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At least 199 records · Page 11Linked to original sources

PubMed1987

Airway closure with methacholine-induced bronchoconstriction.

We examined airway closure with methacholine-induced bronchoconstriction in eight normal seated adults at a mean lung volume of 39% total lung capacity. Closure was evaluated in two ways. Regional closure was examined by comparing the regional distributions of 133Xe boluses distributed according to N2O uptake with those distributed by pulmonary perfusion; regions that exhibited less N2O uptake than perfusion were interpreted as having airway closure. In addition, we measured single-breath washouts of the same boluses; differences between the washouts indicated closure that was not necessarily regional. Basal airway closure increased with methacholine inhalation from 21 +/- 3 to 46 +/- 4% (means +/- SE; P less than 0.001). This was due to both decreased basal N2O uptake and a relative increase of basal perfusion. Washout curves of boluses distributed by perfusion did not change with bronchoconstriction. Before bronchoconstriction, washouts of boluses distributed by N2O uptake did not differ significantly from those distributed by perfusion. During bronchoconstriction, single-breath washouts of boluses distributed by N2O uptake showed increased concentration differences (P less than 0.015) that were significantly greater than those resulting from boluses delivered by perfusion. Changes in basal closure did not correlate with washout changes. We conclude that methacholine inhalation induced bronchoconstriction-increased basal airway closure and also increased airway closure in other lung regions in a way that did not relate to basal closure.

Adult↗

PubMed1988

Bronchoalveolar cell activation after inhalation of a bronchoconstricting agent.

Airway inflammation is thought to be an important determinant of bronchoconstriction and bronchial hyperreactivity. We have recently demonstrated that bronchoconstriction induced by an aqueous extract of cotton bracts (CBE) is associated with bronchoalveolar complement activation, release of polymorphonuclear neutrophil (PMN) chemoattractants by pulmonary cells, and increased numbers of bronchoalveolar lavage PMN's. In the present study we performed bronchoalveolar lavage (BAL) on subjects after CBE or control (saline) challenge and examined whether BAL cells were activated in vitro to produce other inflammatory agonists. After CBE administration, cultured BAL cells released increased amounts of the reactive O2 species, superoxide (O2-.), and the cyclooxygenase products prostaglandin E2 and thromboxane B2. Although none of these in vitro parameters of BAL cell activation appeared to correlate with the degree of bronchoconstriction induced by CBE, BAL fluid levels of thromboxane B2 were also increased after CBE administration and in vivo amounts of this eicasanoid did correlate with the degree of bronchoconstriction induced by CBE (r = 0.50, P less than 0.04). Finally, although cell culture supernatants were highly chemotactic for PMN's, concentrations of leukotriene B4 were not increased, suggesting other chemotaxins were released by BAL cells in this setting. We conclude that CBE administration activates bronchoalveolar cells to release reactive O2 species and cyclooxygenase products that may be important in the bronchoconstricting response to CBE.

Adult↗

PubMed1989

Tachykinins mediate hypocapnia-induced bronchoconstriction in guinea pigs.

The aim of this study was to determine whether hypocapnia causes bronchoconstriction by releasing tachykinins (TKs) from C-afferent nerves in airways. Hypocapnia-induced bronchoconstriction (HIBC) was induced in anesthetized vagotomized guina pigs by ventilating lungs with a heated humidified hypocapnic gas mixture for 15 min after sudden circulatory arrest. The intensity of bronchoconstriction was assessed by calculating changes in dynamic compliance and by measuring the relaxation lung volume at the completion of experiments. Visualization of the airways by tantalum bronchography showed constriction of segmental bronchi with relative sparing of more proximal airways. Hypocapnia-induced bronchoconstriction was prevented by prior administration of salbutamol aerosol. Three experimental interventions were used to investigate the role of TKs in HIBC: 1) repeated capsaicin injections to deplete airway sensory nerves of TKs, 2) treatment with phosphoramidon, an inhibitor of enkephalinase, the main enzyme responsible for TK inactivation, and 3) topical airway anesthesia. Capsaicin pretreatment markedly attenuated the hypocapnia-induced changes in dynamic compliance (P less than 0.0005) and relaxation lung volume (P less than 0.0002), whereas phosphoramidon augmented these changes (P less than 0.02, P less than 0.03, respectively). Topical anesthesia of airways with lignocaine postponed the onset of bronchoconstriction, whereas the longer-acting, more lipid-soluble local anesthetic, bupivacaine, almost completely prevented HIBC. We conclude that, in the guinea pig lung, HIBC is mediated by TKs that are released after the activation of bronchial axonal reflexes.

