Endothelin and Bronchial Asthma

Nomura, Akihiri; Uchida, Yoshiyuki; Kameyama, Masaaki; Saotome, Masao; Oki, Kazuhiko; Hasegawa, Shizuo

doi:10.1016/s0140-6736(89)90814-3

Cited by 100 publications

(41 citation statements)

References 3 publications

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“…Furthermore, elevated concentrations of ET-1 in the bronchoalveolar lavage fluid from patients with symptomatic asthma have also been detected (Nomura et al, 1989;Mattoli et al, 1991). The high potency of ET-1 in inducing contraction of airway smooth muscle both in vivo and in vitro (for recent reviews see Filep, 1993;Hay et al, 1993a) led to the assumption that it plays a pathophysiological role in asthma.…”

Section: Introductionmentioning

confidence: 99%

Acute pro‐inflammatory actions of endothelin‐1 in the guinea‐pig lung: involvement of ET_A and ET_B receptors

Filep

Fournier

Földes-Filep

1995

British J Pharmacology

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1 Although recent observations suggest that endothelin-l (ET-1) may play a role in the pathogenesis of asthma, to date little is known about the effects of ET-1 on parameters other than bronchoconstriction. The objectives of the present experiments were to study whether intravenously administered ET-1 could exert pro-inflammatory actions in the guinea-pig lung and to assess the involvement of endothelin ETA and ETB receptors in these events by using the ETA receptor-selective antagonist, FR 139317, the novel ETA/ETB receptor antagonist, bosentan and the ETB receptor-selective agonist, IRL 1620. 2 Bolus i.v. injection of ET-1 (0.1-1 nmol kg-') to anaesthetized guinea-pigs evoked dose-dependent increases in mean arterial blood pressure which lasted for 6-12 min. This was accompanied by a dose-dependent haemoconcentration (8-15% plasma volume losses) and increases (up to 546%) in albumin extravasation in the trachea, upper and lower bronchi, but not in the pulmonary parenchyma. Qualitatively similar changes were observed following i.v. injection of the ETB receptor agonist, IRL 1620 (0.3 and 1 nmol kg-'), although IRL 1620 appeared to be about 3 times less potent than ET-1. The ETA receptor-selective antagonist, FR 139317 (2.5 mg kg-') inhibited the ET-1 (1 nmol kg-')-induced pressor response, haemoconcentration and albumin extravasation by 75, 77 and 60-70%, respectively, whereas it did not attenuate IRL 1620 (1 nmol kg-')-induced changes. The ETA/ETB receptor antagonist, bosentan (10mgkg-') almost completely inhibited the pressor, haemoconcentration and permeability effects of both ET-I and IRL 1620. 3 ET-1, but not IRL 1620 (0.1-1 nmol kg-1), produced a dose-dependent neutropenia with relative lymphocytosis and monocytosis, but did not induce influx of neutrophil granulocytes into pulmonary tissues or the bronchoalveolar space. ET-1 (1 nmol kg-')-induced neutropenia was prevented by pretreatment of the animals with FR 139317 (2.5 mg kg-'), bosentan (10 mg kg-') or adrenaline (90 nmol kg-'), indicating that ET-1 caused intravascular sequestration of neutrophil granulocytes. 4 ET-1 or IRL 1620 (10-II_ 10-6 M) alone did not activate alveolar macrophages in vitro, whereas at a concentration of 10-8 M, ET-1, but not IRL 1620, markedly potentiated superoxide production in response to f-Met-Leu-Phe (10-9-10-7 M) and platelet-activating factor (PAF, 10-9-10-7 M), but not to phorbol 12-myristate 13-acetate (10-9 M). ET-1 did not affect f-Met-Leu-Phe-or PAF-induced increases in intracellular free calcium concentration. This potentiating effect of ET-1 was abolished by FR 139317 (1.5 X 10-7 M). 5 We conclude that, in addition to evoking airway contractions, ET-1 exerts pro-inflammatory actions via activation of the ETA and to a lesser extent the ETB receptors, and therefore, might contribute to the airway inflammation present in asthma. These findings also suggest the therapeutic potential of ETA/ETB receptor and perhaps ETA receptor-selective antagonists in this disease.

