| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
1 First Department of Internal Medicine and 2 Department of Laboratory Medicine, Kumamoto University School of Medicine, Kumamoto 860, Japan
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
ACKNOWLEDGEMENTS
FOOTNOTES
REFERENCES
ABSTRACT 
Hamamoto, Junji, Hirotsugu Kohrogi, Osamu Kawano,
Hajime Iwagoe, Kazuhiko Fujii, Nahomi Hirata, and Masayuki Ando.
Esophageal stimulation by hydrochloric acid causes neurogenic
inflammation in the airways in guinea pigs. J. Appl.
Physiol. 82(3): 738-745, 1997.
To
investigate whether tachykinins are released in the airways in response
to stimulation of the esophagus, we studied the airway plasma
extravasation induced by intraesophageal HCl in the presence or absence
of neutral endopeptidase inhibitor phosphoramidon and NK1-receptor antagonist FK-888 in
anesthetized guinea pigs. The airway plasma leakage was
evaluated by measuring extravasated Evans blue dye in the animals
pretreated with propranolol and atropine. Infusion of 1 N HCl into the
esophagus significantly increased plasma extravasation in the trachea.
Phosphoramidon significantly potentiated plasma extravasation in the
trachea and main bronchi, whereas FK-888 significantly inhibited that extravasation in a dose-related manner. In the capsaicin-treated animals, airway plasma extravasation was completely inhibited even in
the presence of phosphoramidon. Tracheal plasma extravasation potentiated by phosphoramidon was significantly inhibited in the bilateral vagotomized animals. These results suggest that
1) tachykinin-like substances are
released to cause plasma extravasation in the airways as a result of
intraesophageal HCl stimulation and
2) there are neural pathways
communicating between the esophagus and airways, including the vagus
nerve.
asthma; tachykinins; cough; esophageal reflux; axon reflex
INTRODUCTION GASTROESOPHAGEAL REFLUX (GER) is a common clinical
disorder associated with a variety of respiratory symptoms, including
chronic cough and the exacerbation of asthma (15, 16, 37). Although GER
causes pulmonary symptoms by microaspiration of the gastric content, it
is not possible to document this pathogenesis consistently. Therefore,
other mechanisms must be considered. The vagally mediated reflex has
been suggested as the cause of the esophageal-tracheobronchial reflex
(28), because acidification of the esophagus has been shown to increase
total respiratory resistance in dogs and humans (27, 28). Although the
cholinergic nerve has been reported to be involved in the pathway (2),
the involvement of C fibers contained in the vagal nerve has not been
shown.
Tachykinins such as substance P and neurokinin A exist in the C fibers,
which are distributed in the epithelium, smooth muscle, and blood
vessels of airway tissues in many mammals, including humans (14, 24).
Tachykinins affect the airway tissues in many ways and induce
neurogenic inflammation: for example, they contract airway smooth
muscle (31, 39), increase bronchial secretion (3), increase vascular
permeability (26), and induce cough (19). It is known that tachykinins
are released from the lung by capsaicin (pungent principal of red
pepper), histamine, bradykinin, prostaglandin
F2 Tachykinins are effectively degraded by peptidase, especially neutral
endopeptidase (NEP), which exists in the airways (17) and lungs (23,
32). The inhibition of NEP potentiates sensitivity and reactivity to
tachykinins in the airways (7, 19, 36), including human airways (12).
Furthermore, recombinant NEP inhibits cough induced by substance P and
capsaicin (20). These reports suggest that NEP degrades tachykinins,
thereby reducing their physiological effects in the airways.
Nerves containing tachykinins and tachykinin-binding sites exist in the
esophagus as well as in the airways (18, 40). Because the esophageal
and pulmonary systems share a similar embryological origin, the
foregut, it would not be surprising if they also shared a common nerve
pathway. Thus we postulated that a nonadrenergic noncholinergic (NANC)
excitatory nerve communicating between airways and esophagus might
exist. If so, stimulation of the esophagus with gastric acid would
cause tachykinin release in the airways through the pathway. To test
this hypothesis, we examined the airway plasma extravasation by
stimulating the esophagus by using HCl in the presence or absence of
NEP inhibitor, in the presence or absence of
NK1-receptor antagonist, and in
normal or tachykinin-depleted animals.
