Montelukast exerts no acute direct effect on NO synthases

Abstract

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.

Inhibition of multidrug resistance proteins by MK571 restored the erectile function in obese mice through cGMP accumulation

“…However, to the best of our knowledge, there are no scientific evidence that the LTD4-CysLT1 pathway has any role on the erectile function nor does on the NO signaling pathway. 57 A study carried out in human or guinea pig trachea showed that MK571 (19 μM) did not affect histamine-, ACh-, serotonin-, prostaglandin F2alpha-, U46619-(a stable analog of thromboxane A2), or prostaglandin D2-induced contractions. In human trachea, MK571 antagonized only LTD4-induced contraction.…”

Potential of Inducible Nitric Oxide Synthase as a Therapeutic Target for Allergen-Induced Airway Hyperresponsiveness: A Critical Connection to Nitric Oxide Levels and PARP Activity

“…The interesting aspect of this study is that the protection was recovered in the chronic HDM asthma model after NO supplementation by nitrite administration. The dose of nitrite used in this study was shown to deliver low-to-moderate levels of NO and protects against several oxidative stress-related conditions including hypoxic vasodilation, ischemia of the heart and liver, and postoperative ileus [ 26 , 32 , 33 ]. It is important to acknowledge that the failure of iNOS inhibition to protect against AHR in chronic asthma may be related to other factors besides NO; however, the level of the gas may constitute a major determinant in the protection against AHR.…”