Animals↗

PubMed1987

Cholinergic-mediated bronchoconstriction induced by prostaglandin D2, its initial metabolite 9 alpha,11 beta-PGF2, and PGF2 alpha in asthma.

In this study, we have investigated the contribution of cholinergic-mediated bronchoconstriction in the airway response provoked by inhaled prostaglandin (PG)D2, its metabolite 9 alpha, 11 beta-PGF2, and PGF2 alpha, which are generated during mast cell activation in vivo and are potent bronchoconstrictor agonists in humans. The effect of prior inhalation of 1 mg ipratropium bromide (IB) on the bronchoconstrictor response to inhaled methacholine (MCh), PGD2, 9 alpha, 11 beta-PGF2, and PGF2 alpha was determined in 7 allergic asthmatic subjects by measuring changes in SGaw, FEV1, and Vmax30. Methacholine, PGD2, and 9 alpha, 11 beta-PGF2 caused concentration-related bronchoconstriction with PGD2 and 9 alpha, 11 beta-PGF2 being between 45 and 112 times more potent than MCh (p less than 0.05), depending on the method used to measure airway caliber. Preinhalation of IB displaced the concentration response curves to MCh between 69- and 196-fold to the right, and this was significantly greater than that observed with PGD2 (12- to 23-fold, p less than 0.02) and 9 alpha, 11 beta-PGF2 (12- to 22-fold, p less than 0.02). Ipratropium bromide inhibited the bronchoconstriction achieved with the highest concentration of agonist by 73 to 91% with MCh, 46 to 79% with PGD2, and 32 to 38% with 9 alpha, 11 beta-PGF2. Ipratropium bromide did not affect the bronchoconstriction pattern to inhaled PGF2 alpha, irrespective of the nature of the response. We conclude that although PGD2 and 9 alpha, 11 beta-PGF2 are potent contractile agonists of human smooth muscle in vitro, bronchoconstriction observed with these mediators in vivo results from a combination of both direct and cholinergic-mediated mechanisms.

Adult↗

PubMed1978

The role of hyperventilation in exercise-induced bronchoconstriction.

Significant bronchoconstriction, comparable in severity to that observed after moderate treadmill exercise, was induced in asthmatic children by voluntary isocapnic hyperventilation of 3-min and 10-min duration. In both hyperventilation and exercise, nasal breathing inhibited the bronchoconstrictive responses, whereas mouth breathing potentiated the bronchoconstrictive response. In the asthmatic children, 10 min of voluntary isocapnic hyperventilation did not represent a greater bronchoconstrictive stimulus than did 10 min of exercise or 3 min of isocapnic hyperventilation. This study also showed that in normal children there was no measurable airway response after either voluntary isocapnic hyperventilation or moderate exercise. Finally, this study indicates that it is the stimulation of upper airway receptors by relatively cold and dry air, rather than hyperventilation per se, that provokes exercise-induced bronchoconstriction.

Adolescent↗

PubMed1984

Morphine sulfate inhibits bronchoconstriction in subjects with mild asthma whose responses are inhibited by atropine.

