Bronchial responsiveness among inbred mouse strains. Role of airway smooth-muscle shortening velocity.

To investigate the relationship between bronchial responsiveness and airway smooth-muscle (ASM) contractile properties, we studied inbred mice with known interstrain differences in airway responsiveness. Using oscillatory mechanics, we confirmed that A/J mice were hyperresponsive to methacholine (MCh) as compared with mice of the C3H/HeJ and C57BL/6J strains. Analysis of respiratory system resistance and elastance at different flow oscillation frequencies indicated that interstrain differences in responsiveness are present in both central and peripheral airways of these mice. We used video microscopy to measure the rate of contraction of explanted airways, and found that the airways of A/J mice contracted more rapidly than those of C3H/HeJ or C57BL/6J mice. In studies of a fourth strain (Balb/C) of mice, we found both bronchial hyperresponsiveness and increased ASM shortening velocity. The rank order of responsiveness among strains was the same as that for shortening velocity (A/J > Balb/C > C3H/HeJ > C57BL/6J). Furthermore, in each strain of mice, shortening velocity correlated with the achieved degree of airway narrowing and with a greater likelihood of airway closure in individual airways. In contrast, generation of isometric tension in trachealis, morphometric measurements of tracheal ASM, tracheal myosin content, and dose-response curves for MCh of explanted intraparenchymal bronchi failed to correspond to the in vivo phenotype of airway reactivity. These results indicate that bronchial responsiveness is related to ASM shortening velocity, and underscore the importance of smooth-muscle dynamics in understanding the mechanisms of bronchial responsiveness.

Modulation of ET-1-induced contraction of human bronchi by airway epithelium-dependent nitric oxide release via ET(A) receptor activation.

1. The purpose of this work was to investigate whether endothelin-1 (ET-1) was able to induce the release of an inhibitory factor from the airway epithelium in isolated human bronchi and to identify this mediator as well as the endothelin receptor involved in this phenomenon. 2. In intact bronchi, ET-1 induced a concentration-dependent contraction (-logEC50 = 7.92+/-0.09, n = 18) which was potentiated by epithelium removal (-logEC50 = 8.65+/-0.11, n = 17). BQ-123 , an ET(A) receptor antagonist, induced a significant leftward shift of the ET-1 concentration-response curve (CRC). This leftward shift was abolished after epithelium removal. 3. L-NAME (3 x 10(-3) M), an inhibitor of nitric oxide (NO) synthase, induced a significant leftward shift of the ET-1 CRC, and abolished the potentiation by BQ-123 (10(-8) M) of ET-1-induced contraction. 4. In intact preparations, the ET(B) receptor antagonist BQ-788 induced only at 10(-5) M a slight rightward shift of the ET-1 CRC. In contrast, in epithelium-denuded bronchi or in intact preparations in the presence of L-NAME, BQ-788 displayed a non-competitive antagonism toward ET-1-induced contraction. 5. IRL 1620, a selective ET(B) receptor agonist, induced a contraction of the isolated bronchus (-logEC50=7.94+/-0.11, n= 19). This effect was not modified by epithelium removal or by BQ-123. BQ-788 exerted a competitive antagonism against IRL 1620 which was similar in the presence or absence of epithelium. 6. These results show that ET-1 exerts two opposite effects on the human airway smooth muscle. One is contractile via ETB-receptor activation, the other is inhibitory and responsible of NO release which counteracts via ETA-receptor activation the contraction.

Indirect muscarinic receptor activation by pentamidine on airway smooth muscle.

1. Pentamidine is routinely used to reduce the incidence of Pneumocystis carinii pneumonia in patients infected with human immunodeficiency virus, but it has been described as inducing pulmonary adverse effects, such as cough and bronchospasm. 2. In this paper we have investigated the effects of pentamidine on guinea-pig isolated main bronchi and human isolated bronchi. Pentamidine induced a concentration-dependent contraction in both preparations with pD2 values of 9.64 +/- 0.07 (n = 8) and 9.73 +/- 0.06 (n = 8) and a maximal effect (Emax) of 40 +/- 4% and 34 +/- 5% of the response to acetylcholine (1 mM) in guinea-pig and human bronchi respectively. Atropine (0.01 to 0.1 microM) and the muscarinic M3 receptor antagonist, hexahydro-siladiphenidol (0.1 and 1 microM) inhibited pentamidine-induced concentration-responses in both preparations in a non-competitive manner, whereas only high concentrations of the M1 receptor antagonist pirenzipine (1 microM) inhibited pentamidine concentration-response curves. 3. The cholinesterase inhibitor, tacrine (1 microM), potentiated the effect of pentamidine; in contrast, morphine inhibited pentamidine-induced responses. 4. The bronchoconstrictor effect of pentamidine on guinea-pig and human isolated bronchi was not modified by the H1 histamine receptor antagonist, mepyramine, by indomethacin or by the neurokinin NK1 and NK2 receptor antagonists, CP-96,345 and SR 48969 respectively, suggesting that neither histamine receptor stimulation, arachidonic acid derivative formation, nor tachykinin release are involved in pentamidine-induced contraction of human and guinea-pig airways. 5. Our overall results suggest that pentamidine induces contraction of guinea-pig and human isolated bronchi through prejunctional cholinergic nerve stimulation.

