Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0010200 (cough)
 23,843 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1. The present study was performed in anaesthetized, artificially ventilated, open-chested rabbits to examine whether (a) the rapidly adapting receptors of the airways were stimulated by exogenously administered bradykinin, and (b) if this sensitivity could be enhanced by the angiotensin-converting-enzyme inhibitor, enalapril. 2. Rapidly adapting receptor activity (n = 8) was recorded from the cervical vagus. Bradykinin was injected intravenously (0.25-1.0 microgram/kg) and a dose-response curve relating receptor activity to bradykinin was elicited. In the control state, the threshold dose of bradykinin required for stimulation of rapidly adapting receptors was 0.53 +/- 0.11 microgram/kg. Five minutes after the administration of enalapril maleate (2 mg intravenously), the dose-response curve was shifted to the left significantly (P < 0.01). 3. In seven other rapidly adapting receptors, enalapril (2 mg) increased the resting activity significantly (P < 0.05) over a period of 60 min. This increase was significantly different from the spontaneous variation in neural activity of rapidly adapting receptors (n = 7) recorded over a period of 60 min. 4. Bradykinin either alone (0.25-1.0 microgram/kg) or in the presence of enalapril did not stimulate the slowly adapting receptors (n = 5) of the airways. 5. These results show that (a) exogenous bradykinin stimulates the rapidly adapting receptors, (b) the sensitivity of rapidly adapting receptors to bradykinin is enhanced by enalapril and (c) enalapril increases the resting activity of rapidly adapting receptors. It is suggested that the cough reported after the administration of enalapril may be due to stimulation of rapidly adapting receptors of the airways.
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PMID:Responses of airway rapidly adapting receptors to bradykinin before and after administration of enalapril in rabbits. 133 Apr 1

Axon reflex mechanisms may be involved in the pathogenesis of asthma, but there has been no direct evidence that endogenous tachykinins cause bronchoconstriction in asthmatic subjects. We have studied the effect of a tachykinin receptor antagonist (FK-224) on bronchoconstriction induced by inhalation of bradykinin in asthmatic patients. In a double-blind, placebo-controlled, crossover trial, ten subjects with stable asthma were given FK-224 (4 mg) or placebo by inhalation 20 min before challenge with bradykinin (0-1250 micrograms/ml, five breaths of each concentration) given with 5 min intervals. Bradykinin caused dose-dependent bronchoconstriction in all subjects. FK-224 significantly opposed the bronchoconstrictor effect; the geometric mean of the cumulative concentration required to elicit a 35% fall in specific airway conductance was 5.3 micrograms/ml after placebo and 40 micrograms/ml after FK-224 (p < 0.001). Inhalation of bradykinin caused coughing in three subjects, which was inhibited by FK-224 in all three. Antagonism of the tachykinin receptor by FK-224 greatly inhibited both bronchoconstriction and coughing induced by bradykinin in asthmatic patients, suggesting that tachykinin release from the airway sensory nerves is involved in responses to bradykinin. Tachykinin receptor antagonists may be useful in the treatment of asthma.
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PMID:Protection against bradykinin-induced bronchoconstriction in asthmatic patients by neurokinin receptor antagonist. 135 19

Bradykinin (BK) has several effects on airway function which may be relevant in obstructive airways disease. These effects are mediated via B2-receptors. BK is a potent bronchoconstrictor in animals and humans in vivo. Bradykinin contracts airway smooth muscle, is a potent bronchial vasodilator, increases microvascular leakage, stimulates epithelial cells to release bronchodilators and stimulates mucus secretion. Perhaps its most important action is the activation of sensory nerves in airways, leading to reflex bronchoconstriction, coughing and neurogenic inflammation through the release of neuropeptides from sensory nerves.
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PMID:Effect of bradykinin on airway function. 146 77

