Abstract
The cysteinyl leukotrienes (CysLTs) LTC4, LTD4 and LTE4 are potent proinflammatory lipid mediators that play a central role in inflammation, contraction and remodelling of airways observed in asthmatics. Montelukast, a competitive inhibitor of the cysteinyl leukotriene-1 (CysLT1) receptor attenuates asthmatic airway inflammation, contraction and remodelling. As a number of studies have shown that montelukast reduced exhaled nitric oxide (NO) levels, a marker of inflammation that correlates with the severity of asthma, we investigated whether or not a direct inhibition of NO synthase (NOS) by montelukast takes place. In an ex vivo rat lung perfusion and ventilation model the NOS-dependent vasodilation effect after lipopolysaccharide (LPS) infusion was assessed with and without montelukast. Functional organ bath studies using isolated aortic rings from the same species aimed to assess effects of montelukast on the inducible and endothelial NOS isoenzymes (i- and eNOS) as well as on iNOS expression. Neuronal NOS (nNOS) was assessed by field stimulated rabbit corpus cavernosum, and isolated human iNOS enzyme activity was assessed for potential inhibition. Montelukast failed to cause vasoconstriction in LPS challenged rat lung, or to inhibit i- and eNOS activity as well as iNOS expression in aortic rings from the same species. Also the assays for nNOS in rabbit corpus cavernosum and on isolated human iNOS enzyme gave no evidence for a direct inhibition by montelukast in physiological and supraphysiological concentrations up to 10-4 M. We therefore conclude that montelukast has no acute NOS inhibitor action. Its effect on exhaled NO is therefore probably indirectly mediated by a modulation of the asthmatic airway inflammation.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 525-533 |
| Number of pages | 9 |
| Journal | Pulmonary Pharmacology and Therapeutics |
| Volume | 20 |
| Issue number | 5 |
| DOIs | |
| State | Published - Oct 1 2007 |
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Keywords
- Leukotrienes
- Lung vascular resistance
- Montelukast
- Nitric oxide synthases
ASJC Scopus subject areas
- Pulmonary and Respiratory Medicine
- Biochemistry, medical
- Pharmacology (medical)
Cite this
Montelukast exerts no acute direct effect on NO synthases. / Hamacher, Jürg; Eichert, Katja; Braun, Clemens; Grebe, Thomas; Strub, Andreas; Lucas, Rudolf; Eltze, Manfrid; Wendel, Albrecht.
In: Pulmonary Pharmacology and Therapeutics, Vol. 20, No. 5, 01.10.2007, p. 525-533.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Montelukast exerts no acute direct effect on NO synthases
AU - Hamacher, Jürg
AU - Eichert, Katja
AU - Braun, Clemens
AU - Grebe, Thomas
AU - Strub, Andreas
AU - Lucas, Rudolf
AU - Eltze, Manfrid
AU - Wendel, Albrecht
PY - 2007/10/1
Y1 - 2007/10/1
N2 - The cysteinyl leukotrienes (CysLTs) LTC4, LTD4 and LTE4 are potent proinflammatory lipid mediators that play a central role in inflammation, contraction and remodelling of airways observed in asthmatics. Montelukast, a competitive inhibitor of the cysteinyl leukotriene-1 (CysLT1) receptor attenuates asthmatic airway inflammation, contraction and remodelling. As a number of studies have shown that montelukast reduced exhaled nitric oxide (NO) levels, a marker of inflammation that correlates with the severity of asthma, we investigated whether or not a direct inhibition of NO synthase (NOS) by montelukast takes place. In an ex vivo rat lung perfusion and ventilation model the NOS-dependent vasodilation effect after lipopolysaccharide (LPS) infusion was assessed with and without montelukast. Functional organ bath studies using isolated aortic rings from the same species aimed to assess effects of montelukast on the inducible and endothelial NOS isoenzymes (i- and eNOS) as well as on iNOS expression. Neuronal NOS (nNOS) was assessed by field stimulated rabbit corpus cavernosum, and isolated human iNOS enzyme activity was assessed for potential inhibition. Montelukast failed to cause vasoconstriction in LPS challenged rat lung, or to inhibit i- and eNOS activity as well as iNOS expression in aortic rings from the same species. Also the assays for nNOS in rabbit corpus cavernosum and on isolated human iNOS enzyme gave no evidence for a direct inhibition by montelukast in physiological and supraphysiological concentrations up to 10-4 M. We therefore conclude that montelukast has no acute NOS inhibitor action. Its effect on exhaled NO is therefore probably indirectly mediated by a modulation of the asthmatic airway inflammation.
AB - The cysteinyl leukotrienes (CysLTs) LTC4, LTD4 and LTE4 are potent proinflammatory lipid mediators that play a central role in inflammation, contraction and remodelling of airways observed in asthmatics. Montelukast, a competitive inhibitor of the cysteinyl leukotriene-1 (CysLT1) receptor attenuates asthmatic airway inflammation, contraction and remodelling. As a number of studies have shown that montelukast reduced exhaled nitric oxide (NO) levels, a marker of inflammation that correlates with the severity of asthma, we investigated whether or not a direct inhibition of NO synthase (NOS) by montelukast takes place. In an ex vivo rat lung perfusion and ventilation model the NOS-dependent vasodilation effect after lipopolysaccharide (LPS) infusion was assessed with and without montelukast. Functional organ bath studies using isolated aortic rings from the same species aimed to assess effects of montelukast on the inducible and endothelial NOS isoenzymes (i- and eNOS) as well as on iNOS expression. Neuronal NOS (nNOS) was assessed by field stimulated rabbit corpus cavernosum, and isolated human iNOS enzyme activity was assessed for potential inhibition. Montelukast failed to cause vasoconstriction in LPS challenged rat lung, or to inhibit i- and eNOS activity as well as iNOS expression in aortic rings from the same species. Also the assays for nNOS in rabbit corpus cavernosum and on isolated human iNOS enzyme gave no evidence for a direct inhibition by montelukast in physiological and supraphysiological concentrations up to 10-4 M. We therefore conclude that montelukast has no acute NOS inhibitor action. Its effect on exhaled NO is therefore probably indirectly mediated by a modulation of the asthmatic airway inflammation.
KW - Leukotrienes
KW - Lung vascular resistance
KW - Montelukast
KW - Nitric oxide synthases
UR - http://www.scopus.com/inward/record.url?scp=34447559355&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=34447559355&partnerID=8YFLogxK
U2 - 10.1016/j.pupt.2006.05.001
DO - 10.1016/j.pupt.2006.05.001
M3 - Article
C2 - 16815057
AN - SCOPUS:34447559355
VL - 20
SP - 525
EP - 533
JO - Pulmonary Pharmacology and Therapeutics
JF - Pulmonary Pharmacology and Therapeutics
SN - 1094-5539
IS - 5
ER -