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)

Water and secretions interact in airways to produce the sol and gel layers that allow for entrapment of foreign materials and subsequent clearance by ciliary movement and by cough. Active Cl ion transport produces fluid, and this process is activated by products of mast cells (leukotrienes), eosinophils (major basic protein), and by other inflammatory mediators (prostaglandins, bradykinin). Gland secretions produce the bulk of the volume of secretions. Airway irritation stimulates gland secretion reflexly via vagal muscarinic pathways. Recently, the sensory nerves have been discovered to release substance P and other neuropeptides when the airways are irritated. The stimulatory effects of neuropeptides on gland secretion (and on other inflammatory sites) are modulated by enkephalinase a membrane-bound enzyme that cleaves neuropeptides and thereby inactivates them. Up- or down-regulation of enkephalinase is predicted to change the degree of inflammatory response to neuropeptides. Finally, the cell surface of airway epithelial cells have been discovered to secrete large molecular weight glycoconjugates; these secreted products are increased markedly by a series of proteinases produced by inflammatory cells (neutrophils, mast cells) and by bacteria. Their exact physiologic roles are still unknown but they may contribute to the bulk and viscoelastic properties of airway secretions, and they may serve an important role in bacterial, viral and inflammatory cell adhesion.
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PMID:Secretion and ion transport in airways during inflammation. 333 78

We examined an endogenous substance causing cough in awake guinea pigs. An intraperitoneal injection of phosphoramidon, a selective inhibitor of neutral endopeptidase (E.C. 3.4.24.11), caused cough in a dose-dependent fashion for approximately 40 min. At a dose of 3 x 10(-3) mol/kg, phosphoramidon caused a total of 11.6 +/- 1.4 coughs in 40 min. Phosphoramidon (3 x 10(-3) mol/kg)-induced cough was significantly inhibited by systemic pretreatment with capsaicin (p < 0.01). Aerosols of FK 888 (1 min), a specific inhibitor of substance P (NK1) receptor, inhibited phosphoramidon (3 x 10(-3) mol/kg)-induced cough in a dose-dependent fashion with complete inhibition at a dose of 10(-5) M. Likewise, aerosols of FK 224 (10(-5) M; 1 min), another inhibitor of NK1 and NK2 receptors, or lidocaine (4%, 1 min) significantly inhibited phosphoramidon (3 x 10(-3) mol/kg)-induced cough (p < 0.01). Furthermore, aerosols of FK 888 (10(-5) M; 1 min) significantly inhibited cough induced by cigarette smoke in awake guinea pigs (p < 0.01). These results suggest that substance P released from sensory nerves in the airway may be an endogenous substance causing cough and the substance P antagonist may be the drug for treatment of cough in respiratory disease.
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PMID:Evidence for substance P as an endogenous substance causing cough in guinea pigs. 750 93

To examine the role of substance P (SP) in cough during bronchoconstriction, we studied the effects of an aerosolized beta-adrenoceptor agonist, procaterol, and a specific inhibitor of SP (NK1) receptor, FK 888, on bronchoconstriction and cough induced by aerosols of histamine and acetylcholine (ACh) in unsensitized guinea pigs and by those of ovalbumin (OA) antigen in guinea pigs sensitized to OA. Intensity of bronchoconstriction was evaluated by the time to onset of bronchoconstriction after the inhalation of bronchoconstrictors. Both procaterol (10(-6) to 10(-4) M, 2 min) and FK 888 (10(-7) to 10(-5) M, 2 min) dose dependently decreased the number of coughs and increased the time to onset of bronchoconstriction induced by histamine (10(-2) M, 15 s). Procaterol attenuated histamine-induced cough only at the concentrations effective to inhibit bronchoconstriction. However, FK 888 at concentrations of 10(-7) and 10(-6) M decreased the number of coughs without effect on bronchoconstriction. Likewise, the inhibitory effects of procaterol (10(-5) M, 2 min) on the number of coughs were parallel to those on bronchoconstriction induced by ACh (10(-1) M, 15 s) and OA antigen (0.1% concentration, 30 s), but FK 888 (10(-6) M, 2 min) decreased the number of coughs without effect on bronchoconstriction induced by them. The number of coughs induced by histamine (10(-2) M, 15 s) was inhibited by systemic capsaicin treatment and enhanced by phosphoramidon (10(-5) M, 5 min) without effect on bronchoconstriction. (ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Role of substance P in cough during bronchoconstriction in awake guinea pigs. 753 3

