Endothelin receptor subtypes in human and guinea‐pig pulmonary tissues

Hay, Douglas W. P.; Luttmann, Mark A.; Hubbard, Walter C.; Undem, Bradley J.

doi:10.1111/j.1476-5381.1993.tb13938.x

Cited by 109 publications

(110 citation statements)

References 53 publications

(62 reference statements)

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“…For example, ET-1-induced contraction in guinea-pig bronchus was mediated predominantly via ETB receptors (Hay, 1992), although evidence for multiple receptor subtypes in this tissue has been reported (Tschirhart et al, 1991). Furthermore, ETB receptors were also primarily responsible for mediating ET-1-induced contraction in human bronchus (Hay et al, 1993). However, in rat trachea, both ETA and ET5 receptors coexisted in approximately equal proportions and mediated responses which made approximately equivalent contributions to ET-1-induced increases in airway smooth muscle tone (Henry, 1993).…”

Section: Discussionmentioning

confidence: 99%

Predominance of endothelin_A (ET_A) receptors in ovine airway smooth muscle and their mediation of ET‐1‐induced contraction

Goldie

Grayson

Knott

et al. 1994

British J Pharmacology

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1 Autoradiographic studies were conducted to investigate the receptor subtypes for endothelin-I that were present in the ovine respiratory tract. In addition, the receptor subtypes mediating contraction of airway smooth muscle and the possible involvement of extracellular Ca2" and inositol phosphate generation in intracellular signal transduction were assessed.2 Specific [251I]-ET-1 binding in ovine trachea increased in a time-and concentration-dependent manner. Autoradiographic studies demonstrated that significant binding was associated with airway smooth muscle, although higher densities of specific binding were associated with submucosal glands and with cells immediately below the epithelial basement membrane (lamina propria). The ETA receptorselective antagonist, BQ 123 (1 AM), virtually abolished specific binding to airway smooth muscle.Quantitative analyses of autoradiographic data describing the time-dependence of specific ['2511]-ET-1 binding in ovine airway smooth muscle in the presence and absence of BQ 123 or sarafotoxin S6c, revealed a homogeneous population of ETA receptors. BQ 123 (1 JtM) also abolished specific binding to structures associated with submucosal glands, whereas the ETB receptor selective agonist, sarafotoxin S6c (100 nM) had little effect on this binding, indicating the predominance of ETA receptors at these sites. In contrast, ETB receptors predominated in the lamina propria, since sarafotoxin S6c abolished specific binding in this tissue.3 High levels of specific ['251]-ET-l binding were also detected in the alveoli and in the walls of blood vessels and small airways in ovine peripheral lung. Specific binding associated with alveoli was reduced to similar extents by BQ 123 (1 M; 54%) and sarafotoxin S6c (100 nM; 40%), suggesting the coexistence of both ETA and ETB receptors in approximately equal proportions in this tissue. In contrast, specific binding to blood vessels and to peripheral bronchial smooth muscle was abolished in the presence of BQ 123 (1 tM), but was unaffected by sarafotoxin S6c, indicating the presence of only ETA receptors at these sites. 4 ET-1 caused concentration-dependent contractions of ovine tracheal smooth muscle which were inhibited in the presence of BQ 123 (1 JLM). ET-1 also caused concentration-dependent contraction of ovine lung parenchyma strips. In contrast, the ETB receptor-selective agonists, sarafotoxin S6c and BQ 3020, were virtually inactive as spasmogens in both tracheal smooth muscle and lung strip preparations. Thus contraction was mediated by ETA receptors in ovine tracheal smooth muscle and this is consistent with binding and autoradiographic data demonstrating a homogeneous population of these binding sites in this tissue. Contraction of parenchymal lung strip preparations to ET-1 was mediated via non-ETB receptors, presumably ETA receptors, with contributions to this response perhaps coming from airway and vascular smooth muscle and from alveolar wall contractile cells. 5 ET-1-induced contraction of tracheal smooth muscle was not signi...

