Effect of nitric oxide synthases inhibitors on exogenous irritant-induced bronchial hyper-reactivity in guinea pigs (original) (raw)
Related papers
Nitric oxide regulatory role in sensitized guinea pig trachea
Life Sciences, 1997
Nitric oxide (NO) has been cited to play an important regulatory role in airway function. Moreover, the NO synthase expression in models of inflammation is documented. The aim of this study was to investigate, in vitro, the NO modulation of cholinergic responses in sham-sensitized and ovalbumin-sensitized guinea pig trachea by using L-arginine (L-ARG), a precursor of NO synthesis, and L-Ng-nitro-arginine-methyl-ester (L-NAME), an inhibitor of NO synthase.Our results showed that NO's ability to modulate cholinergic responses in ovalbuminsensitized guinea pig trachea is lost. Indeed L-ARG and L-NAME modify acetylcholine sensitivity in sham-sensitized guinea pig but not in ovalbumin-sensitized guinea pig. 0 1997 Elsevier Science Inc.
British Journal of Pharmacology, 1998
Using a conscious, unrestrained guinea-pig model of allergic asthma, we investigated the role of endogenous nitric oxide (NO) in the regulation of airway (hyper)reactivity to histamine before and after the allergen-induced early and late asthmatic reactions, by examining the eect of inhalation of the NO synthase inhibitor N o-nitro-L-arginine methyl ester (L-NAME, 12 mM, 15 min) on the histamine-induced airway obstruction of ovalbumin-sensitized guinea-pigs before, and at 5.5 h and 23.5 h after allergen challenge. 2 Before allergen challenge, inhaled L-NAME caused a signi®cant 2.02+0.25 fold increase (P50.01) in airway reactivity to histamine; this eect was reversed within 2.5 to 6 h after administration. 3 After the allergen-induced early asthmatic reaction at 5 h after ovalbumin provocation, a signi®cant 3.73+0.67 fold increase (P50.01) of the airway reactivity to histamine was observed; subsequent inhalation of L-NAME at 5.5 h had no eect on the airway hyperreactivity, reassessed at 6 h. 4 After the late asthmatic reaction, at 23 h after ovalbumin provocation, a reduced, but still signi®cant airway hyperreactivity to histamine (2.18+0.40 fold; P50.05) was observed. Subsequent inhalation of L-NAME now signi®cantly potentiated the partially reduced airway hyperreactivity 1.57+0.19 fold (P50.05) to the level observed after the early asthmatic reaction. 5 When administered 30 min before allergen exposure, L-NAME signi®cantly enhanced the allergeninduced early asthmatic reaction. However, when administered at 5.5 h after allergen provocation, L-NAME did not aect the subsequent late asthmatic reaction. 6 These results indicate that endogenous NO is involved the regulation of histamine-and allergeninduced bronchoconstriction and that a de®ciency of cNOS-derived NO contributes to the allergeninduced airway hyperreactivity to histamine after the early asthmatic reaction, while a recovery of NO de®ciency may account for the partial reversal of the allergen-induced airway hyperreactivity after the late asthmatic reaction.
European Journal of Pharmacology, 2006
Nitric oxide (NO) is a marker of airway inflammation in humans, despite not having effects on basal bronchial tone. Inhibition of NO synthesis can lead to enhanced airway reactivity in humans and it is therefore of importance to understand how bronchial provocation can affect endogenous NO. Presently, we have studied the role of exhaled nitric oxide in airway reactivity by measuring changes in pulmonary mechanics in response to histamine in anaesthetized guinea pigs. Two groups were challenged i.v. and four groups were challenged by aerosol at different doses. One of the i.v. and one of the aerosol groups received an inhibitor of NO synthesis, N ω-nitro-L-arginine methyl ester (L-NAME), to reduce endogenous production of NO before histamine challenge. All animals with intact NO production showed a decrease in exhaled nitric oxide after challenge. There were positive correlations between the peak in exhaled nitric oxide and pulmonary resistance, and between the decrease in exhaled nitric oxide and lung compliance. L-NAME pretreatment increased the reactivity to aerosolized histamine but not to i.v. histamine. We conclude that the different ways of administration elicit different response patterns of exhaled nitric oxide, resistance, and compliance, even when compared at similar insufflation pressure changes. The effects of L-NAME suggest that, although different mechanisms might be responsible for the changes in pulmonary mechanics, inhibition of endogenous NO enhances decrements in pulmonary function when histamine is administered in an aerosol. The close relationship between changes in exhaled nitric oxide and changes in lung compliance and pulmonary resistance merits further studies on the relationship between NO and airway reactivity.
