Characterization of the endothelin receptor subtype mediating epithelium‐derived relaxant nitric oxide release from guinea‐pig trachea

Emanueli, Costanza; Ricciardolo, Fabio Luigi Massimo; Vergnani, L; Bertrand, Claude; Ricci, Franco; Manzoli, Nadia; Folkerts, Gert; Nijkamp, Frans P.; Geppetti, Pierangelo

doi:10.1038/sj.bjp.0702174

Cited by 14 publications

(9 citation statements)

References 19 publications

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“…The most evident consequences of ET A -and ET B -receptor activation in the lungs are vasoconstriction and bronchoconstriction, respectively (Michael and Markewitz 1996). However, both receptor subtypes also counteract these pressor responses by causing release of NO and dilatory prostaglandins (Uhlig et al 1995;Lal et al 1996;Clement et al 1998;Emanueli et al 1998). Thus, activation of ET A -receptors on presumably airway epithelial cells leads to relaxation of airway smooth muscle, while activation of ET Breceptors on endothelial cells results in vascular smooth muscle relaxation.…”

Section: Discussionmentioning

confidence: 93%

Differential effects of the mixed ET A /ET B -receptor antagonist bosentan on endothelin-induced bronchoconstriction, vasoconstriction and prostacyclin release

Martin

Held

Uhlig

2000

Naunyn-Schmiedeberg's Archives of Pharmacology

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Endothelins are a family of potent endogenous mediators that have been implicated in a number of airway and other diseases. Recently, the non-peptide mixed ET(A)/ET(B) endothelin receptor antagonist bosentan has been successfully tested in the treatment of cardiovascular diseases. It was the aim of the present study to characterize the effects of bosentan on the pulmonary actions of endothelin- (ET-1), endothelin-3 (ET-3) and the ET(B)-receptor agonist IRL1620 in the isolated perfused and ventilated rat lung (IPL) and in precision-cut lung slices (PCLS). In the IPL, bosentan completely prevented the IRL1620-induced vasoconstriction (IC50 3 microM). The inhibition by bosentan of ET-1-elicited vasoconstriction showed a biphasic course, reflecting the inhibition of ET(A)-and ET(B)-mediated vasoconstriction (IC50 0.2 microM and 19 microM, respectively). In addition, bosentan prevented the ET-1- (IC50 6 microM) and IRL1620-induced (IC50 3 microM) prostacyclin release. Bosentan also completely prevented the bronchoconstriction induced by IRL1620 in the IPL (IC50 20 microM) and in PCLS (IC50 13 microM). In PCLS, the pD2-values were ET-1 7.20+/-0.23, ET-3 7.51+/-0.27 and IRL1620 7.33+/-0.29. Bosentan at 100 microM caused a rightward shift of the concentration-response curve of ET-1, ET-3 and IRL1620 by a factor of 5, 46 and 64, respectively. In all cases the slope of the Schild regression was lower than unity, disregarding a simple interaction of bosentan with one receptor. With respect to ET-1-induced bronchoconstriction, in the IPL bosentan in concentrations of up to 10 microM aggravated ET-1-induced bronchoconstriction probably due to the blockade of bronchodilatory ET(A)-receptors (IC50 0.3 microM) and even at 100 microM showed only very little protection from ET- -induced bronchoconstriction in the IPL and in the PCLS. The similar IC50-values for ET-1-induced vasoconstriction and bronchodilation suggest that only one type of ET(A)-receptor is involved. The differing IC50-values between IRL1620-induced bronchoconstriction and prostacyclin release, the slope of the Schild regression and the failure of bosentan to prevent the ET-1-induced bronchoconstriction suggest a complex interaction between the known ET-receptors or the existence of unknown ET(B)-receptor subtypes.

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Section: Discussionmentioning

confidence: 93%

Differential effects of the mixed ET A /ET B -receptor antagonist bosentan on endothelin-induced bronchoconstriction, vasoconstriction and prostacyclin release

Martin

Held

Uhlig

2000

Naunyn-Schmiedeberg's Archives of Pharmacology

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“…Bradykinin, endothelin-1, substance P, adenosine, and calcitonin-gene related peptide, applied to the inside of intact tracheal tubes, provoke concentration-dependent relaxations (9,93,(101)(102)(103)316). The relaxations are reversed into contractions (or contractions are markedly potentiated) by NOS inhibitors, indicating that the relaxant effect in the airways is mediated by the release of endogenous NO (9,93,(101)(102)(103)316).…”

Section: In Vitro Studiesmentioning

confidence: 93%

“…The relaxations are reversed into contractions (or contractions are markedly potentiated) by NOS inhibitors, indicating that the relaxant effect in the airways is mediated by the release of endogenous NO (9,93,(101)(102)(103)316). This effect was mimicked by removal of airway epithelium (111), suggesting that airway epithelium releases NO, which counteracts smooth muscle contraction induced by different spasmogens (9,93,(101)(102)(103)316). These striking results demonstrate the functional importance of epithelium in airway reactivity, not merely considered as a physical protective barrier between spasmogens and smooth muscle but as a modulator of bronchomotor tone via the release of relaxant substances (so-called epithelium-derived relaxing factors).…”