The dose-response (dose, 0.01, 0.05, 0.1, 0.5, 1, and 5 mg) profiles of 10 atopic and 10 nonatopic subjects were determined for nasal patency, secretion weight, pulmonary function, eustachian tube function, middle-ear function, and symptoms after intranasal inhalation challenges with histamine, bradykinin, methacholine, prostaglandin D2, and prostaglandin F2 alpha (PGF2 alpha). Results demonstrated that challenge with PGF2 alpha increased nasal patency, whereas challenge with all other substances decreased patency. The relationship between substances in eliciting a nasal congestive response was prostaglandin D2 greater than histamine greater than bradykinin greater than methacholine. A similar effect ordering was noted for the postchallenge development of eustachian tube dysfunction. Secretion weights were significantly greater after challenge with histamine compared to all other substances. A decrease in pulmonary function was observed only after challenge with PGF2 alpha, although the effect was not statistically significant. No changes in middle-ear pressure were observed for challenges with any of the substances. Only histamine challenge provoked sneezing, whereas challenge with either of the prostaglandins provoked cough. With the exception of methacholine, all substances caused symptoms of rhinorrhea, congestion, and sore throat. Bradykinin was particularly effective in provoking "pain/pressure"-related symptoms. With the exception of secretion weight, the differences between responses of atopic and nonatopic subjects were not statistically significant. These results document mediator specificity in the physiologic and symptomatic responses to intranasal challenge.
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PMID:Physiologic responses to intranasal dose-response challenges with histamine, methacholine, bradykinin, and prostaglandin in adult volunteers with and without nasal allergy. 226 47

The effect of bradykinin was studied by inhalation in normal and asthmatic human subjects, as well as on human bronchial smooth muscle in vitro. Bradykinin caused cough and retrosternal discomfort in all subjects and bronchoconstriction in asthmatic subjects. Bradykinin was approximately 10 times more potent than histamine and methacholine, and there was a significant correlation between the subjects' sensitivity to histamine and bradykinin. Bradykinin-induced bronchoconstriction was prolonged when compared with that of histamine and the C-fiber stimulant capsaicin. This bronchoconstriction was subject to tachyphylaxis, which was also associated with desensitization of the subjects to inhaled histamine. The provocative dose causing a 35% fall in specific airway conductance (PD35) was unaffected by aspirin (1 g orally). However, ipratropium bromide (0.25 mg by nebulizer) significantly inhibited the effect of bradykinin, the PD35 being 0.8 mumol (range, 0.16 to 3.4) and 0.15 mumol (range, 0.047 to 1.15) after active dose and placebo, respectively (p less than 0.05). Likewise, cromolyn sodium (40 mg dry powder) also significantly reduced response to bradykinin, with a PD35 of 0.04 mumol (range, 0.13 to 0.31) after placebo and 0.39 mumol (range, 0.05 to 4.45) after SCG (p less than 0.05). Bradykinin only weakly constricted human bronchial smooth muscle in vitro. Bradykinin at 10(-4) caused only 21.5 +/- 5.5% of the maximal carbamylcholine contraction in 11 of 18 airways. Captopril did not enhance the effect of bradykinin. Bradykinin is a potent bronchoconstrictor of human airways in vivo, acting in part through cholinergic mechanisms but not because of the formation of prostaglandins.
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PMID:Bradykinin-induced bronchoconstriction in humans. Mode of action. 354 15

Bradykinin is released in the lungs in asthma and pulmonary anaphylaxis. It has negligible direct bronchoconstrictor effects in humans or dogs, but inhaled as aerosol it causes cough and reflex bronchoconstriction in asthmatics and some normal subjects. The afferent nerves responsible for these reflex effects have not been identified. We recorded vagal impulses in anesthetized dogs to determine whether lung afferents were stimulated by bradykinin. C-fiber endings in the intrapulmonary airways accessible from the systemic circulation were stimulated by bradykinin injected into the left atrium (0.5-1.0 micrograms/kg) or bronchial artery (1.5 micrograms), activity increasing 15-fold on average. C-fiber endings accessible from the pulmonary circulation were relatively insensitive to bradykinin. Bradykinin caused a small increase in firing of some rapidly adapting (irritant) receptors, but the effect appeared to be secondary to vascular changes. Bradykinin had variable effects on slowly adapting stretch receptors, but did not stimulate them directly. Thus vagally mediated sensory or reflex effects initiated by bradykinin in the lung are probably due to stimulation of "bronchial" C-fibers.
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PMID:Bradykinin stimulates afferent vagal C-fibers in intrapulmonary airways of dogs. 737 22

