Nitric oxide (NO), a neurotransmitter of inhibitory nonadrenergic noncholinergic (iNANC) nerves in airways, is a radical with a short half-life, and its function may be modified by airway inflammation. To test this hypothesis, we examined whether airway allergic inflammation affects iNANC responses mediated by NO in guinea pigs in vitro. Animals sensitized with ovalbumin (OA) were challenged with 0.03% OA (OA group) or saline (saline group) by inhalation on 3 consecutive days. On the day after the final challenge, iNANC responses elicited by electrical field stimulation (2 to 16 Hz) or relaxation responses to 3-morpholinosydnonimine (SIN-1), 10(-8) to 10(-4) M, were obtained in the tracheal strips precontracted by histamine (3 x 10(-6) M) in the presence of atropine and propranolol (both 10(-6) M). The INANC responses of the OA group were significantly attenuated compared with those of the saline group (p < 0.05), and the inhibitory effect of a NO synthase (NOS) inhibitor, Nm-nitro-L-arginine methyl ester, on the INANC responses was abolished in the OA group. SIN-1-induced tracheal smooth muscle relaxation was also significantly affected by antigen exposure (p < 0.05), the effect of which disappeared in the presence of a NO scavenger, carboxy PTIO (3 x 10(-6) M). The impairment of the INANC responses after antigen exposure was significantly restored by superoxide dismutase (1,000 U/ml), especially at lower frequencies. Histochemical demonstration of NADPH-diaphorase-positive nerves representing neural NOS density was not different between the two groups. These results suggest that allergic airway inflammation impairs neural NO-induced relaxation, presumably by inhibiting the access of neural NO to the airway smooth muscle.

Recent reports suggest the involvement of vascular phenomena in exercise-induced asthma. Sensory neuropeptides, such as substance P (SP), which causes airway vascular dilatation and plasma leakage, have been demonstrated to play a role in hyperpnea-induced airway narrowing in animal studies. The purpose of this study was to investigate the importance of tachykinins in exercise-induced airway narrowing in patients with asthma using a selective neurokinin 1-receptor (NK1-receptor) antagonist, FK-888. In a double-blind, placebo-controlled, crossover trial, nine subjects with stable asthma were given FK-888 (2.5 mg) or placebo by inhalation 20 min before each exercise at a level previously demonstrated to cause a fall of at least 40% in specific airway conduction (SGaw). Inhalation of FK-888 had no significant effect on baseline SGaw. While the recovery from exercise-induced airway narrowing was significantly faster after treatment with FK-888 the area under the curve for SGaw during the 50 min after exercise was significantly reduced (p<0.05) and the time taken for the SGaw to recover to within 65% of baseline after exercise was also significantly shorter with FK-888 than the placebo (p<0.05). However, treatment with FK-888 did not significantly attenuate the maximal fall in SGaw. These results suggest that NK1-receptor-mediated mechanisms are involved in the recovery phase of exercise-induced airway narrowing. The possible mechanisms of these phenomena are discussed.

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Role of endogenous nitric oxide in airway microvascular leakage induced by inflammatory mediators. N. Kageyama, M. Miura, M. Ichinose, M. Tomaki, J. Ishikawa, Y. Ohuchi, N. Endoh, K. Shirato. ERS Journals Ltd 1997. ABSTRACT: This study examines the role of endogenous nitric oxide (NO) in airway microvascular leakage induced by inflammatory mediators, which play an important role in asthmatic airways.Guinea-pigs were anaesthetized and mechanically-ventilated with monitoring of arterial blood pressure, and airway microvascular leakage induced by intravenous injection of substance P (SP), leukotriene D 4 (LTD 4 ) and histamine was evaluated using Evans blue dye and Monastral blue dye in the presence and absence of the NO synthase inhibitors, L-N G -nitroarginine methyl ester (L-NAME) and L-N Gmonomethyl arginine (L-NMMA). The effect of a soluble guanylate cyclase inhibitor, LY83583, on SP-induced dye leakage was also examined.Intravenous injection of SP (1 µg·kg -1 ), LTD 4 (1 µg·kg -1 ) and histamine (100 µg·kg -1 ) significantly increased dye extravasation at all airway levels. Pretreatment with L-NAME (10 mg·kg -1 i.v.) and L-NMMA (100 mg·kg -1 i.v.) significantly inhibited SP-induced extravasation, and L-arginine (100 mg·kg -1 i.v.) reversed L-NAMEinduced inhibition. L-NAME (10 mg·kg -1 i.v.) also significantly inhibited LTD 4 -induced dye extravasation only in central airways, and this inhibitory effect was abolished by a neurokinin-1 (NK 1 ) antagonist, FK888 (10 mg·kg -1 i.v.) pretreatment. Histamineinduced dye extravasation was not affected by L-NAME. LY83583 (2.5 and 7.5 mg·kg -1 i.v.) partially but significantly reduced SP-induced dye leakage.These results suggest that endogenous nitric oxide plays a role in neurokinin-1 receptor-mediated airway microvascular leakage, and presumably involves the guanylate cyclase pathway. Eur Respir J., 1997; 10: 13-19

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