Increased responsiveness of human pulmonary arteries in patients with positive bronchodilator response

Cases, Enrique; Vila, José M.; Medina, Pascual; Aldasoro, Martı́n; Segarra, Gloria; Lluch, Salvador

doi:10.1111/j.1476-5381.1996.tb16043.x

Cited by 10 publications

(6 citation statements)

References 15 publications

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“…In a porcine model of endotoxic shock bosentan, a dual ET receptor antagonist, completely abolished both the pulmonary hypertensive response and the increased airway resistance indicating that both the pulmonary arterial and airway changes were mediated by ET-1 (18). Similarly in human pulmonary artery rings taken at lobectomy, the responsiveness to ET-1 was increased in patients with reversible airways constriction detected on preoperative pulmonary function testing (19), again supporting the concept of co-constriction of bronchial and adjacent pulmonary arterial smooth muscle.…”

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confidence: 76%

Porcine Pulmonary Artery and Bronchial Responses to Endothelin-1 and Norepinephrine on Recovery from Hypoxic Pulmonary Hypertension

Schindler

Hislop²,

Haworth³

2006

Pediatr Res

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Many infants recovering from acute lung disease and pulmonary hypertension still have evidence of reactive airways disease at one year of age, suggesting longer-term airway effects. We hypothesized that parallel changes in smooth muscle would occur in airways and pulmonary arteries from animals with pulmonary hypertension and during normoxic recovery. Thus, two-hour-old piglets were subjected to 3 d chronic hypobaric hypoxia and 3-d-old piglets were subjected to 11 d hypoxia. Some animals were allowed to recover in room air for 3 or 6 d. The amount of smooth muscle and responses of isolated paired bronchial and pulmonary artery rings to endothelin-1 (ET-1) and norepinephrine were studied at the end of hypoxic exposure, on recovery and in age-matched control animals. In all hypoxia induced pulmonary hypertensive animals, smooth muscle area and ET-1 contractile response was increased in the pulmonary arteries and bronchi. Norepinephrine-induced relaxant response was impaired significantly in both bronchi and pulmonary arteries. After 3 d recovery, pulmonary arterial smooth muscle area decreased by 65%, and ET-1-induced contractile responses were normal for age. In the airways, ET-1 contractile response only normalized after six days and bronchial smooth muscle was still increased. After 6 d recovery pulmonary arterial norepinephrineinduced relaxant response had returned to normal, but bronchial response remained impaired. Thus during pulmonary hypertension, both bronchial and pulmonary arterial smooth muscle area and contractile responses are increased. On recovery, regression of bronchial structural and functional abnormalities is slower than in pulmonary arteries. A natomically, the pulmonary arteries and airways lie in close proximity and local mediator release may affect both bronchial and pulmonary vascular reactivity. Pulmonary hypertension in children with congenital heart disease is associated not only with an elevated pulmonary arterial vascular resistance and medial smooth muscle hypertrophy, but also with increased respiratory system resistance and bronchial smooth muscle hypertrophy (1).Fifty percent of infants requiring Extra Corporeal Membrane Oxygenation (ECMO) for persistent pulmonary hypertension of the newborn still required pulmonary medications after six months, despite ECMO utilizing a strategy of lung rest to prevent lung injury (2). Twenty-six percent of infants who participated in the UK randomized ECMO trial, many of whom had severe persistent pulmonary hypertension, still had evidence of reactive airways disease with cough and wheeze at one year of age, and 8% still required regular pulmonary medications (3). These changes could be due to the damaging effects of high pressure and the high FiO 2 used during the mechanical ventilation given before instituting ECMO (4), however pulmonary hypertension may have contributed to the end result by affecting both the pulmonary arteries and bronchi. The clinical findings also suggest that any bronchial changes, once present, are slow to re...

