Effect of endogenous nitric oxide inhibition on airway responsiveness to histamine and adenosine-5'-monophosphate in asthma

Abstract

Background-Nitric oxide (NO) may be bronchoprotective in asthma, possibly due to a direct action on airway smooth muscle or through mast cell stabilisation. To investigate this the eVects of two doses of nebulised N G -nitro-L-arginine methyl ester (L-NAME), a non-selective NO synthase (NOS) inhibitor, on exhaled NO levels and airway responsiveness to histamine, a direct smooth muscle spasmogen, and adenosine-5'-monophosphate (AMP), an indirect spasmogen which activates mast cells, were evaluated in patients with mild asthma. Methods-The study consisted of two phases each with a double blind, randomised, crossover design. In phase 1, 15 subjects inhaled either L-NAME 54 mg or 0.9% saline 30 minutes before histamine challenge. Nine of these subjects were studied in a similar fashion but were also challenged with AMP. In phase 2, 13 subjects (eight from phase 1) performed the same protocol but inhaled L-NAME in a dose of 170 mg or 0.9% saline before being challenged with histamine and AMP. Results-The mean (95% CI) reduction in exhaled NO levels after L-NAME 54 mg was 78% (66 to 90) but this did not alter airway responsiveness; the geometric mean (SE) concentration provoking a fall of 20% or more in forced expiratory volume in one second (PC 20 ) after L-NAME and saline was 0.59 (1.26) and 0.81 (1.26) mg/ml, respectively, for histamine and 20.2 (1.7) and 17.2 (1.6) mg/ml, respectively, for AMP. In contrast, L-NAME 170 mg reduced NO levels to a similar extent (81% (95% CI 76 to 87)) but increased airway responsiveness by approximately one doubling dose to both spasmogens; the geometric mean (SE) PC 20 for histamine after L-NAME 170 mg and saline was 0.82 (1.29) and 1.78 (1.19) mg/ml, respectively (p<0.001), and for AMP was 11.8 (1.5) and 24.3 (1.4) mg/ml, respectively (p<0.001). Conclusions-These results suggest that L-NAME increases airway responsiveness in asthma. This may occur through mechanisms separate from NO inhibition or through pathways independent of those responsible for production of NO measured in exhaled air. (Thorax 1998;53:483-489)

Enhanced nitric oxide production associated with airway hyporesponsiveness in the absence of IL-10

“…Subsequent inhibition of NO with NOS-selective inhibitors increased AR (Figs. 5 and 7), suggesting that NO could be acting as a bronchodilator in the case where IL-10 is absent and consistent with prior studies in humans, in which L-NAME increased AR (29). This interpretation would be consistent with fact that a lack of IL-10 results in increased airway NO production, as observed in the present study.…”

“…This initial expected difference was verified by our exhaled gas measurement technique and subsequently was shown to be altered with administration of NOS-specific inhibitors L-NAME and L-NIL (Fig. 3), similar to findings reported in humans given L-NAME (29). That the brake on NO production was likely present in the IL-10-sufficient case has been shown previously by Todt et al (30), who reported measurable IL-10 protein (0.65-0.75 ng/ml) in the lungs of naïve C57 mice.…”

“…However, the alterations in humans occur in asthma with increased AR, a situation that is superficially counterintuitive, as elevated NO production might be expected to decrease AR (15). However, it is possible that elevated E NO in asthma may reflect increased production of NO as a potential homeostatic bronchoprotective agent (29). In this context, enhanced NO could act to minimize AR in the face of strong proinflammatory stimuli and subsequent products that increase AR (12,28).…”

Dissection of experimental asthma with DNA microarray analysis identifies arginase in asthma pathogenesis

“…Our demonstration that CAT2 is overexpressed is consistent with reports of the elevated levels of arginine and nitrotyrosine in airway epithelial cells of asthmatic subjects (44,45). Previous studies have shown that pharmacologic inhibition of NOS enhances agonistinduced airway constriction in vitro (46,47) and in vivo (46,48,49). In addition, in a guinea pig model of asthma, a specific deficiency of bronchodilating cNOS-derived NO has been shown to contribute to AHR (47,48,50).…”

Nitric Oxide in Health and Disease of the Respiratory System

“…This suggests an effect of high doses of corticosteroids in renewing eNOS activity by suppression of iNOS expression. A significant potentiation of NOS inhibitors has also been found in AHR to AMP and histamine, but not to allergen-induced bronchoconstriction in asthmatics (412,413).…”