Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P20366 (substance P)
 21,176 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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 kg-1, i.v.). 3. Infusion of NKA (0.03-0.1 microgram kg-1 min-1), SP (1 microgram kg-1 min-1) or NKB (1 microgram kg-1 min-1) potentiated the bronchoconstrictor response to electrical stimulation of the dorsal medulla. The doses of tachykinins tested were subthreshold for direct activation of airway smooth muscle, because they were devoid of direct bronchoconstrictor effects. The relative rank order potency for augmentation of centrally induced bronchospasm was NKA > NKB approximately SP, suggesting activation of the NK2 receptor subtype. 4. Infusion of NKA, SP and NKB had no effect on bronchoconstrictor responses to i.v. methacholine (1 microgram kg-1) indicating that a prejunctional neural mechanism of action was responsible for the effects on CNS stimulation-induced bronchospasm. 5. Potentiation of the bronchoconstrictor response to dorsal medullary stimulation produced by infusion of NKA was blocked by pretreatment with the NK2 antagonist SR 48968 (1 mg kg-1, i.v.) but not by the NK1 antagoinst CP 96,345 (1 mg kg-1, i.v.). 6. The potentiation of CNS-induced bronchospasm produced by infusion of SP was partially inhibited by CP 96,345 (1 mg kg-1, i.v.) but not by SR 48968 (1 mg kg-1, i.v.). Treatment with combined SR 48968 (1 mg kg-1, i.v.) and CP 96,345 (1 mg kg-1, i.v.) completely blocked the SP-induced potentiation of CNS-stimulated bronchospasm. 7. These results identify an important modulatory role for NK2 receptors, located at prejunctional sites on parasympathetic nerves, on cholinergic bronchoconstrictor responses in guinea-pigs. 8. It is proposed that substances that release tachykinins from airway sensory nerves, e.g. inflammatory mediators or irritants, may induce hyperresponsiveness of cholinergic bronchomotor responses by activation of NK2-receptors on parasympathetic airway nerves. Furthermore, these studies indicate that endogenous tachykinins are not involved in the maintenance of basal cholinergic bronchomotor tone in the intact guinea-pig.
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PMID:Augmentation of neurally evoked cholinergic bronchoconstrictor responses by prejunctional NK2 receptors in the guinea-pig. 873 30

The present work assesses the effects of the acute administration of adenosine on tachykinergic bronchoconstriction induced in different ways (exogenously administered capsaicin or substance P and vagal electrical stimulation) in anaesthetized and curarized guinea-pigs. Adenosine (30-3000 micrograms kg-1, i.v.) enhanced significantly and dose-relatedly the airway narrowing induced by a single dose of capsaicin (0.5-2 micrograms kg-1, i.v.), both in normal and in vagotomized animals. A smaller and less dose-dependent enhancement by the nucleoside of the pulmonary resistance increase induced by substance P (5-15 micrograms kg-1, i.v.) was observed. This effect was almost completely prevented by the H1 antagonist diphenhydramine (1 mg kg-1, i.v.), which also unmasked an inhibitory action of adenosine at the highest doses. Diphenhydramine, on the contrary, did not significantly modify the potentiation by adenosine of capsaicin-mediated bronchoconstriction. Finally, the nucleoside dose-dependently inhibited the atropine-resistant bronchospasm following vagal electrical stimulation. The use of the selective adenosinic agonists R-N6-[2-phenylisopropyl]adenosine (1-100 micrograms kg-1, i.v.) and 5'-N-methylcarboxamidoadenosine (1-100 micrograms kg-1, i.v.) before the administration of capsaicin, revealed the ability of the first to reproduce the enhancement induced by adenosine, while the second had an inhibitory effect. It is concluded that adenosine has both excitatory and inhibitory modulatory effects on airway responsiveness to excitatory non-adrenergic non-cholinergic (e-NANC) stimuli. The excitatory effects, revealed with substance P and capsaicin, support the hypothesis that adenosine may play a role as an asthma mediator.
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PMID:Effects of adenosine on NANC bronchoconstriction in anaesthetized guinea-pigs. 879 95

