Role of the neutral endopeptidase 24.11 in the conversion of big endothelins in guinea‐pig lung parenchyma

Lebel, Nathalie; D’Orléans-Juste, Pedro; Fournier, Alain; Sirois, Pierré

doi:10.1111/j.1476-5381.1996.tb15172.x

Cited by 15 publications

(8 citation statements)

References 46 publications

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“…The suppressor effects of thiophan on ET-1 (1-31)-induced eicosanoid release highlight the possible production of a bioactive metabolite of ET-1 (1-31) by NEP 24.11. Furthermore, the big ET-1 response is also altered by thiophan in parenchymal strips of guinea pig lung, as reported previously by Lebel et al [12].…”

Section: Discussionsupporting

confidence: 68%

Endothelin-1 (1-31) induces a thiorphan-sensitive release of eicosanoids via ETB receptors in the guinea pig perfused lung

et al. 2002

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A B S T R A C TMaturation of big endothelin-1 (big ET-1) commonly produces the 21 amino acid vasoactive ET-1, which binds two ET receptors (ET A and ET B ) to produce its effects. In the guinea pig, the systemic administration of ET-1 produces a bronchoconstrictor response that is mediated indirectly via the release of thromboxane A 2 through ET B receptor activation. A new potent metabolite of big ET-1, ET-1 (1-31), has been reported to act as an ET A receptor selective agonist. In this study we investigated the effects of ET-1 (1-31), compared with ET-1, on the release of eicosanoids in the isolated and perfused guinea pig lung. We also clarified the implication of ET receptors in these effects using selective ET A or ET B receptor antagonists, BQ-123 and BQ-788 respectively. Finally, using the neutral endopeptidase 24.11 (NEP 24.11) inhibitor, thiorphan, we determined the involvement of this enzyme on ET-1 (1-31) effects. Infusion of ET-1 (1-31) (50 nM) stimulates a marked release of thromboxane A 2 and prostacyclin equivalent to that observed with a ten times lower concentration of ET-1 (5 nM). BQ-788 (5 nM and 10 nM), but not BQ-123 (1 µM), decreases the release of thromboxane A 2 and prostacyclin triggered by both agonists. Interestingly, thiorphan (25 µM) abolishes the eicosanoid-releasing properties of big ET-1 (100 nM) and ET-1 (1-31). This study demonstrates that ET-1 (1-31) is less potent than ET-1 in stimulating the release of eicosanoids through ET B receptor activation in the guinea pig perfused lung. Moreover, the inhibitory properties of thiorphan indicate the possible existence of a bioactive metabolite of ET-1 (1-31). We therefore suggest that NEP 24.11 in the pulmonary vasculature, is implicated in the cleavage of ET-1 (1-31) to produce ET-1 which will further act on both ET receptors.

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Section: Discussionsupporting

confidence: 68%

Endothelin-1 (1-31) induces a thiorphan-sensitive release of eicosanoids via ETB receptors in the guinea pig perfused lung

et al. 2002

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“…CGS 26303 is a potent inhibitor of neutral endopeptidase (NEP) 24.11 as well as ECE and thus due consideration must be given to the possibility that the effects observed in the current study may, at least in part, have resulted from NEP inhibition. NEP is present in the airway epithelium of several animal species, including humans [26, 27], and is thought to play a role in the catabolism of ET‐1 [14, 28]. Thus, in the present study, CGS 26303‐induced inhibition of NEP may have had several effects.…”

Section: Discussionmentioning

confidence: 72%

The role of endothelin in mediating virus‐induced changes in endothelinB receptor density in mouse airways

Henry¹,

Carr²,

Goldie³

et al. 1999

Eur Respir J

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Emerging evidence supports a mediator role for endothelin (ET)-1 in airway diseases including asthma. Respiratory tract viral infections, are associated with increased levels of ET and altered ET receptor density and function in murine airways. To determine whether these virus-induced effects are causally linked, perhaps involving ET-1-induced ET B receptor downregulation, the current study investigated the influence of in vivo administration of CGS 26303, an ET-converting enzyme inhibitor, on virus-induced changes in ET-content and ET B receptor density.CGS 26303 (5 mg . kg -1 . day -1) or placebo was administered to mice via osmotic minipumps implanted subcutaneously. Two days after implantation, mice were inoculated with influenza A/PR-8/34 virus or sham-infected, and all measurements were performed on tissue obtained on the fourth day post-inoculation.Viral infection was associated with elevated levels of immunoreactive ET and decreased densities of ET B receptors in murine airways. Both of these effects were attenuated in virus-infected mice that had received CGS 26303. Virus-induced increases in wet lung weight were also inhibited by CGS 26303. Importantly, administration of CGS 26303 had no effect on the titres of infectious virus in the lungs and similarly, viral infection had no effect on the plasma levels of free CGS 26303.In summary, CGS 26303 inhibited the virus-induced changes in both immunoreactive endothelin content and endothelin B receptor density. These findings are consistent with the postulate that the elevated epithelial expression of endothelin-1 during respiratory tract viral infection is a contributing factor in the downregulation of endothelin B receptors in airway smooth muscle. Whether inhibitors of endothelin synthesis attenuate virus-induced exacerbations of asthma or airways hyperresponsiveness remains to be established. Eur Respir J 1999; 14: 92±97. The levels of endothelin (ET)-1 in the airways are significantly elevated in respiratory diseases such as asthma [1] as well as in several animal models of airways disease, including allergic inflammation [2,3] and respiratory tract viral infection [4]. ET-1, via its potent actions on a raft of different cell types within the airways and lungs (for review see [5]), may contribute significantly to airway wall remodelling, oedema, bronchial obstruction, long-lasting bronchoconstriction and the development of airway hyperresponsiveness in asthma and during respiratory tract viral infections.Respiratory syncitial virus induces the expression of ET-1 in bronchial epithelial cells [6] and the levels of immunoreactive (ir)-ET-1 are elevated in murine airways and lung during influenza A viral infection [4]. Increases in the production of ET-1 by the airway epithelium would be expected to lead to enhanced stimulation of ET A and ET B receptors in adjacent tissues such as the airway smooth muscle. However, respiratory tract viral infection in mice was associated with reductions in ET B receptor density, which was reflected in attenuated...