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confidence: 76%

Porcine Pulmonary Artery and Bronchial Responses to Endothelin-1 and Norepinephrine on Recovery from Hypoxic Pulmonary Hypertension

Schindler

Hislop²,

Haworth³

2006

Pediatr Res

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“…Increases in urinary ET-1 instead correlate with decreases in oxygenation, possibly through hypoxic release of ET-1 from the kidney [61,62]. Smokers also have impaired ET-1 mediated vasodilation that correlates with bronchial hyperresponsiveness and may contribute to pulmonary hypertension [63,64]. …”

Section: Airway Diseasesmentioning

confidence: 99%

Role of endothelin-1 in lung disease

2001

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ARDS = acute respiratory distress syndrome; BAL = bronchoalveolar lavage; BO = bronchiolitis obliterans; ECE = endothelin converting enzyme; ETA = endothelin A; ETB = endothelin B; ET-1 = endothelin-1; FEV1 = forced expiratory volume in 1 s; NO = nitric oxide.Available online http://respiratory-research.com/content/2/2/090 Introduction ET-1, ET-2, and ET-3 are members of a peptide family that has been the subject of much interest in the past decade. Our laboratory and that of Highsmith identified this peptide vasoconstrictor secreted from endothelial cells [1][2][3] that was subsequently isolated, sequenced, cloned, and named by Yanagisawa in 1988 [4]. The many diverse and overlapping functions of these peptides have since implicated endothelins in both homeostatic mechanisms as well as diseases of the lungs. This review will focus on the role of endothelins (particularly ET-1), emphasizing the need to better understand endothelin biology and function in a wide variety of disorders including diseases of the airways and pulmonary vasculature, lung tumors, the acute respiratory distress syndrome, and fibrotic diseases (Table 1). Endothelin biochemistryThe endothelins are a family of 21 amino acid peptides, of which there are three distinct isoforms (ET-1, ET-2, and ET-3). The isoforms ET-2 and ET-3 differ from ET-1 by two and six amino acids, respectively, and share significant homology, especially at the carboxy terminus with sarafotoxins a-e (Fig. 1). Endothelin-1 is the most abundant isoform and has been best characterized. The lung has the highest levels of ET-1 secreted by endothelium, smooth muscle, airway epithelium, and a variety of other cells (Table 2). ET-1 also circulates in the plasma. In the normal lung, ET-1 mainly localizes to vascular endothelium, airway and vascular smooth muscle cells and, to a lesser degree, the epithelium. ET-2 has similar biologic functions as ET-1 and is found in the myocardium, kidney and placental tissues. ET-3 also circulates in plasma and is found in the central nervous system, gastrointestinal tract, lung, and kidney although the cellular source is not clear. The gene for ET-1 is located on chromosome 6, that for ET-2 on chromosome 1, and the gene for ET-3 on chromosome 20 [5].All three endothelins are synthesized as preprohormones and post-translationally processed to active peptides. ET-1 processing has been best characterized and begins with the 212 amino acid peptide (preproET-1), which is then proteolytically cleaved by endopeptidases to big ET-1 Review Role of endothelin-1 in lung disease AbstractEndothelin-1 (ET-1) is a 21 amino acid peptide with diverse biological activity that has been implicated in numerous diseases. ET-1 is a potent mitogen regulator of smooth muscle tone, and inflammatory mediator that may play a key role in diseases of the airways, pulmonary circulation, and inflammatory lung diseases, both acute and chronic. This review will focus on the biology of ET-1 and its role in lung disease.

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“…Although the contribution of membrane potential to regulation of the intracellular calcium concentration is different in bronchial vs. arterial smooth muscle (27), there is a close functional relationship between bronchioles and pulmonary arteries. Thus, arterial rings from patients with a positive bronchodilator test exerted hyperresponsiveness to contractile agonists (8), and both bronchial and vascular smooth muscle exhibit hypertrophy in pulmonary hypertension (44). Therefore, the results obtained in bronchioles were compared with those in pulmonary arteries.…”

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confidence: 99%

Mechanisms underlying epithelium-dependent relaxation in rat bronchioles: analogy to EDHF-type relaxation in rat pulmonary arteries

