.2011.-Pulmonary hypertension (PH) is characterized by pulmonary arteriolar remodeling with excessive pulmonary vascular smooth muscle cell (VSMC) proliferation. This results in decreased responsiveness of pulmonary circulation to vasodilator therapies. We have shown that extracellular acidosis inhibits VSMC proliferation and migration in vitro. Here we tested whether induction of nonhypercapnic acidosis in vivo ameliorates PH and the underlying pulmonary vascular remodeling and dysfunction. Adult male Sprague-Dawley rats were exposed to hypoxia (8.5% O2) for 2 wk, or injected subcutaneously with monocrotaline (MCT, 60 mg/kg) to develop PH. Acidosis was induced with NH4Cl (1.5%) in the drinking water 5 days prior to and during the 2 wk of hypoxic exposure (prevention protocol), or after MCT injection from day 21 to 28 (reversal protocol). Right ventricular systolic pressure (RVSP) and Fulton's index were measured, and pulmonary arteriolar remodeling was analyzed. Pulmonary and mesenteric artery contraction to phenylephrine (Phe) and high KCl, and relaxation to acetylcholine (ACh) and sodium nitroprusside (SNP) were examined ex vivo. Hypoxic and MCT-treated rats demonstrated increased RVSP, Fulton's index, and pulmonary arteriolar thickening. In pulmonary arteries of hypoxic and MCT rats there was reduced contraction to Phe and KCl and reduced vasodilation to ACh and SNP. Acidosis prevented hypoxia-induced PH, reversed MCT-induced PH, and resulted in reduction in all indexes of PH including RVSP, Fulton's index, and pulmonary arteriolar remodeling. Pulmonary artery contraction to Phe and KCl was preserved or improved, and relaxation to ACh and SNP was enhanced in NH4Cl-treated PH animals. Acidosis alone did not affect the hemodynamics or pulmonary vascular function. Phe and KCl contraction and ACh and SNP relaxation were not different in mesenteric arteries of all groups. Thus nonhypercapnic acidosis ameliorates experimental PH, attenuates pulmonary arteriolar thickening, and enhances pulmonary vascular responsiveness to vasoconstrictor and vasodilator stimuli. Together with our finding that acidosis decreases VSMC proliferation, the results are consistent with the possibility that nonhypercapnic acidosis promotes differentiation of pulmonary VSMCs to a more contractile phenotype, which may enhance the effectiveness of vasodilator therapies in PH. pulmonary artery; pulmonary circulation; nitric oxide; vascular smooth muscle PULMONARY HYPERTENSION (PH) is a serious disease and a major and expanding public health problem with ϳ1,000 new patients diagnosed every year in the United States (6,20). PH is characterized by increased pulmonary arterial pre...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Improved pulmonary vascular reactivity and decreased hypertrophic remodeling during nonhypercapnic acidosis in experimental pulmonary hypertension

Christou

Reslan

Mam

et al. 2012

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…8,14 Sham-operated rats served as controls. Isolated lungs of CHF and control rats were prepared for real-time fluorescence microscopy as reported.…”

Section: Methodsmentioning

confidence: 99%

“…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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“…Her ikisi de %0,9 NaCl ile sulandırılıp 3 dakika içinde uygulandığında vazodilatör etki ile pulmoner vasküler direnci azaltır, venöz oksijen satürasyo-nunu artırır ve sistemik hemodinamik etkileri yoktur. 52 İnsülin Enjekte insülinin ağrılı olması hasta uyumunu zorlaştırdığın-dan hasta uyumunu artırmak için inhaler insülin formları geliştirilmiştir. İnhaler insülin kullanımıyla düşük kan şekeri düzeyi enjekte insülin kullanımında olduğu gibi sağlağlana-bilmekte ve kan şekeri dalgalanmaları engellenebilmektedir.…”

Section: Kısa Etkili Bronkodilatörler (Salbutamol)unclassified

Inhaled Therapy in Children

Pekcan¹

2012

Solunum

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Inhaled nitric oxide versus aerosolized iloprost for the treatment of pulmonary hypertension with left heart disease*

Abstract: Inhaled vasodilators may offer an effective, safe, and pulmonary-selective strategy for the treatment of pulmonary hypertension in left heart disease, and inhaled iloprost may be superior to NO in this condition.

Cited by 37 publications

References 29 publications

Improved pulmonary vascular reactivity and decreased hypertrophic remodeling during nonhypercapnic acidosis in experimental pulmonary hypertension

Improved pulmonary vascular reactivity and decreased hypertrophic remodeling during nonhypercapnic acidosis in experimental pulmonary hypertension

Lung Endothelial Dysfunction in Congestive Heart Failure

Inhaled Therapy in Children

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