Impairment of Neural Nitric Oxide-mediated Relaxation after Antigen Exposure in Guinea Pig Airwaysin vitro

Abstract

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.

Genetic polymorphisms in arginase I and II and childhood asthma and atopy

“…21 Deficiency of NO can induce airway hyperresponsiveness, as shown in allergen-challenged guinea pigs. [22][23][24] With low concentrations of arginine, NOS generates superoxide and NO that interact to form peroxynitrite, which leads to airway cell injury. 25 Another potential mechanism for a role of arginase in asthma pathogenesis relates to increasing production of ornithine, a precursor of polyamines (ie, putrescine, spermidine, and spermine) and proline.…”

Airway hyperresponsiveness in asthma: lessons fromin vitromodel systems and animal models: Fig. 1—

“…1) [77,96,97]. A deficiency of cNOS activity and endogenous bronchodilating NO contributing to AHR was also demonstrated after repeated allergen challenge of sensitised guinea pigs [98,99]. Importantly, it was demonstrated that a reduction in cNOS-derived NO may also contribute to AHR in patients with severe asthma [100], and may similarly be induced by allergen exposure [101].…”

Nitric Oxide in Health and Disease of the Respiratory System

“…Furthermore, it has been noted that the circadian variations of the iNANC response may contribute to overnight bronchoconstriction in patients with nocturnal asthma (274). Neural NO-induced relaxation is impaired in guinea pig airways after allergen exposure, without affecting nNOS expression, suggesting a reduced neural NOS activity when allergic inflammation is exacerbated (296).…”