To determine whether morphine sulfate alters the bronchoconstrictive response to inhalation of distilled water, we gave 13 subjects with mild asthma 0.15 mg/kg morphine sulfate or normal saline intravenously, after which they inhaled increasing volumes of nebulized distilled water from an ultrasonic nebulizer. We constructed stimulus-response curves, and by interpolation determined the provocative output of the nebulizer that resulted in a 50% increase in SRaw from baseline (PO50). On a separate day the subjects inhaled 2.0 mg of atropine sulfate 30 min before they inhaled distilled water. We compared the bronchoconstrictive response after morphine and after atropine with the bronchoconstrictive response after saline by determining the ratio of the PO50 values. Atropine was considered effective in inhibiting bronchoconstriction in 7 of the 13 subjects in whom the ratio of PO50 after atropine to the PO50 after saline was greater than 2.0. By similar criteria, morphine was also considered effective in 5 of these 7 subjects. Neither atropine nor morphine was effective in the remaining 6 subjects. By chi-square analysis, we found a positive correlation between the inhibitory effects of morphine and those of atropine (p less than 0.05). In the 5 subjects in whom morphine was effective, naloxone reversed the inhibitory effect of morphine. Atropine caused significant baseline bronchodilation when compared with placebo (normal saline), whereas morphine did not. We conclude that opiate receptor stimulation by morphine causes inhibition of the vagally mediated component of water-induced bronchoconstriction.

Adult↗

PubMed1986

High frequency transthoracic ventilation improves gas exchange during experimental bronchoconstriction in rabbits.

In order to evaluate the efficacy of ventilation by high frequency transthoracic oscillation in obstructive lung disease, we studied 10 anesthetized and paralyzed rabbits during experimental bronchoconstriction. In order to generate body surface oscillation, the animals were placed in a body-box connected to a piston pump. Two frequencies were successively applied in random order: 1 Hz, representing "conventional" ventilation, and 5 Hz for high frequency ventilation. During the control period, the magnitudes of the oscillation were adjusted such that the tidal volumes thus produced yielded normocapnia (PaCO2 = 40 +/- 2 mmHg) for at least 3 min at each frequency. The same tidal volumes were then used after a bronchoconstriction induced by aerosolized carbachol. We obtained a severe and stable bronchoconstriction and oscillated the animals at 1 and 5 Hz at identical tidal volumes as those used during the control period. Identical at the 2 frequencies of oscillation during the control period, the rate of CO2 elimination with bronchoconstriction was significantly higher (p less than 0.05) at 5 Hz (15.9 +/- 3.3 ml/min) than at 1 Hz (14.2 +/- 3.9 ml/min); PaCO2 was also significantly lower at 5 Hz than at 1 Hz. Mean arterial PO2 was significantly higher (p less than 0.01) at 5 Hz (58 +/- 4 mmHg) than at 1 Hz (46 +/- 12 mmHg) during bronchoconstriction. Mean alveolararterial O2 pressure difference was significantly lower (p less than 0.01) at 5 Hz (49 +/- 13 mmHg) than at 1 Hz (59 +/- 11 mmHg). Only a minor increase in lung volume was found during high frequency ventilation, and no significant hemodynamic changes occurred.(ABSTRACT TRUNCATED AT 250 WORDS)

Airway Resistance↗

PubMed1986

The effect of indomethacin on exercise-induced bronchoconstriction and refractoriness after exercise.

Exercise causes bronchoconstriction in asthmatic subjects, which is usually followed by a refractory period during which exercise of the same intensity will cause less bronchoconstriction. This study examined the role of contractile prostaglandins in the initial bronchoconstriction after exercise and the role of inhibitory prostaglandins in the refractoriness after exercise. Subjects were pretreated with indomethacin, 50 mg twice daily, on 1 occasion or placebo on 2 occasions for 3 days. This was followed by 2 exercise challenges on a bicycle ergometer at least 30 min apart. Indomethacin did not alter the initial bronchoconstriction after exercise. The maximal fall in FEV1 after the first exercise challenge after placebo was 0.67 +/- 0.17 L and 0.68 +/- 0.17 L, and after indomethacin it was 0.67 +/- 0.12 L. Indomethacin, however, did prevent refractoriness after exercise. The maximal fall in FEV1 after the second exercise challenge after placebo was 0.31 +/- 0.06 L and 0.36 +/- 0.12 L, and after indomethacin it was 0.64 +/- 0.12 L. These results indicate that indomethacin pretreatment does not alter bronchoconstriction after exercise, and they also indicate that indomethacin pretreatment prevents refractoriness after exercise in asthmatic subjects.