Section: In Vitro Studiesmentioning

confidence: 99%

Nitric Oxide in Health and Disease of the Respiratory System

Ricciardolo¹,

Sterk²,

Gaston³

et al. 2004

Physiological Reviews

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773

649

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During the past decade a plethora of studies have unravelled the multiple roles of nitric oxide (NO) in airway physiology and pathophysiology. In the respiratory tract, NO is produced by a wide variety of cell types and is generated via oxidation of l-arginine that is catalyzed by the enzyme NO synthase (NOS). NOS exists in three distinct isoforms: neuronal NOS (nNOS), inducible NOS (iNOS), and endothelial NOS (eNOS). NO derived from the constitutive isoforms of NOS (nNOS and eNOS) and other NO-adduct molecules (nitrosothiols) have been shown to be modulators of bronchomotor tone. On the other hand, NO derived from iNOS seems to be a proinflammatory mediator with immunomodulatory effects. The concentration of this molecule in exhaled air is abnormal in activated states of different inflammatory airway diseases, and its monitoring is potentially a major advance in the management of, e.g., asthma. Finally, the production of NO under oxidative stress conditions secondarily generates strong oxidizing agents (reactive nitrogen species) that may modulate the development of chronic inflammatory airway diseases and/or amplify the inflammatory response. The fundamental mechanisms driving the altered NO bioactivity under pathological conditions still need to be fully clarified, because their regulation provides a novel target in the prevention and treatment of chronic inflammatory diseases of the airways.

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“…These findings suggest that bradykinin releases bronchodilator NO from the guinea-pig airway epithelium. A similar bronchodilator mechanism has been shown to be activated by other mediators, including histamine (20), substance P (33), endothelin (34), and others (35).…”

Section: Discussionmentioning

confidence: 95%

Detection of Nitric Oxide Release Induced by Bradykinin in Guinea Pig Trachea and Main Bronchi Using a Porphyrinic Microsensor

Ricciardolo¹,

Vergnani²,

Wiegand³

et al. 2000

Am J Respir Cell Mol Biol

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Indirect evidence using nitric oxide (NO) synthase (NOS) inhibitors suggests that in guinea-pig airways bradykinin releases bronchoprotective NO. In this study, using a recently developed electrochemical method of NO measurement based on a porphyrinic microsensor, we investigated whether bradykinin releases NO from guinea-pig airways and whether the epithelium is the main source of NO. Further, the Ca(2+)-dependence of bradykinin-induced NO release was assessed stimulating airway preparations with bradykinin in Ca(2+)-free conditions. We also studied the immunohistochemical distribution of the Ca(2+)- dependent constitutive isoforms of NOS (constitutive NOS [cNOS]: neuronal and endothelial [ecNOS]) in our preparations. The porphyrinic microsensor was placed in the bathing fluid onto the mucosal surface of tracheal or main bronchial segments. Addition of bradykinin vehicle (0.9% saline) did not cause any detectable change of the baseline signal. Addition of bradykinin caused an upward shift of the baseline that reached a maximum within 1 to 2 s. The amplitude of the response to bradykinin was concentration-dependent between the range 1 nM to 10 microM, with a maximum effect at 10 microM. Bradykinin-induced NO release was higher in tracheal than in main bronchial segments. The selective bradykinin B(2) receptor antagonist D-Arg(0)-[Hyp(3), Thi(5), D-Tic(7), Oic(8)]bradykinin (1 microM) inhibited NO release induced by a submaximum concentration of bradykinin (1 microM). The ability of bradykinin to release NO was markedly reduced in epithelium-denuded segments, and abolished in Ca(2+)-free conditions and after pretreatment with N(G)-monomethyl-L-arginine (100 microM), but not with N(G)-monomethyl-D-arginine. Both cNOS isoforms were present in trachea and main bronchi, ecNOS being the predominant isoform in the epithelium. The study shows that bradykinin via B(2) receptor activation caused a rapid and Ca(2+)-dependent release of NO, mainly, but not exclusively, derived from the epithelium. It also shows that both cNOS isoforms may be involved in bradykinin-evoked NO release.

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Characterization of the endothelin receptor subtype mediating epithelium‐derived relaxant nitric oxide release from guinea‐pig trachea

Cited by 14 publications

References 19 publications

Differential effects of the mixed ET A /ET B -receptor antagonist bosentan on endothelin-induced bronchoconstriction, vasoconstriction and prostacyclin release

Differential effects of the mixed ET A /ET B -receptor antagonist bosentan on endothelin-induced bronchoconstriction, vasoconstriction and prostacyclin release

Nitric Oxide in Health and Disease of the Respiratory System

Detection of Nitric Oxide Release Induced by Bradykinin in Guinea Pig Trachea and Main Bronchi Using a Porphyrinic Microsensor

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