1. The activity of CDP840, a novel, potent and selective cyclic nucleotide phosphodiesterase type 4 (PDE 4) inhibitor, was evaluated in guinea-pig models (in vitro and in vivo) of bronchospasm, ozone-induced airway hyperresponsiveness (AHR) and non-cholinergic bronchoconstriction. Comparisons were made with (i) other PDE 4 inhibitors: CT1731 (S-enantiomer of CDP840), rolipram, RP73401 and (ii) the clinically used agents salbutamol and theophylline. 2. CDP840 relaxed isolated trachea, under basal tone (EC50 4.5 +/- 1.1 microM) being 17 fold less potent than rolipram (EC50 0.26 +/- 0.13 microM) but attaining the same Emax (83 +/- 6% of the response to 300 microM papaverine). 3. CDP840 relaxed tracheae pre-contracted with carbachol (IC25 39 +/- 9 microM) and histamine (IC25 4 +/- 1 microM) producing monophasic curves. Stereoselectivity was not observed with CT1731 against either carbachol (IC25 33 +/- 11 microM) or histamine (IC25 17 +/- 10 microM). Aminophylline was 1.6 fold (carbachol) and 11 fold (histamine) less potent than CDP840. Rolipram and RP73401 produced tri-phasic relaxation curves but were of similar potency (at the IC25 level) to CDP840 against carbachol (rolipram 18 +/- 5 microM, RP73401 39 +/- 1 microM) whereas against histamine they were approximately 20 fold more potent (rolipram 0.2 +/- 0.1 microM, RP73401 0.2 +/- 0.1 microM). In producing > 30% (carbachol) and > 60% (histamine) relaxation these inhibitors had similar potency and were poor compared to salbutamol. 4. Pre-incubation with CDP840 (10 microM) did not antagonize histamine-induced contraction of isolated trachea; however, it did cause a slight potentiation of the subsequent relaxation to salbutamol (IC50 23 +/- 1 to 15 +/- 2 nM). 5. Pretreatment (1 h) with either CDP840 (1 mg kg-1, i.p. or 3 mg kg-1, i.v.) or rolipram (1 mg kg-1, i.p.) did not bronchodilate or antagonize bronchospasm due to inhaled histamine in anaesthetized, ventilated guinea-pigs. Salbutamol (1 mg kg-1, i.p.) did not bronchodilate but caused a parallel 7 fold rightward shift in the histamine dose-response curve. 6. Stimulation of the vagus nerve in the presence of atropine resulted in a frequency-related bronchoconstriction. CDP840 and rolipram (i.v.) inhibited the response being approximately equipotent (EC50 approximately 10 micrograms kg-1). Neither drug inhibited bronchospasm to inhaled substance P. 7. CDP840 (1-10 micrograms kg-1 i.p.) dose relatedly inhibited ozone-induced bronchoconstriction. CT1731 (1 mg kg-1), rolipram (1 mg kg-1), RP73401 (10 micrograms kg-1) and aminophylline (10 mg kg-1) had no effect. Ozone-induced AHR to inhaled histamine was inhibited by CDP840 in a dose-related manner, 10 micrograms kg-1 abolishing the AHR. This effect was stereoselective as CT1731 was approximately 30 fold less potent than CDP840. Rolipram was approximately 100 fold less potent and RP73401 and aminophylline had no effect. CDP840 was orally active being approximately 10 fold less potent compared to i.p. administration. 8. CDP840 is a poor spasmolytic and anti-spasmogenic agent in response to exogenous mediators; however, it potently inhibits vagally mediated non-cholinergic bronchoconstriction and ozone-induced AHR to histamine. It is possible that regulation of cyclic AMP by PDE 4 contributes to neuronal sensitivity in the airways. Furthermore, CDP840 may suppress AHR without being an overt bronchodilator. Such a profile of activity may have therapeutic benefit in airways diseases such as asthma.
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PMID:Inhibition of bronchospasm and ozone-induced airway hyperresponsiveness in the guinea-pig by CDP840, a novel phosphodiesterase type 4 inhibitor. 881 43