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“…NEP is involved in the metabolism of other vasoactive peptides, such as bradykinin (39,40) and adrenomedullin (41), which were not investigated; therefore, accumulation of these peptides in the plasma or tissues may play a role in the decrease in BP. The in vivo modulation of endothelin metabolism by NEP (42,43) cannot explain the difference in BP-lowering efficacy between omapatrilat and fosinopril, according to our measurements of plasma endothelins. Omapatrilat slightly and transiently increased plasma Big-ET1 concentrations and had no effect on plasma ET1 concentrations.…”

Section: Effects Of Sodium Balance On Omapatrilat-induced Changes In mentioning

confidence: 99%

Physiologic Consequences of Vasopeptidase Inhibition in Humans

Azizi

Lamarre-Cliché²,

Labatide-Alanore³

et al. 2002

Journal of the American Society of Nephrology

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Abstract. The in vivo inhibition of angiotensin-converting enzyme (ACE) and neutral endopeptidase (NEP) were monitored simultaneously by sequentially measuring the urinary excretion of N-Acetyl-Ser-Asp-Lys-Pro and of the atrial natriuretic factor to compare the magnitude and the duration of action of a vasopeptidase inhibitor, omapatrilat, and an ACE inhibitor, fosinopril. Single oral doses of 40 or 80 mg of omapatrilat or 20 mg of fosinopril were administered to 24 normotensive, sodiumdepleted or -replete volunteers in a placebo-controlled crossover study. ACE inhibition persisted longer after treatment with omapatrilat than with fosinopril, and there was no major difference between the effects of 40 and 80 mg of omapatrilat. The duration of NEP inhibition by omapatrilat was shorter than that of ACE inhibition. Although omapatrilat effectively inhibited NEP, it had a mild and transient natriuretic effect and did not increase natriuresis more than fosinopril. Omapatrilat induced a decrease in BP and an increase in plasma renin more rapidly and more effectively than fosinopril. The BP and renin effects of omapatrilat persisted despite high sodium intake, which neutralized the effects of fosinopril. The simultaneous inhibition of ACE and NEP may be more effective in reducing BP than the inhibition of ACE alone and less dependent on sodium balance.Omapatrilat is a vasopeptidase inhibitor that has a similar nanomolar inhibitory constant for both neutral endopeptidase (NEP) and angiotensin I-converting enzyme (ACE) in vitro (1). This drug is designed to treat hypertension (2) and congestive heart failure (3,4). In animal models, NEP inhibition may have additional beneficial effects on target organs damage beyond ACE inhibition (5-8). Omapatrilat was shown to have a greater antihypertensive efficacy in hypertensive patients than ACE inhibitors, such as lisinopril (9,10) or enalapril (11). Vasopeptidase inhibition could have an advantage over selective ACE inhibition for the treatment of patients with congestive heart failure. However, the beneficial effect of omapatrilat on cardiovascular morbidity compared with lisinopril in patients with congestive heart failure suggested by the IMPRESS study (4) has not been confirmed by the results of the OVERTURE study (12), in which no significant difference in terms of cardiovascular morbidity or mortality between 40 mg of omapatrilat daily and 10 mg of enalapril twice daily was reported.We have previously reported the BP and hormonal effects of a single oral dose of 10 mg of omapatrilat in sodium-depleted normotensive subjects (13). Omapatrilat (10 mg) had a shorter BP-lowering effect than a single oral dose of 20 mg of fosinopril, despite the fact that, at the dose used, both drugs appeared to have a similar potency in inhibiting ACE, whereas omapatrilat, by inhibiting NEP, increased urinary atrial natriuretic peptide (ANP) and blunted the decrease in plasma ANP due to ACE inhibition (13).The doses of omapatrilat subsequently used in the clinical development program were high...

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Role of the neutral endopeptidase 24.11 in the conversion of big endothelins in guinea‐pig lung parenchyma

Cited by 15 publications

References 46 publications

Endothelin-1 (1-31) induces a thiorphan-sensitive release of eicosanoids via ETB receptors in the guinea pig perfused lung

Endothelin-1 (1-31) induces a thiorphan-sensitive release of eicosanoids via ETB receptors in the guinea pig perfused lung

The role of endothelin in mediating virus‐induced changes in endothelinB receptor density in mouse airways

Physiologic Consequences of Vasopeptidase Inhibition in Humans

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