Adult↗

PubMed1998

The effect of the NK2 tachykinin receptor antagonist SR 48968 (saredutant) on neurokinin A-induced bronchoconstriction in asthmatics.

Inhalation of neurokinin (NK) A causes bronchoconstriction in patients with asthma. The NKA-induced bronchoconstriction in isolated human airways is mediated via the NK2 receptor and inhibited by SR 48968, a potent and specific nonpeptide tachykinin NK2 receptor antagonist. In the present study, the effect of orally administered SR 48968 on NKA-induced bronchoconstriction was examined in 12 mild asthmatics. On the screening day and during the study periods, increasing concentrations of NKA (3.3 x 10(-9) to 1.0 x 10(-6) mol x mL(-1)) were inhaled, until the forced expiratory volume in one second (FEV1) and specific airway conductance (sGaw) decreased by at least 20 and 50%, respectively. During the study periods, 100 mg SR 48968 or matched placebo was ingested in a double-blind, randomized, crossover fashion and NKA provocation was performed at 1.5 and 24 h after dosing. At 1.5 h, the mean (SEM) log10 provocative concentration of NKA causing a 20% fall in FEV1 (PC20 FEV1) was -6.25 (0.20) after SR 48968 and -6.75 (0.17) after placebo (p=0.05); the mean log10 provocative concentration of NKA causing a 35% fall in sGaw (PC35 sGaw) was -7.02 (0.28) after SR 48968 and -7.64 (0.19) after placebo (p=0.05). At 24 h, the mean log10 PC20 FEV1 was -6.21 (0.17) after SR 48968 and -6.65 (0.11) after placebo (p=0.05); the mean log10 PC35 sGaw was -6.85 (0.23) after SR 48968 and -7.17 (0.15) after placebo (nonsignificant). As PC20 FEV1 and/or PC35 sGaw were not reached in up to 4 patients per SR 48968 group, the differences between SR 48968 and placebo were underestimated. In conclusion, oral treatment with 100 mg SR 48968 caused a significant inhibition of neurokinin A-induced bronchoconstriction in asthmatics. This finding constitutes the first evidence of inhibition of sensory neuropeptide-induced bronchoconstriction by a selective tachykinin receptor antagonist in humans.

Adult↗

PubMed1989

Pulmonary gas exchange during histamine-induced bronchoconstriction in asthmatic subjects.

Bronchial provocation for testing airway hyperreactivity is now well-established. However, the effects of histamine-induced bronchoconstriction on pulmonary gas exchange in man have not been systematically studied. We empirically noted marked decreases in PaO2 in some asthmatic subjects following induced bronchoconstriction. Nine subjects with mild, stable asthma were studied, each on two separate days. The first determined the dose of inhaled histamine necessary to decrease FEV1 by 20 percent and the relationship to lung volume and to pulmonary resistance by the interrupter technique (Rint). On the second day arterial blood gases, ventilation, Rint, and the anatomic (VDan) and physiologic (VDphys) dead spaces were measured simultaneously. There was a significant (p less than 0.05), profound fall in PaO2 (mean, -21.8 mm Hg) and in P(A-a)O2 (mean +14.7 mm Hg) within 5 min after bronchoconstriction, associated with a significant (p less than 0.05) increase in respiratory frequency (mean +5.1 min-1); and decrease in tidal volume (mean, -0.3 L). The ratio VDphys/VT increased significantly (p less than 0.05; mean change, +0.08) even though VDan and VDphys did not. Bronchoconstriction induced the broadening of ventilation (V)/perfusion (Q) ratios, with, most likely, an increase in areas of high V/Q. Histamine-induced bronchoconstriction in mild asthma results in a marked fall in PaO2 due to induced V/Q inequality. Therefore, histamine airway challenge should be used with caution in patients with any preexisting hypoxemia.

Adult↗

PubMed1986

Regional deposition of particles in human lung after induced bronchoconstriction.