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.
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PMID:Indirect muscarinic receptor activation by pentamidine on airway smooth muscle. 893 15

Sch 37224 is an experimental antiallergy compound that inhibits hyperventilation-induced bronchoconstriction (HIB) in guinea pigs and cold air bronchospasm in human asthmatics. HIB in guinea pigs may involve the release of tachykinins such as neurokinin A (NKA) and substance P (SP), and the action of Sch 37224 in this model may relate to inhibition of these neuropeptides. We studied the effect of Sch 37224 on the neuropeptide component of HIB that was enhanced in guinea pigs treated with the neutral endopeptidase inhibitors, thiorphan and phosphoramidon. Pulmonary resistance (RL) and dynamic lung compliance (CDyn) were measured in anesthetized, mechanically ventilated guinea pigs. RL and CDyn were measured at baseline (1 ml/100 g tidal volume and 50 breaths/min) and after a 10-min period of hyperventilation (1 ml/100 g, 150 breaths/min). Hyperventilation produced modest changes in RL (+41 +/- 12%) and CDyn (-12 +/- 3%) which were markedly enhanced by treatment with 3 mg/kg of either thiorphan or phosphoramidon (RL + 269 +/- 43% for thiorphan, + 292 +/- 63% for phosphoramidon and CDyn -65 +/- 3% for thiorphan, -51 +/- 13% for phosphoramidon). In the presence of thiorphan or phosphoramidon, the bronchospasm to hyperventilation was significantly reduced (> 70%) with 5 mg/kg, p.o., of Sch 37224. In other studies, the peptidergic (conducted in the presence of ipratropium bromide and phosphoramidon) bronchoconstrictor response to intravenous nicotine (1 mg/kg) was also inhibited by Sch 37224 (0.3-10 mg/kg, p.o.). However, Sch 37224 (5 mg/kg, p.o.) had no effect on the bronchoconstrictor response to intravenous NKA. These results indicate that Sch 37224 inhibits the neuropeptide component of HIB and nicotine in guinea pigs and this effect appears to be mediated by the inhibition of the release of tachykinins from airway C fibers.
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PMID:Sch 37224, an experimental antiallergy compound, inhibits the neuropeptide component of hyperventilation- and nicotine-induced bronchoconstriction in guinea pigs. 906 56

The major pulmonary effects of tachykinins are produced by activation of both NK1- and NK2-receptors. A variety of animal models have been used to profile activity of the tachykinins, particularly rodents and guinea pigs, but little information exists regarding methods to evaluate NK1- and NK2-receptor antagonist activity in dogs. This study describes a simple method in dogs to measure NK1- and NK2-receptor agonist and antagonist activity of drugs in the same preparation. We measured pulmonary resistance (RL), dynamic lung compliance (CDyn), minute volume (MV), and mean arterial blood pressure (MAP) before and after challenge with aerosolized NKA (1%) and i.v. SP (100 ng/kg) to quantify responses to the tachykinin challenge. Challenge with NKA produced an increase in RL and a decrease in CDyn, and this bronchospasm was inhibited by the NK2-antagonist SR 48968 (ID50 RL=1.3 mg/kg and ID50 CDyn=1.3 mg/kg, p.o.). The NK1-antagonist, CP 99994 was inactive against NKA-induced bronchospasm at doses up to 10 mg/kg, p.o. When the dogs were challenged with SP, there was a fall in MAP and an increase in MV and both responses were inhibited by CP 99994 (ID50 MV=2.3 mg/kg and ID50 BP=4.5 mg/kg, p.o.), but not by SR 48968 at doses up to 3 mg/kg, p.o. These results identify that NK2-receptors mediate the bronchoconstrictor effect of NKA, and NK1-receptors mediate the hypotension and respiratory stimulation due to SP in dogs. This method offers many advantages for evaluating the effects of tachykinin antagonists including the fact that it is relatively simple to perform and has the capacity to assess both NK1 and NK2 antagonist activity in the same preparation.
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PMID:A method to measure dual NK1/NK2-antagonist activity in dogs. 969 68