Involvement of tachykinin NK1 and NK2 receptors in substance P-induced microvascular leakage hypersensitivity and airway hyperresponsiveness in guinea-pigs.

Tachykinins, such as substance P, might be involved in the development of airway hyperresponsiveness (AHR) and airway inflammation. However, it is unknown which tachykinin receptors mediate these biological activities. The effects of two antagonists of tachykinin neurokinin-1 (NK1) and tachykinin neurokinin-2 (NK2) receptors, SR 140333 and SR 48968, respectively, were investigated on substance P (SP)-induced airway hyperresponsiveness and potentiation of the histamine-induced increase in microvascular leakage, in phosphoramidon-pretreated guinea-pigs. Guinea-pigs were pretreated with phosphoramidon (0.1 mM aerosol for 15 min) and exposed 15 min later to saline solution alone or to saline solution containing SP (0.1 mg.mL-1 for 30 min). Twenty four hours later, the animals were anaesthetized and prepared for the recording of the pulmonary inflation pressure (PIP) to acetylcholine or for the investigation of microvascular leakage to histamine. Pretreatment of the guinea-pigs with a single dose of SR 48968 (1 mg.kg-1, i.p.) 30 min before SP exposure, significantly prevented the development of AHR, whereas SR 140333 (1 mg.kg-1, i.p.) did not. In a second set of experiments, phosphoramidon-pretreated guinea-pigs exposed to SP presented a significant potentiation of the histamine-induced increase in microvascular leakage in pulmonary airways. When the guinea-pigs were pretreated with SR 140333, an inhibition of the increased microvascular leakage to histamine was observed. In contrast, no significant inhibitory activity was noted when the guinea-pigs were pretreated with SR 48968. The present data demonstrate the importance of tachykinin NK2 receptor stimulation in the development of airway hyperresponsiveness and that of tachykinin NK1 receptor stimulation in microvascular leakage hypersensitivity in phosphoramidon-pretreated and substance P-exposed guinea-pigs. The results also suggest a dissociation between the presence of microvascular leakage and the occurrence of airway hyperresponsiveness.

SR 140333 prevents potentiation by citric acid of plasma exudation induced by histamine in airways.

We here report a model of potentiation by citric acid of airway microvascular leakage induced by histamine and its modification by the tachykinin NK1 and NK2 receptor antagonists, SR 140333 ((S)1-{2-[3-(3,4-dichlorophenyl)-1-(3-iso-propoxyphenylacetyl)p iperidin- 3-yl]ethyl}-phenyl-1-azoniabicyclo[2.2.2]octane, chloride) and SR 48968 (S)-N-methyl-N-[4-(4-acetyl-amino-4-phenylpiperidino)-2-(3,4- dichlorophenyl-butyl]benzamide. Guinea-pigs exposed to an acrosol of citric acid 0.4 M for 1 h developed 24 h later a hyperresponsiveness to histamine-induced microvascular leakage measured by Evans blue dye extravasation. SR 140333, but not SR 48968 (1 mg kg-1 given each once 30 min before citric acid exposure), prevented this potentiation. These results provide further evidence of the role of tachykinin and tachykinin NK1 receptor stimulation on airway hyperresponsiveness and its neurogenic inflammatory component.

Effects of three alpha 2-adrenoceptor agonists, rilmenidine, UK 14304 and clonidine on bradykinin- and substance P-induced airway microvascular leakage in guinea-pigs.

The effects of three alpha 2-adrenoceptor agonists, clonidine, rilmenidine and UK 14304 on the increase of microvascular permeability induced by bradykinin or substance P in guinea-pigs airways have been studied in vivo. Extravasation of intravenously (i.v.) injected Evans blue dye was used as index of permeability. The effects of the three alpha 2-adrenoceptor agonists on the contraction induced by bradykinin (0.3 micrograms.kg-1, i.v.) and substance P (0.3 micrograms.kg-1, i.v.) were also studied on the isolated guinea-pig trachea. The increase of plasma exudation induced by bradykinin (0.3 micrograms.kg-1, i.v.) was inhibited partially by rilmenidine and UK 14304 (20 micrograms and 100 micrograms, intratracheally) respectively. These two substances had no action on the effects of substance P. The effects of rilmenidine and UK 14304 were abolished by alpha 2-blockers (idazoxan 1mg.kg-1 i.v. and RX 821001 100 micrograms.kg-1, i.v.), but they were not altered by the alpha 1-blocker prazosin (30 micrograms.kg-1, i.v.). Under similar conditions, clonidine or the alpha 1-adrenoceptor agonist methoxamine were without significant effects. In vitro, rilmenidine and UK 14304 inhibited partially the contractile effects of bradykinin but not those of substance P. To conclude, both rilmenidine and UK 14304 inhibit the bradykinin-induced increase of vascular permeability in the airways, and they probably do so on peptidergic nerve endings at the prejunctional level since these substances are without effect on substance P. The absence of activity of clonidine in our study might be due to a difference in spectrum of action on the several types of alpha 2-adrenergic or imidazole receptors.