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Section: Discussionmentioning

confidence: 99%

Predominance of endothelin_A (ET_A) receptors in ovine airway smooth muscle and their mediation of ET‐1‐induced contraction

Goldie

Grayson

Knott

et al. 1994

British J Pharmacology

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“…It has been suggested that ET-1 may be involved in the regulation of vascular tone in the foetomaternal region during pregnancy since it has been found to increase to high levels in plasma during delivery (Nisell et al, 1990). Although the pharmacology of ETs has been extensively studied in blood vessels of various animal species (for a recent review see Rubanyi & Polokoff, 1994), few studies have been performed in vessels of human origin (Hemsen et al, 1991;Hay et al, 1993;Maguire & Davenport, 1995;Bacon & Davenport, 1996). The …”

Section: Introduction Methodsmentioning

confidence: 99%

Characterization of endothelin receptors in the human umbilical artery and vein

Bogoni

Rizzi

Calò

et al. 1996

British J Pharmacology

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1The aim of the present study was to characterize pharmacologically endothelin receptors that are present in human umbilical vessels. 2 Endothelin-1 (ET-1) and endothelin-2 (ET-2) are potent stimulants of both the human umbilical artery (pEC5o 7.9 and 7.5) and vein (pEC50 8.1 and 8.0). Endothelin-3 (ET-3) is inactive on the artery but contracts the vein (pEC50 7.6). IRL1620 is inactive in both vessels. The order of potency of agonists is suggestive of a typical ETA receptor in the artery (ET-1 = ET-2 > > ET-3) and a mixture of ETA and ETB receptors in the vein (ET-1 = ET-2> ET-3). 3 The selective ETA receptor antagonist, BQ123, competitively inhibits the effect of ET-1 in the human umbilical artery (pA2 6.9), while in the vein, only a mixture of BQ123 and BQ788 (a selective ETB antagonist) weakly displaces to the right the cumulative concentration-response curve to ET-1. Contractions induced by ET-3 in the vein are inhibited by BQ788 (pA2 7.6), but not by BQ123.4 Inhibition of Ca21 channels by nifedipine (0.1 ,uM) is accompanied by a significant decrease of the maximal response to ET-1 by 40% in the artery and by 30% in the vein. The response of the vein to ET-3 is almost abolished by nifedipine. 5 The results indicate that: (i) endothelins contract the human isolated umbilical artery via stimulation of an ETA receptor type; (ii) the contraction induced by ET-1 in the vein is mediated by both ETA and ETB receptors, while ET-3 stimulates the ETB receptor; (iii) the contribution of Ca21 channels to the contraction mediated by the ETB receptor appears to be more important than to that mediated by the ETA receptor.

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“…However, the vast majority of the binding sites for ET-1 on bronchial smooth muscle cells consists of ET B receptors. Consequently, in humans and guinea pigs, the ET A receptor antagonist BQ-123 antagonized ET-1-induced contraction of the pulmonary artery, but had no effect on bronchoconstriction, which was, on the other hand, markedly enhanced by application of the ET B agonist sarafotoxin S6c (12). In line with these findings, there was no bronchodilating effect due to inhaled LU-135252 in our study; moreover, mean airway pressure of volume-controlled mechanical ventilation remained unchanged in both groups.…”

Section: Discussionmentioning

confidence: 99%

Inhalation of the ET_Areceptor antagonist LU-135252 selectively attenuates hypoxic pulmonary vasoconstriction

