Montelukast exerts no acute direct effect on NO synthases.
The cysteinyl leukotrienes (CysLTs) LTC(4), LTD(4) and LTE(4) 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 (CysLT(1)) 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.
Hamacher
Jürg
J
Biochemical Pharmacology, University of Konstanz, 78457 Konstanz, Germany. hamacher@greenmail.ch
Eichert
Katja
K
Braun
Clemens
C
Grebe
Thomas
T
Strub
Andreas
A
Lucas
Rudolf
R
Eltze
Manfrid
M
Wendel
Albrecht
A
D000085:Acetates / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D001013:Aorta, Thoracic; D003521:Cyclopropanes; D004305:Dose-Response Relationship, Drug; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D020024:Leukotriene Antagonists / Q000008:administration & dosage / Q000494:pharmacology*; D008070:Lipopolysaccharides; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D008297:Male; D052248:Nitric Oxide Synthase Type I / Q000187:drug effects* / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000187:drug effects* / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000187:drug effects* / Q000378:metabolism; D010413:Penis / Q000187:drug effects / Q000201:enzymology; D011804:Quinolines / Q000008:administration & dosage / Q000494:pharmacology*; D011817:Rabbits; D051381:Rats; D017208:Rats, Wistar; D013440:Sulfides; D014655:Vascular Resistance / Q000187:drug effects; D014661:Vasoconstriction / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects
D000085:Acetates; D003521:Cyclopropanes; D020024:Leukotriene Antagonists; D008070:Lipopolysaccharides; D011804:Quinolines; D013440:Sulfides; D052248:Nitric Oxide Synthase Type I; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C093875:montelukast