The successful introduction of angiotensin converting enzyme (ACE) inhibitors in the treatment of patients with essential hypertension or heart failure has increased interest in the (patho)physiological role of the renin-angiotensin system (RAS). ACE is not only involved in the formation of angiotensin II from angiotensin I, but also inactivates vasoactive substances such as bradykinin and substance P. Accumulation of these substances during treatment with ACE inhibitors may contribute to both their therapeutic action and certain adverse effects associated with their use, such as cough and angioneurotic oedema. Renin inhibitors offer an alternative approach to inhibit the RAS. The major advantage of these, still experimental, drugs is their high specificity for the RAS since angiotensinogen is the only known substrate of renin. The currently available renin inhibitors are pseudopeptides that are rapidly taken up by the liver and excreted in the bile. Consequently, these drugs are subjected to a considerable first pass effect which limits their oral bioavailability. Additionally, plasma elimination half-life times are short and the duration of action is limited. Despite these shortcomings, single oral or intravenous administration results in a 80 to 90% inhibition of plasma renin activity and a slight reduction in blood pressure in patients with hypertension. The extent of blood pressure reduction is dependent on the patient's salt balance. After 1 week of oral treatment with the renin inhibitor remikiren, the antihypertensive effect was reduced in salt-repleted hypertensive patients. Subsequent intravenous administration of the drug did not further affect blood pressure, indicating that it was not the first pass effect that was limiting the efficacy of remikiren.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Clinical pharmacokinetics and efficacy of renin inhibitors. 758 99

It is now well-established that sensory nerves stimulation in the airway induces bronchoconstriction and inflammation, but also protective reflexes, such as coughing. These effects are mediated through the release of tachykinins (substance P and neurokinin A) and we have recently shown that SR 48968, a tachykinin NK2-receptor antagonist, inhibited cough induced by citric acid. In this paper, we have studied the effects of SR 48968 administered by aerosol. We have also investigated the effects of SR 140333, a tachykinin NK1-receptor antagonist, and the combination of both SR 48968 and SR140333 to determine whether tachykinin NK1 receptors are involved in cough. Finally, we have studied the combined effects of SR 48968 and salbutamol to find out whether the antitussive effect of SR 48968 is a consequence of the inhibition of bronchoconstriction. Unanaesthetized guinea-pigs were placed in a transparent chamber and exposed to an aerosol of citric acid (0.4 M). The number of coughs was counted by visual inspection and by determination of sounds and pressure variations in the chamber. By the aerosol route, SR 48968 was an efficient antitussive and 16 times more potent than codeine. SR 140333 (0.1-1 mg.kg-1 i.p.) did not exert any antitussive effect but it potentiated the maximal effect induced by SR 48968. Finally, salbutamol, in a dose (0.3 mg.kg-1) which inhibits bronchoconstriction, but not cough induced by citric acid, did not modify the antitussive effect of SR 48968.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effect of the two tachykinin antagonists, SR 48968 and SR 140333, on cough induced by citric acid in the unanaesthetized guinea pig. 758 94