The percentage 24-hr lung retention (Ret24), a measure of penetration to the aveoli, of 4 micron monodispersed Teflon particles, aerodynamic diameter 6 micron, was studied in 8 healthy nonsmokers. The particles were inhaled at 0.2 1/sec with maximally deep breaths. Bronchoconstriction was induced by inhalation of a methacholinebromide aerosol for one exposure before and for one exposure after inhalation of the Teflon particles. Airway resistance (Raw) was measured using a whole body pletysmograph before and after the induction of bronchoconstriction and increased on an average by a factor 2-3. Ret24 was significantly lower when the Teflon particles were inhaled during bronchoconstriction than when bronchoconstriction was induced after inhalation of the Teflon particles, 26 +/- 12% and 48 +/- 6% (mean +/- SD), respectively. These experimental data agree fairly well with data on deposition due to impaction and sedimentation using a lung model where the diameters of the airways were varied so that an increase in airway resistance occurs similar to that produced in our experimental subjects. However, the experimental data tended to be lower than the theoretical ones when the particles were inhaled during the induced bronchoconstriction. In this study, where the mucociliary transport system was stimulated by methacholinebromide, the percentage 3-hr retention (Ret3) was highly correlated with Ret24, r = 0.97, i.e., Ret3 can be used instead of the Ret24. This implies that radionuclides with shorter half-lives which give lower radiation doses, can be used, and that subjects can be studied within shorter periods of time.

Adult↗

PubMed1988

Role of cyclooxygenase products of arachidonic acid metabolism in Ascaris antigen-induced bronchoconstriction in sensitized dogs.

The pharmacologic modulation of Ascaris allergen-induced bronchoconstriction was investigated in beagle dogs sensitized by experimental infection with Ascaris suum ova. Ascaris-induced increases in total lung resistance (RL) and falls in dynamic lung compliance (Cdyn) were unaffected by pretreatment with an antihistamine (pyrilamine) given alone but were significantly attenuated (P less than .05) by the cyclooxygenase enzyme inhibitor, indomethacin. The combination of pyrilamine and indomethacin also produced a significant (P less than .01) inhibition of Ascaris-induced bronchoconstriction, greater than that produced by indomethacin given alone but the difference between the two treatment groups was not statistically significant. The combination of an antihistamine, the cyclooxygenase inhibitor indomethacin and the leukotriene synthesis inhibitor, U-60,257, almost completely abolished Ascaris-induced bronchoconstriction (91% inhibition of Cdyn changes; 93% inhibition of RL changes). The inhibition was significantly greater than that produced by cyclooxygenase inhibition alone. The leukotriene synthesis inhibitor piriprost (U-60,257) given alone or in combination with pyrilamine produced no inhibition of Ascaris-induced changes in RL or Cdyn. The leukotriene antagonist FPL55712 or the thromboxane synthase inhibitor U-63,557A also showed little or no activity in this model, whereas the thromboxane receptor antagonist AH23848 produced a marked inhibition of Ascaris-induced bronchoconstriction. We conclude that Ascaris-induced bronchoconstriction is mediated primarily by cyclooxygenase products of arachidonic acid metabolism. The role of histamine and lipoxygenase products can only be revealed during an effective cyclooxygenase blockade.

Animals↗

PubMed1987

Afferent nerves in reflex bronchoconstriction.

Bronchomotor tone is controlled by reflex mechanisms that have afferent pathways originating from different sites and from receptors transducing different stimuli: mechanoreceptors, thermoreceptors, chemoreceptors and nociceptors. Mechanical and chemical irritations of the nasal cavity and the nasopharynx usually lead to a decrease in bronchomotor tone. However, in patients with asthma and chronic obstructive lung diseases, nasal stimulation causes bronchoconstriction. Some experimental data indicate a bronchoconstrictive effect of nasal cooling. At present, it is not possible to identify specific receptors as responsible; but specific cold receptors have been found in the nose. Mechanical and chemical irritations of the larynx, cooling of the larynx, and exposure to both hypo- and hypertonic water solutions cause bronchoconstriction. Of the several receptors described in the larynx the following could be involved: rapidly adapting irregularly firing irritant receptors with myelinated fibres, specific cold receptors and C-fibre receptors. Of possible relevance is the marked inhibitory effect that low temperatures have on laryngeal mechanoreceptors. All the four types of nervous receptors present within the tracheobronchial tree and lung parenchyma contribute to the regulation of bronchomotor tone. Rapidly-adapting irritant receptors, and bronchial and pulmonary C-fibre receptors, that respond to several mechanical and chemical challenges, cause a reflex bronchoconstriction. Slowly-adapting stretch receptors are stimulated by increases in broncho-motor tone and reflexly inhibit bronchoconstriction subserving a negative feedback mechanism.