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

Bradykinin and related kinins are peptidic hormones, formed in tissues and fluids during inflammation. Various functional sites have been proposed as mediators of the biological effects of kinins, including the B1, B2 and B3 receptors. The existence of the B1 and the B2 receptor has largely been confirmed, whilst that of the B3 receptor is controversial and needs further confirmation. The role of bradykinin in the pathophysiology of asthma is not well understood, but bradykinin was proposed as a putative mediator of asthma, since asthmatic subjects are hyperresponsive to bradykinin, and since immunoreactive kinins are increased in the bronchoalveolar lavage fluids of asthmatic patients. Kinins could provoke bronchoconstriction by acting directly on smooth muscle and/or indirectly by their inflammatory properties. They may also contribute to the symptomatology of allergic and viral rhinitis, since they are the only mediators detected to date that are generated in nasal secretion during experimental and natural rhinovirus colds. Moreover, they can induce relevant symptoms when applied to airway mucosa. It has also been proposed that coughing during treatment with angiotensin-converting enzyme (ACE) inhibitors is linked to the action of kinins, since ACE is able to degrade kinins, and since the effects of ACE inhibitors are reduced by kinin antagonists. Due to their mitogenic properties, kinins have been proposed to regulate lung carcinoma growth. Their action remains speculative, but some findings are of great interest in order to define their role in these pathologies. Despite many studies in animals and in humans, the mode of action of kinins in airways is still poorly understood.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Kinins and respiratory tract diseases. 838 34

Cough accompanied by an increased sensitivity of the cough reflex is the most common symptom of inflammatory airway disease. This symptom is also frequently reported in patients receiving angiotensin-converting enzyme (ACE) inhibitors as therapy for heart failure or hypertension, although the underlying mechanism is unknown. We have investigated the possibility that the inflammatory peptide bradykinin, normally degraded by ACE, causes sensitization of airway sensory nerves and an enhancement of the cough reflex in conscious guinea pigs. Treatment of guinea pigs for two weeks with captopril led to an increased cough response to inhaled citric acid, which was prevented by concomitant treatment with the bradykinin receptor antagonist icatibant. A similar icatibant-sensitive enhancement of citric acid-evoked cough was seen in untreated animals after prior inhalation of bradykinin, although cough evoked by hypertonic saline was unaffected. In electrophysiological studies performed in vitro, responses of single vagal C fibers to capsaicin, applied to receptive fields of single-fiber units in the trachea, were also markedly increased after perfusion with bradykinin, whereas A delta fiber responses to hypertonic saline were unaffected. These results indicate that bradykinin-evoked sensitization of airway sensory nerves may underlie the pathogenesis of ACE-inhibitor cough. Bradykinin receptor antagonists may be of benefit in treating chronic cough seen with this and other inflammatory conditions.
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PMID:Bradykinin-evoked sensitization of airway sensory nerves: a mechanism for ACE-inhibitor cough. 867 30

One adverse effect of the angiotensin-converting enzyme (ACE) inhibitors used for treatment of hypertension and congestive heart failure is the production of dry coughs. Imidapril is a new type of ACE inhibitor with a very low incidence of coughs. The magnitude and the mechanism of cough potentiation of imidapril and other ACE inhibitors has been studied in guinea-pigs. In normal guinea-pigs single and repeated dosing of imidapril at 0.1 to 100 mg kg-1 had no effect on capasaicin- or citric acid-induced coughs. Single and repeated dosing of enalapril and captopril at 10 to 30 mg kg-1, respectively, significantly increased the number of capsaicin-induced coughs. Repeated dosing of 1 mg kg-1 enalapril also significantly augmented the capsaicin cough. In bronchitic guinea-pigs imidapril also had no effect on the coughs induced by the two stimulants. Enalapril and captopril significantly increased the number of coughs induced not only by capsaicin but also by citric acid. Lower doses of enalapril were enough to augment the capsaicin-induced coughs, whereas medium to large doses failed to augment the cough irrespective of the protocol of administration. Bradykinin-induced discharges of the vegal afferents from the lower airway were significantly increased by enalaprilat but not by imidaprilat. Capsaicin-induced discharges of the afferents were, on the other hand, significantly depressed by enalaprilat, but not by imidaprilat. Interestingly, enalaprilat depression of the discharges was significantly reversed by Hoe-140, a bradykinin B2 receptor blocker. In guinea-pigs pretreated with a low dose of enalapril, arterial infusion of bradykinin significantly potentiated the coughs induced by capsaicin. The results indicated that imidapril was less potent than enalapril and captopril in potentiating cough responses induced by capsaicin and citric acid in guinea-pigs, and further suggest that bradykinin might be a key substance in the mechanism of the potentiation of coughs associated with ACE inhibitors.
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PMID:Studies on the magnitude and the mechanism of cough potentiation by angiotensin-converting enzyme inhibitors in guinea-pigs: involvement of bradykinin in the potentiation. 895 4


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