Kroigaard

Dalsgaard

Simonsen

2010

American Journal of Physiology-Lung Cellular and Molecular Phys

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Kroigaard C, Dalsgaard T, Simonsen U. Mechanisms underlying epithelium-dependent relaxation in rat bronchioles: analogy to EDHFtype relaxation in rat pulmonary arteries. Am J Physiol Lung Cell Mol Physiol 298: L531-L542, 2010. First published January 29, 2010 doi:10.1152/ajplung.00220.2009.-This study investigated the mechanisms underlying epithelium-derived hyperpolarizing factor (EpDHF)-type relaxation in rat bronchioles. Immunohistochemistry was performed, and rat bronchioles and pulmonary arteries were mounted in microvascular myographs for functional studies. An opener of small (SKCa) and intermediate (IKCa)-conductance calcium-activated potassium channels, NS309 (6,7-dichloro-1H-indole-2,3-dione 3-oxime) was used to induce EpDHF-type relaxation. IK Ca and SKCa3 positive immunoreactions were observed mainly in the epithelium and endothelium of bronchioles and arteries, respectively. In 5-hydroxytryptamine (1 M)-contracted bronchioles (828 Ϯ 20 m, n ϭ 84) and U46619 (0.03 M)-contracted arteries (720 Ϯ 24 m, n ϭ 68), NS309 (0.001-10 M) induced concentration-dependent relaxations that were reduced by epithelium/endothelium removal and by blocking IK Ca channels with charybdotoxin and in bronchioles also by blocking SK Ca channels with apamin. Inhibition of cyclooxygenase, nitric oxide synthase, and cytochrome 2C isoenzymes, or blockade of large (BK Ca)-conductance calciumactivated potassium channels with iberiotoxin, failed to reduce NS309 relaxation. In contrast to the pulmonary arteries, relaxations to a ␤ 2-adrenoceptor agonist, salbutamol, were reduced in bronchioles by removing the epithelium or blocking IK Ca and/or SK Ca channels. Extracellular K ϩ (2-20 mM) induced relaxation in both bronchioles and arteries. An inhibitor of Na ϩ -K ϩ -ATPase, ouabain, abolished relaxations to NS309, salbutamol, and K ϩ . These results suggest that IK Ca and SKCa3 channels are located in the epithelium of bronchioles and endothelium of pulmonary arteries. Analog to the endotheliumderived hyperpolarizing factor (EDHF)-type relaxation in pulmonary arteries, these channels may be involved in EpDHF-type relaxation of bronchioles caused by epithelial K ϩ efflux followed by activation of Na ϩ -K ϩ -ATPase in the underlying smooth muscle layer.NS309; salbutamol; potassium; endothelium; GEA 3175 THE RESPIRATORY EPITHELIUM releases factors that regulate bronchial smooth muscle relaxations (20), and removal of the bronchial epithelium in larger airways has been shown to enhance the effect of contractile agonists and reduce the relaxing response in bronchioles (50, 51). Nitric oxide (NO) and prostaglandin E 2 (PGE 2 ) are mediators of human bronchiole smooth muscle epithelium-dependent relaxations (22). In addition, a non-NO nonprostanoid epithelium-dependent hyperpolarizing factor (EpDHF) is also involved in epitheliumdependent relaxations. Epoxyeicosatrienoic acids (EETs) have been suggested to account for EpDHF-mediated relaxation in guinea pig airways (3). In comparison, opening of intermediate (IK Ca ) and endothelial subt...

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Increased responsiveness of human pulmonary arteries in patients with positive bronchodilator response

Cited by 10 publications

References 15 publications

Porcine Pulmonary Artery and Bronchial Responses to Endothelin-1 and Norepinephrine on Recovery from Hypoxic Pulmonary Hypertension

Porcine Pulmonary Artery and Bronchial Responses to Endothelin-1 and Norepinephrine on Recovery from Hypoxic Pulmonary Hypertension

Role of endothelin-1 in lung disease

Mechanisms underlying epithelium-dependent relaxation in rat bronchioles: analogy to EDHF-type relaxation in rat pulmonary arteries

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