To investigate the role of NK1 receptors in the pathogenesis of bronchoconstriction and cough in asthma, we performed a randomized, double-blind, crossover study on the effects of a selective non-peptide tachykinin NK1 receptor antagonist (CP-99,994) on baseline measures of lung function and on hypertonic saline-induced bronchoconstriction and cough in 14 male subjects with mild asthma. CP-99,994 (250 micrograms/2 hours) and placebo were administered intravenously in 2-h infusions during consecutive visits 5 to 7 d apart. Specific airway resistance (SRaw) was measured and spirometry was performed at baseline and at 35 and 60 min. Next, hypertonic saline challenge was performed by delivering 10 breaths of saline of increasing concentration (0.9 to 7% in 1% increments at 5-min intervals) via an ultrasonic nebulizer until SRaw increased from baseline by 200% or 20 units, whichever was greater. Throughout the challenge cough was counted from a taped record made from two microphones placed close to the subject's larynx. We found that CP-99,994 did not significantly affect SRaw or spirometric measures of lung function during the first hour of infusion. Although CP-99,994 infusion markedly attenuated the bronchoconstrictor response to the saline challenge in two subjects, it did not significantly decrease the area under curves obtained for SRaw and cough during saline challenge for the group as a whole (p = 0.9 for SRaw;p = 0.8 for cough). We conclude that administration of 250 micrograms/kg of CP-99,994 over 2 h does not significantly inhibit hypertonic saline-induced bronchoconstriction or cough in subjects with mild asthma and does not have acute bronchodilator activity in these subjects.
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PMID:Effect of an NK1 receptor antagonist (CP-99,994) on hypertonic saline-induced bronchoconstriction and cough in male asthmatic subjects. 766 99

An isolated perfused lung model was developed in which the mechanisms of regulation of sensory neuropeptide overflow and bronchoconstrictor responses evoked by antidromic vagal nerve stimulation or various irritants could be studied. For further comparison, non-adrenergic non-cholinergic (NANC) bronchoconstriction was also studied in guinea-pig isolated bronchus and in vivo. In the isolated guinea-pig lung, spontaneous strong postmortem bronchoconstriction occurred; this had to be overcome by the beta 2-adrenoceptor agonist terbutaline. Vagal stimulation, capsaicin, resiniferatoxin (RTX), nicotine, and pH 5 buffer all caused sensory peptide release and bronchoconstriction via a capsaicin-sensitive mechanism. Bradykinin and histamine also stimulated sensory peptide release but evoked bronchoconstriction mainly via capsaicin-resistant mechanisms. Stimulation at low frequency (1 Hz) caused similar degree of sensory nerve activation (peptide release in perfused lung and NANC bronchial contraction in bronchus) as stimulation at 10 Hz. Dactinomycin and the non-peptide SR 48968 selectively blocked the bronchoconstriction induced by neurokinin 2 (NK2) receptor agonists and also depressed that induced either by vagal stimulation or capsaicin, with no prejunctional effect on the overflow of calcitonin gene-related peptide (CGRP). Furthermore, SR 48968 inhibited the bronchoconstriction to citric acid aerosol. The NK1 antagonist CP 96345 had only marginal effects on NANC bronchoconstriction. Tetrodotoxin (TTX) and omega-conotoxin (CTX) inhibited neuropeptide release and bronchoconstriction caused by vagal stimulation or a low concentration of capsaicin but only marginally attenuated the effects evoked by a high concentration of capsaicin, or nicotine. Prejunctional alpha 2-adrenoceptor or opiate receptor activation inhibited the neuropeptide release and bronchoconstriction induced by vagal stimulation or a low concentration of capsaicin. Ruthenium red had a selective inhibitory effect on the overflow of neuropeptides [CGRP, neurokinin A (NKA)] and bronchoconstriction induced by capsaicin and its analogue RTX but not on responses induced by vagal stimulation, nicotine, bradykinin and histamine. It also inhibited CGRP and NKA release and bronchoconstriction caused by pH 5 buffer in lung, as well as cough and nasal irritation provoked by citric acid in vivo. The capsaicin receptor antagonist capsazepine inhibited peptide (CGRP, NKA) release and bronchoconstriction produced by capsaicin but not that evoked by vagal stimulation, nicotine and bradykinin, suggesting selectivity. Citric acid (in vivo) and pH 5 buffer (in vitro) produced bronchoconstriction via activation of capsaicin-sensitive sensory nerves. Interestingly, capsazepine also markedly depressed peptide overflow and bronchoconstriction caused by pH 5 buffer in isolated guinea-pig lung.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Regulation of neuropeptide release from pulmonary capsaicin-sensitive afferents in relation to bronchoconstriction. 769 42