METHODS We used 65 male Hartley guinea pigs weighing 250-350 g. These were
treated according to the guidelines of Animal Care at Kumamoto University and the Guiding Principles in the Care and Use of Animals approved by the Council of the American Physiological
Society.
Capsaicin Pretreatment
(8), allergic response (21), and antidromic electrical stimulation of the vagus nerve (34).
Animal Preparation
Animals were anesthetized intraperitoneally with pentobarbital sodium (25 mg/kg). Additional injections were given as necessary. The carotid artery was cannulated to monitor systemic blood pressure (Recticorder, Nihon Kohden Kogyo, Tokyo, Japan) and to sample arterial blood for gas analysis. The jugular vein was cannulated to inject drugs. One hundred percent oxygen was supplied with a loosely fitted 100-ml polyethylene mask. All animals were pretreated intravenously 30 min before experimentation with atropine (1 mg/kg) and propranolol (1 mg/kg) to block muscarinic and
-adrenergic receptors. The doses of
atropine and propranolol were determined according to previous studies
(5).
The esophageal wall was partly sectioned at the level of the fifth tracheal cartilage ring, and a catheter (3-Fr Indwelling Feeding Tube for Infant, ATOM, Tokyo, Japan) was placed in the midesophagus. We ligated the esophagus at the upper portion to inhibit HCl leakage. We then exposed the lower end of esophagus from the abdomen and ligated it to block communication between the esophagus and the stomach. Thus there was no leakage of fluid from the esophagus.
Experimental Procedure
To study the involvement of tachykinins in airway plasma extravasation by esophageal stimulation, we stimulated the esophagus by intraesophageal 1 N HCl (0.4 ml) or saline (0.9%, pH 6.4) infusion and measured the leakage of Evans blue dye in the airways. The esophagus was stimulated for 1 min, and HCl was collected. This procedure did not cause leakage of HCl into the mediastinum because the pH-indicator paper (pH-Box, Merck, Darmstadt, Germany) showed that the pH of the adventitia of the esophagus was 7.0 in all animals. The trachea and bronchi were also examined to investigate the effect of HCl leakage on the airways. After they were fixed in 4% paraformaldehyde and embedded in paraffin, hematoxylin and eosin staining was performed. No histological degeneration such as necrosis was seen in the airway adventitia, muscularis, lamina propria, or epithelium. Effect of phosphoramidon on airway plasma extravasation induced by esophageal stimulation with HCl. Five minutes after injecting phosphoramidon (2.5 mg/kg) or its vehicle (0.9% saline, pH 6.4) intravenously, we injected Evans blue dye (30 mg/kg) intravenously. Then we infused 1 N HCl (0.4 ml) into the esophagus for 1 min. Ten minutes later, we measured the Evans blue dye leakage. The dose of phosphoramidon was determined according to the previous study in which it significantly increased antigen-induced airway extravasation associated with tachykinin release (6). Effect of specific NK1-receptor antagonist FK-888 on the HCl-induced airway plasma extravasation in the presence of phosphoramidon. Three minutes after injecting phosphoramidon, we injected each animal with FK-888 (0.1 mg/kg and 0.4 mg/kg) or its vehicle (4% propylene glycol, 1% ethanol, 95% distilled water). Two minutes later we injected Evans blue dye (30 mg/kg) intravenously, infused 1 N HCl (0.4 ml) for 1 min, and measured the Evans blue dye leakage. Effect of systemic capsaicin treatment on HCl-induced airway plasma extravasation in the presence of phosphoramidon. Five minutes after giving phosphoramidon (2.5 mg/kg) intravenously to all animals, we injected Evans blue dye intravenously (30 mg/kg). Then we infused 1 N HCl (0.4 ml) or 0.9% saline into the esophagus of the capsaicin-treated or nontreated animals for 1 min and measured the Evans blue dye leakage. Effect of bilateral vagotomy on