British Journal of Pharmacology, 2001
In the present study, the roles of nitric oxide (NO) and superoxide anions (O 2 7) in allergeninduced airway hyperreactivity (AHR) after the late asthmatic reaction (LAR) were investigated ex vivo, by examining the eects of the NO synthase inhibitor N o-nitro-L-arginine methyl ester (L-NAME) and superoxide dismutase (SOD) on the responsiveness to methacholine of isolated perfused guinea-pig treacheae from unchallenged (control) animals and from animals 24 h after ovalbumin challenge. 2 At 24 h after allergen challenge, the animals developed AHR in vivo, as indicated by a mean 2.63+0.54 fold (P50.05) increase in sensitivity to histamine inhalation. 3 Compared to unchallenged controls, tracheal preparations from the ovalbumin-challenged guinea-pigs displayed a signi®cant 1.8 fold (P50.01) increase in the maximal response (E max) to methacholine, both after intraluminal (IL) and extraluminal (EL) administration of the agonist. No changes were observed in the sensitivity (pEC 50) to the agonist. Consequently, the DpEC 50 (EL-IL), as a measure of epithelial integrity, was unchanged. 4 In the presence of L-NAME (100 mM, IL), tracheae from control guinea-pigs showed a 1.6 fold (P50.05) increase in the E max of IL methacholine. By contrast, the E max of IL methacholine was signi®cantly decreased in the presence of 100 u ml 71 EL SOD (54% of control, P50.01). 5 Remarkably, the increased responsiveness to IL methacholine at 24 h after allergen challenge was reversed by L-NAME to control (P50.01), and a similar eect was observed with SOD (P50.01). 6 The results indicate that both NO and O 2 7 are involved in the tracheal hyperreactivity to methacholine after the LAR, possibly by promoting airway smooth muscle contraction through the formation of peroxynitrite.
Bronchodilator action of inhaled nitric oxide in guinea pigs
Journal of Clinical …
The effects of inhaling nitric oxide (NO) on airway mechanics were studied in anesthetized and mechanically ventilated guinea pigs. In animals without induced bronchoconstriction, breathing 300 ppm NO decreased baseline pulmonary resis- tance (RL) from 0.138±0.004 ...
American Journal of Respiratory and Critical Care Medicine, 2001
Pharmacological evidence supports a role of a transient decreased endogenous nitric oxide (NO) synthesis in ovalbumin (OVA)-induced early airway hyperresponsiveness in guinea pigs. However, no data are available regarding the expression and activity of the constitutive NO synthases (cNOS; NOS1 and NOS3, nNOS and eNOS, respectively) in this model. Therefore, we evaluated cNOS activity (conversion of L -[ 3 H]arginine to L -[ 3 H]citrulline in the presence of Ca 2 ϩ and calmodulin), nitrate and nitrite (NOx) concentration (modified Griess method), and NOS1 and NOS3 protein expression (Western blot) in lung homogenates and in the tracheal smooth muscle from OVA-immunized and multiple aerosol-challenged guinea pigs (six challenges, once daily). The expression and activity of the inducible NOS isoform (NOS2), the levels of exhaled NO, and the in vivo airway reactivity were also determined. Constitutive NOS activity and NO x concentration were significantly lower 6 h after the last OVA challenge as compared with saline exposure, being similar at 24 h. Expression of NOS1 paralleled cNOS activity, which was reduced 6, but not 24 h after OVA challenge. The decrease in NOS1 expression was accompanied by a significant decrease in the amounts of exhaled NO and by a maximal airway hyperresponsiveness to histamine. The levels of NOS3 were not modified at the two time points evaluated, and no NOS2 expression and activity were found at any time point. Similar modifications were observed in the tracheal smooth muscle. We conclude that OVA stimulation in immunized guinea pigs induced a transient reduction in NOS1 protein expression and activity in the respiratory system, which probably participates in airway hyperresponsiveness.
Journal of Pharmacology and Experimental Therapeutics, 2006
The effects of selective cyclooxygenase (COX) isoform (COX-1, COX-2) inhibition, alone or in combination with nitric-oxide synthase (NOS) blockade, on in vitro tracheal muscle responsiveness to histamine were investigated in healthy and ovalbumin (OVA)-sensitized guinea pigs. Immunohistochemistry showed that COX-1 and COX-2 are constitutively present in normal guinea pig trachea, particularly in the epithelial layer, and that COX-2 expression is enhanced in OVA-sensitized animals both in epithelial and subepithelial tissues. In normal guinea pigs, SC-560 [5-(4-chlorophenyl)-1-(4-methoxyphenyl)-3-trifluoromethylpyrazole] (COX-1 inhibitor) or DFU [5,5-dimethyl-3-(3-fluorophenyl)-4-(4-methylsulphonyl)phenyl-2(5H)-furanone] (COX-2 inhibitor) significantly increased the contractile response to histamine, these effects being not additive. NOS inhibition by L-N G -nitro-arginine methyl ester (L-NAME) did not affect histamine-induced contraction but reversed the increase caused by COX-1 blockade while not modifying the enhancemethyl ester; PGI 2 , prostaglandin I 2 (prostacyclin); ANOVA, analysis of variance.
Possible functional modulation by acetylcholine of nitric oxide on guinea pig isolated trachea
Life sciences, 1998
The aim of this study was to evaluate whether acetylcholine induces NO release. We determined the responses on the cholinergic component of the response to electrical field stimulation (EFS) the effects of L-nitro-arginine-methyl-ester (L-NAME; 1 mM), an inhibitor of NO synthase, of L-Arginine (L-ARG; 1 mM), a precursor of NO synthesis, and methoctramine (0.01-0.1-1 microM), an antagonist of M2 receptors, alone or associated with L-NAME. The experiments were performed on guinea pig isolated intact- or denuded-epithelium tracheal rings contracted in a frequency-dependent manner to EFS. At the maximum frequency tested (30 Hz), the contractile response elicited was 60.36 +/- 0.61% of acetylcholine (100 microM) contraction, while the maximal relaxant effect induced by EFS was -28.40 +/- 0.61% in epithelium intact preparations. A pretreatment with L-NAME significantly (P<0.05) increased the contraction (76.08 +/- 1.39%) and reduced the relaxation elicited by EFS. L-NAME effect on both...