The physiology and pharmacology of the cough reflex were reviewed from the perspective that the cough response and its peripheral mechanisms have diversity, taking reported findings together with the results obtained from our own studies. It is clear that there was a remarkable difference in the magnitude of expiration and sound in coughing between the two types of coughs in guinea pigs: one is caused by mechanical irritation to the airway mucosa or citric acid inhalation and the other caused by inhalation of pharmacological agents such as capsaicin and substance P. Four types of stimulation, i.e., mechanical, physicochemical, chemical and pharmacological stimulation, were discussed with respect to the site and the mechanisms of action in the airway. Mechanical stimulants and chemical stimulants such as citric acid seem to act mainly on A delta-fibers. However, it is unclear whether pharmacological agents act on C-fibers to produce cough. As to the difference in distribution of cough receptors in the airway, pharmacological differences were found between coughs caused by mechanical irritation on the laryngeal sites and the site of bifurcation of the trachea. Furthermore, capsaicin, applied by a topical spraying method newly developed by us, produced cough-like forced expiration when it was sprayed around the site of the bifurcation of the trachea. This response was not depressed by codeine, but depressed by ophiopogonin, a Chinese herbal antitussive; mephenesine; and a neurokinin A antagonist. Mechanisms of cough augmentation in bronchitic guinea pigs were also described briefly. In conclusion, the site of action of cough stimulants and the mechanisms of cough production are still controversial. To solve these problems, we need to develop new methods and strategies for studying the cough reflex.
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PMID:[Cough--diversity and the peripheral mechanisms of production]. 773 92

The influence of Evan's blue dye on capsaicin-induced bronchoconstrictor and cough responses was investigated in the guinea pig. Evan's blue (30 mg kg-1 i.v.) pretreatment shifted the bronchoconstrictor dose-response to capsaicin (0.3-100 micrograms kg-1 i.v.) to the right by 10-fold, but had no effect on the bronchospasm elicited by neurokinin A (0.3-10 micrograms kg-1 i.v.). Evan's blue (0.3-30 mg kg-1 s.c.) also inhibited capsaicin-induced cough in a dose-dependent manner. Evan's blue blocked capsaicin responses by the intravenous, subcutaneous, or inhaled routes of administration. We conclude bronchoconstrictor responses and cough in vivo.
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PMID:Evan's blue dye blocks capsaicin-induced cough and bronchospasm in the guinea pig. 778 78

The effects of inhibition of angiotensin converting enzyme (ACE) and glycopyrrolate on cough caused by inhaled capsaicin were investigated in a double-blind, randomised cross-over study in twelve normal volunteers. The capsaicin challenge was performed before and 2 h after dosing with 75 mg captopril or matched placebo given orally, and 20, 40 and 60 min after giving 1 mg glycopyrrolate i.v. to each subject. Captopril and placebo did not alter the cough response when compared to baseline. Glycopyrrolate, however, caused a significant increase in the threshold sensitivity (D2) from baseline, and a significant decrease in the total cough response at 40 and 60 min both after captopril and placebo. The D2-baseline and D2-40 min after glycopyrrolate (mean SD), respectively, were 3.2 (1.0); 17.9 (4.2) after placebo and 2.5 (8.5); 23.6 (6.9) after captopril. Elimination of vagal influences implies attenuation of the effects of tachykinins but not those prostaglandins. We postulate that tachykinins, such as substance P, play a more important role than prostaglandins in capsaicin-induced cough. We conclude that the vagus is important in the capsaicin-induced cough reflex, but, as suppression of this reflex by glycopyrrolate was delayed, the relevant receptors are either poorly accessible peripheral receptors or they are located in the central nervous system.
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PMID:Effects of glycopyrrolate on capsaicin-induced cough in normal volunteers treated with captopril. 795 39


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