1. We quantified baseline cholinergic tone in the trachealis of mechanically ventilated guinea-pigs and determined the influence of vagal afferent nerve activity on this parasympathetic tone. 2. There was a substantial amount of baseline cholinergic tone in the guinea-pig trachea, eliciting contractions of the trachealis that averaged 24.6 +/- 3.5 % (mean +/- s.e.m.) of the maximum attainable contraction. This tone was essentially abolished by vagotomy or ganglionic blockade, suggesting that it was dependent upon on-going pre-ganglionic input arising from the central nervous system. 3. Cholinergic tone in the trachealis could be markedly and rapidly altered (either increased or decreased) by changes in ventilation (e. g. cessation of ventilation; hyperpnoea; slow, deep breathing) and by lung distention (via positive end-expiratory pressure). These effects were not accompanied by marked alterations in blood gases and were abolished by vagotomy or atropine. By contrast, tachykinin receptor antagonists, which abolished capsaicin-induced bronchospasm, were without effect on baseline cholinergic tone. This and other evidence suggests that capsaicin-sensitive nerves have little if any influence on baseline parasympathetic tone. Likewise, while activation of afferent nerves innervating the larynx can alter airway parasympathetic nerve activity, transection of the superior laryngeal nerves was without effect on baseline cholinergic tone. 4. Cutting the vagus nerves caudal to the recurrent laryngeal nerves, thus leaving the preganglionic parasympathetic innervation of the trachealis intact but disrupting all afferent nerves innervating the lungs and intrapulmonary airways, abolished baseline cholinergic tone in the trachea. Sham vagotomy or cutting the vagi caudal to the lungs did not reduce baseline cholinergic tone. 5. The results indicate that baseline airway cholinergic nerve activity is necessarily dependent upon afferent nerve activity arising from the intrapulmonary airways and lungs. More specifically, the data are consistent with the hypothesis that on-going activity arising from the nerve terminals of intrapulmonary rapidly adapting receptors determines the level of baseline airway cholinergic tone.
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PMID:Regulation of baseline cholinergic tone in guinea-pig airway smooth muscle. 1042 19

The major pulmonary effects of tachykinins, including bronchoconstriction, are mediated by activation of both neurokinin-1 (NK(1)) and neurokinin-2 (NK(2)) receptors. In guinea-pigs NK(1)and NK(2)receptor antagonists interact synergistically to inhibit the bronchoconstriction induced by neurokinin-A (NKA). However, the effect of combined NK(1)and NK(2)receptor antagonists on tachykinin-induced bronchoconstriction in most other species has not been evaluated. In this study, the interactive effects of CP 99994, an NK(1)receptor antagonist and SR 48968, an NK(2)receptor antagonist, were evaluated against NKA-induced brochospasm in dogs. Pulmonary resistance (R(L)) and dynamic lung compliance (C(Dyn)) were measured in anesthetized, spontaneously breathing dogs to measure the bronchoconstrictor response to aerosolized NKA (1%). Mean arterial blood pressure (MAP) and minute volume (MV) were also measured to assess the NK(1)receptor mediated cardiorespiratory response to substance P (100 ng/kg, iv). Pretreatment with SR 48968 (0.3-3 mg/kg, po) in the presence of an NK(1)antagonist dose of CP 99994 (10 mg/kg, po) inhibited the NKA-induced bronchospasm. However, the inhibition produced by SR 48968 plus CP 99994 was no greater than that previously shown for SR 48968 alone. Therefore, dual NK(1)/NK(2)receptor antagonists do not interact synergistically against NKA-induced bronchospasm in dogs. This may relate to the fact that dogs, like humans, have the NK(2)receptor as the predominant receptor subtype producing bronchoconstriction.
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PMID:Combined NK(1)and NK(2)receptor antagonists on the bronchoconstrictor response to NKA in dogs. 1050 6