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Section: Introductionmentioning

confidence: 99%

Acute pro‐inflammatory actions of endothelin‐1 in the guinea‐pig lung: involvement of ET_A and ET_B receptors

Filep

Fournier

Földes-Filep

1995

British J Pharmacology

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“…It may be that endothelin, the most potent vasoconstrictor substance yet isolated, has properties which are relevant to respiratory diseases such as asthma. In a recent report, markedly elevated levels of endothelin were detected in the lavage fluid of a patient in 'status asthmaticus' (Nomura et al, 1989). Little is known of the conditions under which endothelin is released but hypoxia (Hiley, 1989) or a decrease in temperature (Fyhrquist et al, 1990) may be provoking stimuli, both of these factors being associated with asthma.…”

Section: Introductionmentioning

confidence: 99%

The mechanism of action of endothelin in human lung

McKay

Black

Armour

1991

British J Pharmacology

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1 The peptides endothelin-1 (ET-1) and endothelin-2 (ET-2) elicited potent and sustained contractions of human isolated bronchus and pulmonary artery. 2 ET-1 is one of the most potent contractile agonists investigated in these tissues with an EC50 value of 18.3 nm (95% confidence interval: 12.9, 25.9 nM; n = 26) in bronchus and 3.2 nm (95% confidence interval: 0.4, 23.9 nM; n = 5) in the arterial preparation. 3 ET-1 is 2.5 times more potent than ET-2 in both the airway and vascular tissues, and both forms of the peptide have geometric mean EC50 values 5 times greater in the isolated bronchial tissue than in the pulmonary artery.4 Neither pretreatment with the voltage-dependent calcium (VDC) channel antagonist verapamil (1O#M) nor with indomethacin (25 pM) significantly altered the response curve to ET-1 in human isolated bronchus. Removal of calcium from the Krebs-Henseleit solution did not affect ET-1-induced responses. 5 Specific binding on the smooth muscle of human airway and pulmonary arterial tissue to both ET-1 and ET-2 was detected in autoradiographic studies. There appeared to be no difference between the peptides in the location nor the density of binding sites. 6 We conclude that contraction of human bronchial tissue by ET-1 is not dependent upon influence of extracellular calcium nor release of prostaglandins or thromboxane A2. It is likely that the action of ET-1 in this tissue is due to binding of this peptide to specific receptors located on the smooth muscle.

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“…The bronchoalveolar levels of immunoreactive endothelin are increased in asthmatic patients (170,171). Bronchial epithelial cells obtained from asthmatics expressed preproendothelin-1 mRNA and released significant quantites of endothelin-1 into the culture medium, whereas those from normal humans did not (172).…”

Section: V-2 Pulmonary Hypertensionmentioning

confidence: 96%

Molecular Pharmacology and Pathophysiological Significance of Endothelin

Goto

Hama

Kasuya

1996

Japanese Journal of Pharmacology

159

108

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ABSTRACT-Since the discovery of the most potent vasoconstrictor peptide, endothelin, in 1988, explosive investigations have rapidly clarified much of the basic pharmacological, biochemical and molecular biological features of endothelin, including the presence and structure of isopeptides and their genes (endothelin-1, -2 and -3), regulation of gene expression, intracellular processing, specific endothelia converting enzyme (ECE), receptor subtypes (ETA and ETB), intracellular signal transduction following receptor activation, etc. ECE was recently cloned, and its structure was shown to be a single transmembrane protein with a short intracellular N-terminal and a long extracellular C-terminal that contains the catalytic domain and numerous N-glycosylation sites. In addition to acute contractile or secretory actions, endothelin has been shown to exert long-term proliferative actions on many cell types. In this case, intracellular signal transduction appears to converge to activation of mitogen-activated protein kinase. As a recent dramatic advance, a number of non-peptide and orally active receptor antagonists have been developed. They, as well as current peptide antagonists, markedly accelerated the pace of investigations into the true pathophysiological roles of endogenous endothelin-1 in mature animals; e.g., hypertension, pulmonary hypertension, acute renal failure, cerebral vasospasm, vascular thickening, cardiac hypertrophy, chronic heart failure, etc. Thus, the interference with the endothelin pathway by either ECE-inhibition or receptor blockade may

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Endothelin and Bronchial Asthma

Cited by 100 publications

References 3 publications

Acute pro‐inflammatory actions of endothelin‐1 in the guinea‐pig lung: involvement of ET_A and ET_B receptors

Acute pro‐inflammatory actions of endothelin‐1 in the guinea‐pig lung: involvement of ET_A and ET_B receptors

The mechanism of action of endothelin in human lung

Molecular Pharmacology and Pathophysiological Significance of Endothelin

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Endothelin and Bronchial Asthma

Cited by 100 publications

References 3 publications

Acute pro‐inflammatory actions of endothelin‐1 in the guinea‐pig lung: involvement of ETA and ETB receptors

Acute pro‐inflammatory actions of endothelin‐1 in the guinea‐pig lung: involvement of ETA and ETB receptors

The mechanism of action of endothelin in human lung

Molecular Pharmacology and Pathophysiological Significance of Endothelin

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Product

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Acute pro‐inflammatory actions of endothelin‐1 in the guinea‐pig lung: involvement of ET_A and ET_B receptors

Acute pro‐inflammatory actions of endothelin‐1 in the guinea‐pig lung: involvement of ET_A and ET_B receptors