Abstract:1. We examined the effect of exogenously administered tachykinins, neurokinin A (NKA), substance P (SP) and neurokinin B (NKB) on neurally mediated cholinergic bronchoconstrictor responses in guinea-pigs. 2. Electrical stimulation of regions in the dorsal medulla oblongata produced a cholinergic bronchospasm that was not affected by depletion of endogenous tachykinins with capsaicin pretreatment (50 mg kg-1, s.c., 1 week earlier) or by pretreatment with the neutral endopeptidase inhibitor, phosphoramidon (3 mg… Show more
“…In addition, this finding raises the possibility of an interaction between e-NANC and cholinergic responses. In fact, it has been already reported that e-NANC neurotransmitters can induce acetylcholine release from postganglionic cholinergic neurons in guinea pig airways (Myers and Undem, 1991;Delaunois et al, 1996;Hey et al, 1996). In our study, this cholinergic component added to the e-NANC response was only manifested after exposure to the highest 0, concentration, since bronchi from non-exposed animals had similar e-NANC responses with or without atropine.…”
Section: Responses To Carbachol Isoproterenol Nitroprusside and Subsupporting
confidence: 55%
“…Thus, we were able to measure the e-NANC component with or without atropine incubation ( fig 1C). In fact, it has been already reported that e-NANC neurotransmitters can induce acetylcholine release from postganglionic cholinergic neurons in guinea pig airways (Myers and Undem, 1991;Delaunois et al, 1996;Hey et al, 1996). These results allow us to conclude that 0, introduced a cholinergic component into the second slow contraction produced by EFS (fig 5A), and that the true e-NANC response was unaffected by 0, (fig 5B), as we also found with the concentration-response curves to SP in bronchial preparations.…”
Section: Responses To Carbachol Isoproterenol Nitroprusside and Submentioning
Prejunctional and postjunctional effects of several ozone (O3) concentrations, including those found in highly polluted cities, were evaluated in guinea pig airways. Animals bred in O3-free conditions were exposed to air or O3 (0.3, 0.6 or 1.2 ppm) during 4 h, and studied 16-18 h later. Tracheal and bronchial rings were studied in organ baths. Electrical field stimulation (EFS) (100 V, 2 ms, 10 s) was given at increasing frequencies (0.25-16 Hz). Some tissues received atropine (2 microM) and/or propranolol (10 microM). Concentration-response curves to carbachol, isoproterenol, nitroprusside, and substance P were constructed. In tracheas, almost all O3 concentrations decreased the relaxation at low EFS frequencies, but had no effect on the propranolol-resistant (i-NANC) relaxation, suggesting that only adrenergic relaxation was affected. This was a prejunctional effect, since O3 did not modify the responses to isoproterenol. Relaxation induced by a nitric oxide (NO) donor, nitroprusside, was not affected by O3, which agrees with the lack of O3-effect on i-NANC system. O3 did not modify the EFS-induced e-NANC contraction in atropine-treated bronchi, nor the contraction caused by exogenous substance P. By contrast, in bronchi without atropine, 1.2 ppm O3 increased the e-NANC contraction induced by the highest EFS (16 Hz). O3 increased the maximum responses to carbachol in tracheas (1.2 ppm) and bronchi (0.6 and 1.2 ppm). In conclusion, we found that: a) O3 decreased adrenergic relaxation in guinea pig tracheas at low EFS frequencies through a prejunctional alteration; b) O3 did not modify the i-NANC relaxation in tracheas, at least the NO-mediated; c) O3 added a cholinergic component to the bronchial slow-phase (e-NANC) contraction evoked by EFS; and d) O3 enhanced the cholinergic responses in trachea and bronchi by a postjunctional mechanism.