Advances in the understanding of neural mechanisms in asthma may provide novel therapeutic approaches in the treatment of asthma. Excessive activity of cholinergic nerves may be important in asthma. Dysfunction of M2 muscarinic receptors in asthma may lead to excessive bronchoconstriction and mucus secretion and can be induced in animal models by a range of stimuli including allergen, viral infection, ozone, eosinophil products and cytokines. Cholinergic mechanisms may be especially important in certain types of patients and anticholinergic agents provide protection against bronchospasm due to psychogenic factors or beta2-blockers. Non-adrenergic non-cholinergic (NANC) mechanisms, both inhibitory (i-NANC) and excitatory (e-NANC), may play a significant role in the pathophysiology of asthma. The putative neurotransmitters, vasoactive interstinal polypeptide (VIP) and nitric oxide (NO), mediate neural bronchodilation in human airways. There does not appear to be a defect in the i-NANC system in moderate or severe asthma. e-NANC is mediated by the sensory neuropeptides substance P (SP) and the more potent bronchoconstrictor neurokinin A (NKA). Various studies suggest that the SP content of human airways is increased in asthma. Tachykinins are not only present in sensory nerves, but also are produced by inflammatory cells such as alveolar macrophages, dendritic cells, eosinophils, lymphocytes and neutrophils. They can be released into the airways by stimuli such as allergen and ozone. Evidence suggests that in addition to smooth muscle contraction, which is mediated mainly by NK2 receptors, tachykinins also cause mucus secretion, plasma extravasation and stimulate inflammatory and immune cells. These effects are mediated by NK1 receptors. Recent studies have shown that NK2 receptor antagonists such as saredutant partially inhibit NKA-induced bronchoconstriction in asthmatics. Thus, tachykinin receptor antagonists have potential as therapies for asthma.
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PMID:Neural mechanisms in asthma. 1084 78

Airway smooth muscle is innervated by sympathetic and parasympathetic nerves. When activated, airway nerves can markedly constrict bronchi either in vivo or in vitro, or can completely dilate a precontracted airway. The nervous system therefore plays a primary role in regulating airway caliber and its dysfunction is likely to contribute to the pathogenesis of airways diseases. The predominant contractile innervation of airway smooth muscle is parasympathetic and cholinergic in nature, while the primary relaxant innervation of the airways is comprised of noncholinergic (nitric oxide synthase- and vasoactive intestinal peptide-containing) parasympathetic nerves. These parasympathetic nerves are anatomically and physiologically distinct from one another and differentially regulated by reflexes. Sympathetic-adrenergic nerves play little if any role in directly regulating smooth muscle tone in the human airways. Activation of airway afferent nerves (rapidly adapting receptors, C-fibers) can evoke increases in airway smooth muscle parasympathetic nerve activity, or decreases in parasympathetic nerve activity (through activation of slowly adapting receptors). Extrapulmonary afferents can also modulate nerve mediated regulation of airway smooth muscle tone. In guinea pigs and rats, peripheral activation of tachykinin-containing airway afferent nerves evokes bronchospasm via release of substance P and neurokinin A. This effect of airway afferent nerve activation appears to be unique to guinea pigs and rats. The actions and interactions between the components of airway innervation are discussed.
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PMID:Neural regulation of airway smooth muscle tone. 1124 Jan 56


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