Animals↗

PubMed1995

Intratracheal administration of phosphodiesterase III inhibitor attenuates bronchoconstriction in cats: a preliminary report.

The effects of intratracheal administration of MKS 492, a selective phosphodiesterase (PDE) III inhibitor, were studied in five anesthetized bronchoconstricted cats. The animals were challenged by four repeated doses of intratracheal methacholine (67 micrograms/kg), and the degree of bronchoconstriction was assessed from increases in respiratory system resistance (Rrs). All animals demonstrated good bronchoconstrictive responses (i.e., 86-99% increases in Rrs) to methacholine without tachyphylaxis. On a separate day, the cats received the same four doses of methacholine after being pretreated with either intratracheal saline or three different doses of MKS 492 (0.17, 1.7, and 17 micrograms/kg). The increases in Rrs with 1.7 micrograms/kg [52.6 +/- 8.4% (SE)] and 17 micrograms/kg of MKS 492 (44.4 +/- 10.1%) were smaller than those with saline pretreatment (88.1 +/- 16.8%) (P < 0.05). There were no treatment-associated changes in mean arterial pressure or heart rate during administration of MKS 492. We conclude that intratracheal MKS 492 effectively reduced methacholine-induced bronchoconstriction in a dose-dependent fashion without substantial systemic effects. These preliminary results suggest that inhalation of isozyme-selective PDE inhibitors may deserve consideration for clinical trials provided that more extensive preclinical investigations justify such trials.

3',5'-Cyclic-AMP Phosphodiesterases↗

PubMed1994

The protective effects of ipratropium bromide and terbutaline on distilled water-induced bronchoconstriction.

In a randomized, double-blind, placebo-controlled study, we investigated the protective effects of ipratropium bromide 160 micrograms and 320 micrograms and terbutaline 500 micrograms on ultrasonically nebulized distilled water (UNDW)-induced bronchoconstriction in nine stable asthmatic patients. Both drugs caused a significant increase (P < 0.001) in baseline FEV1 with no significant differences between the drugs or both doses of ipratropium bromide. Pre-inhalation of ipratropium bromide 320 micrograms and terbutaline 500 micrograms inhibited UNDW-induced bronchoconstriction (P < 0.01), whereas ipratropium bromide 160 micrograms had no protective effect. The protective effects of ipratropium bromide showed a large interindividual variation. There was no correlation between the increase in baseline FEV1 and PD20 UNDW, indicating that the protective effect on UNDW-induced bronchoconstriction is not dependent on the bronchodilation induced by terbutaline and ipratropium bromide. It also appears that the UNDW-induced bronchoconstriction is at least partly vagally mediated.

Administration, Inhalation↗

PubMed1990

Pharmacological characterization of mediators and vagal influence in the acute allergic bronchoconstriction in guinea pigs.

