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

Abstract

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 insuflation pressure which were abolished by combined administration of histamine and leukotriene antagonists. 3 Challenge with nebulised antigen (0.1-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 insufilation pressure and in exhaled NO caused by ovalbumin challenge was inhibited by combined administration of histamine and leukotriene antagonists. 5In 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 insuiflation pressure in response to ovalbumin, histamine and LTC4. An inhibitor of endogenous NO synthesis, N-nitro-L-arginine methylester (L-NAME, 30 mg kg-' 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.

Nitric oxide synthase inhibition augments acute allergic reactions in the pig airways in vivo

“…Intravenous administration of NOS inhibitors has also been applied in studies on the guinea-pig [9]. In the present study i.v.…”

“…In the acute allergic reaction, endogenous NO has been suggested to play a protective role; this is indicated by small-animal studies, performed on guinea-pigs, which show that inhibition of NO production with NOS inhibitors increases airway responsiveness to allergen and histamine challenge [9,10]. The mechanisms for this have not been pinpointed.…”

“…The mechanisms for this have not been pinpointed. It has been suggested that NO would act primarily as a bronchodilator through a direct effect on bronchial smooth muscle [9,11]. However, another explanation could be that NO, like prostaglandin E 2 [12], is capable of downregulating the activity of the mast cell.…”

Nitric Oxide in Health and Disease of the Respiratory System

“…In contrast to eNOS it has also been postulated that in mice nNOS could have a role in promoting airway hyperresponsiveness (74,75). Different groups of investigators have shown that acute bronchoconstriction induced by allergen inhalation is potentiated by NOS inhibitors in sensitized guinea pigs in vivo, suggesting a modulation by endogenous protective NO on early asthmatic reaction in animal model (286,342,343). Other in vivo studies in guinea pigs have shown that the enhanced airway reactivity induced by allergen (6 h after exposure) is not further potentiated by pretreatment with NOS inhibitors (393,394) and that virus-induced airway reactivity is completely blocked by low doses of inhaled L-arginine (112), suggesting that allergenor virus-induced airway hyperreactivity is due to the impairment of endogenous release of protective NO.…”

Gadolinium Chloride Inhibition of Pulmonary Nitric Oxide Production and Effects on Pulmonary Circulation in the Rabbit

“…In the pulmonary circulation nitric oxide contributes to maintain the low pulmonary vascular resistance and modulates hypoxic pulmonary vasoconstriction (Archer et al 1989;Persson et al 1990;Stamler et al 1994). Other suggested functions for nitric oxide in the lung are host defence (Gustafsson et al 1991;Wei et al 1995), antiobstructive airway relaxation (Persson et al 1995a), ciliary activation (Jain et al 1993), and antioxidative function (Kavanagh et al 1994;Gustafsson 1996).…”