Nerve growth factor increases airway responses and decreases levels of exhaled nitric oxide during histamine challenge in an in vivo guinea-pig model.

There is a growing body of evidence supporting the idea that nerve growth factor (NGF) may be involved in the development of asthma-associated symptoms, such as airway hyper-responsiveness. Increased levels of NGF have recently been described in serum and in the airways of asthmatics. We have examined whether exhaled nitric oxide (NO) levels might be altered during the increased airway responses upon NGF treatment in guinea-pigs in vivo. Intravenous (i.v.) administration of histamine normally elicits a rapid peak in insufflation pressure (IP) and in exhaled NO, followed by a period of decreased concentrations of exhaled NO. Anaesthetized guinea-pigs were pre-treated intravenously with either saline, 4 or 80 ng x kg(-1) NGF 30 min before i.v. challenge with 16 microg x kg(-1) histamine. At 80 ng x kg(-1) NGF significantly enhanced the airway obstruction caused by histamine, whereas the peak acute increase in exhaled NO was not enhanced. Following the increase, came a rapid drop, an effect enforced in the NGF treated animals. Subsequently, the time to return to 90% of resting exhaled NO was increased, from 12 min in saline-treated animals to 48 min in NGF-treated animals. Our data confirm that NGF can enhance airway responses to histamine. Moreover, our study shows a decrease in exhaled NO following a histamine challenge, an effect enhanced by NGF. A reduced ability to release exhaled NO may be a mechanism for increased airway responses during elevated NGF levels. The interaction between NGF and airway NO formation, and its relation to airway responses, merit further investigation.

The promotion of patent airways and inhibition of antigen-induced bronchial obstruction by endogenous nitric oxide.

1. The aim of the present study was to investigate the role of nitric oxide (NO), histamine and leukotrienes in bronchial obstruction. For this, guinea-pigs immunised against ovalbumin were studied under anaesthesia during challenge with antigen or agonists. 2. Challenge with nebulised antigen (0.1-1 mg) elicited dose-dependent increases in insufflation pressure which were abolished by combined administration of histamine and leukotriene antagonists. 3. Challenge with nebulised antigen (0.1-1 mg) also elicited dose-dependent increases in the concentration of endogenous nitric oxide in the exhaled air. After an initial peak, exhaled NO concentrations returned to pre-challenge levels. 4. The increase in insufflation pressure and in exhaled NO caused by ovalbumin challenge was inhibited by combined administration of histamine and leukotriene antagonists. 5. In non-immunised guinea-pigs, challenge of the airways with nebulised histamine (10-1000 nmol) or leukotriene C4 (LTC4, 30-300 pmol) elicited dose-dependent increases in insufflation pressure and in concentrations of endogenous NO in exhaled air. 6. The increase in exhaled NO correlated with the increase in insufflation pressure in response to ovalbumin, histamine and LTC4. An inhibitor of endogenous NO synthesis, N omega-nitro-L-arginine methylester (L-NAME, 30 mg kg-1 i.v.) abolished NO exhalation, and markedly augmented the airway responses to ovalbumin, histamine, or LTC4. 7. The potentiation by L-NAME of the increase in insufflation pressure in response to ovalbumin or histamine was prevented by exogenous NO (20 p.p.m.) in the inhaled air. 8. The results indicate that endogenous NO has an inhibitory effect on bronchial obstruction. Increased NO release during allergen challenge is likely to be due to actions of histamine and leukotrienes.

Endogenous nitric oxide counteracts antigen-induced bronchoconstriction.

In anesthetized, artificially ventilated guinea pigs immunized against ovalbumin, challenge with aerosolized ovalbumin (0.1 mg) elicited a substantial and sustained increase of insufflation pressure. The inhibitor of endogenous nitric oxide (NO) synthesis, L-NAME (N omega-nitro-L-arginine methylester, 30 mg kg-1 i.v.), markedly augmented the response, the potentiation of which could be prevented by NO (20 p.p.m.) in the inhaled air. The results indicate an inhibitory effect of endogenous NO on antigen-induced bronchoconstriction.