“…In addition, this finding raises the possibility of an interaction between e-NANC and cholinergic responses. In fact, it has been already reported that e-NANC neurotransmitters can induce acetylcholine release from postganglionic cholinergic neurons in guinea pig airways (Myers and Undem, 1991;Delaunois et al, 1996;Hey et al, 1996). In our study, this cholinergic component added to the e-NANC response was only manifested after exposure to the highest 0, concentration, since bronchi from non-exposed animals had similar e-NANC responses with or without atropine.…”
Section: Responses To Carbachol Isoproterenol Nitroprusside and Subsupporting
confidence: 55%
“…Thus, we were able to measure the e-NANC component with or without atropine incubation ( fig 1C). In fact, it has been already reported that e-NANC neurotransmitters can induce acetylcholine release from postganglionic cholinergic neurons in guinea pig airways (Myers and Undem, 1991;Delaunois et al, 1996;Hey et al, 1996). These results allow us to conclude that 0, introduced a cholinergic component into the second slow contraction produced by EFS (fig 5A), and that the true e-NANC response was unaffected by 0, (fig 5B), as we also found with the concentration-response curves to SP in bronchial preparations.…”
Section: Responses To Carbachol Isoproterenol Nitroprusside and Submentioning
Prejunctional and postjunctional effects of several ozone (O3) concentrations, including those found in highly polluted cities, were evaluated in guinea pig airways. Animals bred in O3-free conditions were exposed to air or O3 (0.3, 0.6 or 1.2 ppm) during 4 h, and studied 16-18 h later. Tracheal and bronchial rings were studied in organ baths. Electrical field stimulation (EFS) (100 V, 2 ms, 10 s) was given at increasing frequencies (0.25-16 Hz). Some tissues received atropine (2 microM) and/or propranolol (10 microM). Concentration-response curves to carbachol, isoproterenol, nitroprusside, and substance P were constructed. In tracheas, almost all O3 concentrations decreased the relaxation at low EFS frequencies, but had no effect on the propranolol-resistant (i-NANC) relaxation, suggesting that only adrenergic relaxation was affected. This was a prejunctional effect, since O3 did not modify the responses to isoproterenol. Relaxation induced by a nitric oxide (NO) donor, nitroprusside, was not affected by O3, which agrees with the lack of O3-effect on i-NANC system. O3 did not modify the EFS-induced e-NANC contraction in atropine-treated bronchi, nor the contraction caused by exogenous substance P. By contrast, in bronchi without atropine, 1.2 ppm O3 increased the e-NANC contraction induced by the highest EFS (16 Hz). O3 increased the maximum responses to carbachol in tracheas (1.2 ppm) and bronchi (0.6 and 1.2 ppm). In conclusion, we found that: a) O3 decreased adrenergic relaxation in guinea pig tracheas at low EFS frequencies through a prejunctional alteration; b) O3 did not modify the i-NANC relaxation in tracheas, at least the NO-mediated; c) O3 added a cholinergic component to the bronchial slow-phase (e-NANC) contraction evoked by EFS; and d) O3 enhanced the cholinergic responses in trachea and bronchi by a postjunctional mechanism.
“…Catecholamines may inhibit or facilitate acetylcholine overflow through prejunctional a 2 -and b 2 -adrenoceptors, respectively [153][154][155]. Neurokinins such as substance P may enhance cholinergic transmission through facilitatory neurokinin-1 and/or -2 receptors [156,157]. Interestingly, substance P may also induce MBP release from eosinophils, causing M 2 autoreceptor dysfunction, which could act synergistically to direct facilitation [158].…”
Airway hyperresponsiveness (AHR) is a hallmark clinical symptom of asthma. At least two components of AHR have been identified: 1) baseline AHR, which is persistent and presumably caused by airway remodelling due to chronic recurrent airway inflammation; and 2) acute and variable AHR, which is associated with an episodic increase in airway inflammation due to environmental factors such as allergen exposure.Despite intensive research, the mechanisms underlying acute and chronic AHR are poorly understood. Owing to the complex variety of interactive processes that may be involved, in vitro model systems and animal models are indispensable to the unravelling of these mechanisms at the cellular and molecular level.The present paper focuses on a number of translational studies addressing the emerging central role of the airway smooth muscle cell, as a multicompetent cell involved in acute airway constriction as well as structural changes in the airways, in the pathophysiology of airway hyperresponsiveness.
“…Other guinea pigs were given AbNGF 2 days before ozone exposure (which is 3 days before physiological measurements). Other guinea pigs were treated after ozone exposure with either the neurokinin NK 1 receptor antagonist CP-96,345 [3 mg/kg iv (28)] or the NK2 receptor antagonist SR48968 [0.1 mg/kg iv (18)] 30 min before physiological measurements (Fig. 1).…”
Ozone causes persistent airway hyperreactivity in humans and animals. One day after ozone exposure, airway hyperreactivity is mediated by release of eosinophil major basic protein that inhibits neuronal M(2) muscarinic receptors, resulting in increased acetylcholine release and increased smooth muscle contraction in guinea pigs. Three days after ozone, IL-1β, not eosinophils, mediates ozone-induced airway hyperreactivity, but the mechanism at this time point is largely unknown. IL-1β increases NGF and the tachykinin substance P, both of which are involved in neural plasticity. These experiments were designed to test whether there is a role for NGF and tachykinins in sustained airway hyperreactivity following a single ozone exposure. Guinea pigs were exposed to filtered air or ozone (2 parts per million, 4 h). In anesthetized and vagotomized animals, ozone potentiated vagally mediated airway hyperreactivity 24 h later, an effect that was sustained over 3 days. Pretreatment with antibody to NGF completely prevented ozone-induced airway hyperreactivity 3 days, but not 1 day, after ozone and significantly reduced the number of substance P-positive airway nerve bundles. Three days after ozone, NK(1) and NK(2) receptor antagonists also blocked this sustained hyperreactivity. Although the effect of inhibiting NK(2) receptors was independent of ozone, the NK(1) receptor antagonist selectively blocked vagal hyperreactivity 3 days after ozone. These data confirm mechanisms of ozone-induced airway hyperreactivity change over time and demonstrate 3 days after ozone that there is an NGF-mediated role for substance P, or another NK(1) receptor agonist, that enhances acetylcholine release and was not present 1 day after ozone.
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