Petersen¹,

Deja²,

Bartholdy³

et al. 2008

American Journal of Physiology-Regulatory, Integrative and Comp

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(ET)-1 modulates hypoxic pulmonary vasoconstriction (HPV). Accordingly, intravenously applied ET A receptor antagonists reduce HPV, but this is accompanied by systemic vasodilation. We hypothesized that inhalation of an ET A receptor antagonist might act selectively on the pulmonary vasculature and investigated the effects of aerosolized LU-135252 in an experimental model of HPV. Sixteen piglets (weight: 25 Ϯ 1 kg) were anesthetized and mechanically ventilated at an inspiratory oxygen fraction (FI O 2 ) of 0.3. After 1 h of hypoxia at FI O 2 0.15, animals were randomly assigned either to receive aerosolized LU-135252 as bolus (0.3 mg/kg for 20 min; n ϭ 8, LU group), or to receive aerosolized saline (n ϭ 8, controls). In all animals, hypoxia significantly increased mean pulmonary arterial pressure (32 Ϯ 1 vs. 23 Ϯ 1 mmHg; P Ͻ 0.01; means Ϯ SE) and increased arterial plasma ET-1 (0.52 Ϯ 0.04 vs. 0.37 Ϯ 0.05 fmol/ml; P Ͻ 0.01) compared with mild hyperoxia at FI O 2 0.3. Inhalation of LU-135252 induced a significant and sustained decrease in mean pulmonary arterial pressure compared with controls (LU group: 27 Ϯ 1 mmHg; controls: 32 Ϯ 1 mmHg; values at 4 h of hypoxia; P Ͻ 0.01). In parallel, mean systemic arterial pressure and cardiac output remained stable and were not significantly different from control values. Consequently, in our experimental model of HPV, the inhaled ET A receptor antagonist LU-135252 induced selective pulmonary vasodilation without adverse systemic hemodynamic effects. inhalation; selective pulmonary vasodilation; pulmonary arterial hypertension PULMONARY ARTERIAL HYPERTENSION (PAH) can appear in a chronic, progressive ideopatic form, or as a consequence of acute cardiopulmonary decompensation, such as pulmonary embolism. In addition, PAH occurs together with chronic obstructive lung disease or chronic high-altitude exposure (23). A main pathophysiological mechanism for PAH consists of an imbalance between endogenously produced vasodilating and constricting mediators (14). In particular, increased concentrations of the potent constricting peptide endothelin (ET)-1 (11) have been identified as a major characteristic for PAH. The effects of ET-1 to increase pulmonary vascular tone are mediated by ET A and ET B receptors on smooth muscle cells, while ET B receptors at the pulmonary endothelium cause vasodilation (2). Consequently, blockade of pulmonary ET A receptors is an important option for the treatment of PAH, and the use of the dual ET A /ET B receptor antagonist bosentan has been proven to induce clinically relevant improvements with respect to pulmonary hemodynamics and exercise capacity (22). Currently, the selective ET A receptor antagonists sitaxsentan and ambrisetan are evaluated for the treatment of PAH (1, 10).A serious disadvantage of any orally or intravenously applied vasodilator in PAH consists of the systemic vasodilation, which parallels the beneficial pulmonary effects. This may not only reduce exercise capacity, but will become deleterious in hemodynamically unstable patien...

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Endothelin receptor subtypes in human and guinea‐pig pulmonary tissues

Cited by 109 publications

References 53 publications

Predominance of endothelin_A (ET_A) receptors in ovine airway smooth muscle and their mediation of ET‐1‐induced contraction

Predominance of endothelin_A (ET_A) receptors in ovine airway smooth muscle and their mediation of ET‐1‐induced contraction

Characterization of endothelin receptors in the human umbilical artery and vein

Inhalation of the ET_Areceptor antagonist LU-135252 selectively attenuates hypoxic pulmonary vasoconstriction

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Endothelin receptor subtypes in human and guinea‐pig pulmonary tissues

Cited by 109 publications

References 53 publications

Predominance of endothelinA (ETA) receptors in ovine airway smooth muscle and their mediation of ET‐1‐induced contraction

Predominance of endothelinA (ETA) receptors in ovine airway smooth muscle and their mediation of ET‐1‐induced contraction

Characterization of endothelin receptors in the human umbilical artery and vein

Inhalation of the ETAreceptor antagonist LU-135252 selectively attenuates hypoxic pulmonary vasoconstriction

Contact Info

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Predominance of endothelin_A (ET_A) receptors in ovine airway smooth muscle and their mediation of ET‐1‐induced contraction

Predominance of endothelin_A (ET_A) receptors in ovine airway smooth muscle and their mediation of ET‐1‐induced contraction

Inhalation of the ET_Areceptor antagonist LU-135252 selectively attenuates hypoxic pulmonary vasoconstriction