The allergic bronchoconstriction in guinea pigs has been attributed mainly to the release of mast cell mediators. Histamine has been involved in the first minutes of the anaphylactic reaction and new-formed compounds in the subsequent response. In this asthma model the vagal influence has been sparsely investigated. In the present work we evaluated the pharmacological modification of the acute allergic bronchoconstrictor response in guinea pigs sensitized to ovalbumin through aerosol exposure. Pyrilamine (20 micrograms/kg), diethylcarbamazine (a lipoxygenase inhibitor, 10 mg/kg) and dexamethasone (4 mg/kg) each reduced the antigen-induced bronchoconstriction throughout the 30 min studied. Indomethacin (3.1 mg/kg) did not modify the response to the antigen. Atropine (2 mg/kg) plus bilateral vagotomy also diminished this response from 5 min onward. On the other hand, from 5 min ahead pyrilamine-resistant bronchoconstriction was partially inhibited by dexamethasone, and it was almost completely blocked during all of the response when atropine plus bilateral vagotomy were added to dexamethasone. Dipyridamole (an inhibitor of the adenosine uptake, 0.4 mg/kg) enhanced the bronchoconstriction, though this was significant only in the 2-5 min time-interval of the response. These results suggest that histamine and vagal influence play an important role in the whole response to antigen, that other mediators, probably leukotrienes, participate in this response from 5 min onward, and that adenosine could exert a potentiation effect on this response.

Adenosine↗

PubMed1997

Rat big endothelin-1-induced bronchoconstriction and vasoconstriction in the isolated perfused rat lung: role of endothelin converting enzyme and neutral endopeptidase 24.11.

Treatment of animals with big endothelin-1 (bET) causes pulmonary hypertension and bronchoconstriction, both in vivo and in perfused lungs. The biological activity of bET requires proteolytic cleavage to ET-1 by endothelin converting enzymes (ECE) and possibly other proteases such as neutral endopeptidase 24.11 (NEP 24.11). Since the role of NEP 24.11 in the physiological activation of bET is unclear, we investigated the effects of the selective NEP 24.11 inhibitor thiorphan on bET-induced vaso- and bronchoconstriction in the isolated perfused rat lung. We also studied the effects of phosphoramidon and (S)-2-biphenyl-4-yl-1-(1H-tetraol-5-yl)-ehtylaminomethylphosphonic acid (CGS-26303), i.e. agents which block not only NEP 24.11 but also ECE. The bET-induced vasoconstriction was much less prominent than the bronchoconstriction, i.e. after exposure for 110 min vascular and airway conductance were decreased by 33% and 80% respectively. The small bET-induced vasoconstriction was attenuated to a similar degree by pretreatment with any of the three protease inhibitors. However, thiorphan up to a concentration of 10 microM had only little effect on the bET-induced bronchoconstriction, while 10 microM phosphoramidon or CGS-26303 provided half-maximal and 100 microM phosphoramidon complete protection in this model. This profile of inhibitor action suggests that in rat lung ECE is the major enzyme responsible for activation of bET.

Airway Resistance↗

PubMed1996

Characteristics of vagal reflex-mediated tracheal response induced by bronchoconstriction in guinea pigs.

The reflex tracheal response induced by bronchoconstriction was investigated using a newly devised tracheo-bronchi preparation in anesthetized guinea pigs. Tracheal constriction and subsequent dilatation were observed in response to bronchoconstriction induced by the inhalation of 0.001-0.01% histamine and 0.003-0.03% acetylcholine. These tracheal responses were abolished by cervical vagotomy or treatment of the tracheal site with 1% tetrodotoxin. Tracheal constriction and dilatation were significantly inhibited by 0.1% atropine and 1% propranolol, respectively. When high tracheal tone was induced by 0.01% serotonin, the residual tracheal dilatation observed in the presence of propranolol was enhanced, while dilatation was completely inhibited by 1% hexamethonium. Dilatation was also suppressed by 1% N omega-nitro-L-arginine methyl ester (L-NAME) and 1% methylene blue. The tracheal constriction produced by bronchoconstriction was significantly enhanced by propranolol 2 mg/kg, i.v. and L-NAME 10 mg/kg, i.v. These results demonstrate that a vagally mediated reflex tracheal response (constriction followed by dilatation) is induced by bronchoconstriction in anesthetized guinea pigs. Cholinergic nerves may mediate the constriction, and adrenergic and nonadrenergic noncholinergic (NANC) inhibitory nerves may mediate the dilatation. Furthermore, NO may be involved in the NANC reflex tracheal dilatation.

Acetylcholine↗