HCl-induced airway plasma extravasation in the presence of phosphoramidon. All animals were pretreated with phosphoramidon (2.5 mg/kg) intravenously. We cut the bilateral vagal nerve at the fourth tracheal cartilage in five guinea pigs and left five intact. Five minutes later, we injected Evans blue dye (30 mg/kg) intravenously, infused 1 N HCl (0.4 ml) into the esophagus for 1 min, and measured the Evans blue dye leakage 10 min later. Effect of bilateral vagotomy on substance P-induced airway plasma extravasation in the presence of phosphoramidon. To exclude the effect of bilateral vagotomy on local hemodynamics, we studied the airway plasma extravasation induced by substance P in the vagotomized guinea pigs. All animals were pretreated with phosphoramidon (2.5 mg/kg) intravenously. We cut the bilateral vagal nerve at the fourth tracheal cartilage in five guinea pigs and left five intact. Five minutes later, we injected substance P (0.6 µg/kg) for 1 min and Evans blue dye (30 mg/kg) intravenously, and we measured the Evans blue dye leakage 10 min later. In the preliminary experiment, we found that the dose of substance P used in the study caused almost the same Evans blue dye leakage as intraesophageal HCl did in the presence of phosphoramidon (data not shown). During the experiment, we monitored heart rate, arterial blood pressure, and arterial blood-gas analysis. Measurement of airway microvascular leakage. Vascular permeability was quantified by using a modified method of Saria and Lundberg (33). The tissue content of Evans blue dye after experimental intervention was determined by perfusing the systemic circulation with 0.9% saline to remove intravascular dye. After the induction of leakage (10 min after completion of the intraesophageal HCl infusion), the thorax was opened and a blunt-ended 14-gauge needle was passed through a left ventriculotomy into the aorta. The ventricle was cross clamped, and blood was expelled through an incision into the right atrium at 100-mmHg pressure with ~100 ml of 0.9% saline. The lungs were then removed. The connective tissue, vasculature, and parenchyma were gently scraped, and the airways were divided into two components: the lower part of the trachea and the main bronchi. The tissues were blotted dry and weighed, and their dye content was extracted in formamide at 37°C for 24 h. Dye concentration was quantified from light absorbance at 620 nm, and its tissue content (ng dye/mg wet tissue) was calculated from a standard curve of dye concentration in the range of 0.5-10 µg/ml.Drugs
The following drugs were used: atropine sulfate, propranolol, capsaicin, formamide (Sigma Chemical, St. Louis, MO); Tween 80 (Nacalai Tesque, Tokyo, Japan); Evans blue dye, propylene glycol (Wako Pure Chemical, Osaka, Japan); ketamine, salbutamol (Sankyo, Tokyo, Japan); aminophylline (Eisai, Tokyo), phosphoramidon, substance P (Peptide Institute, Osaka, Japan); pentobarbital sodium (Dainippon Pharmaceutical, Osaka, Japan); and 1 N HCl (Katayama Chemical, Osaka, Japan). FK-888 was a generous gift from Fujisawa Pharmaceutical (Osaka, Japan).Capsaicin (5 mg) was suspended in 80% normal saline, 10% Tween 80, and 10% ethanol. Evans blue dye, phosphoramidon, substance P, salbutamol, aminophylline, atropine sulfate, and propranolol were dissolved in 0.9% NaCl. FK-888 was dissolved in 4% propylene glycol, 1% ethanol, and 95% distilled water.
Statistical Analysis
The data are expressed as means ± SE. The data were analyzed for significance by using repeated-measures one-way analysis of variance. Post hoc analysis was performed by using Fisher's protected least-significant difference test. The Mann-Whitney test was used to test the effect of bilateral vagotomy on airway plasma extravasation, heart rate, and arterial blood pressure in the substance P-treated animals. Significance was defined as P < 0.05.RESULTS
We monitored the mean blood pressure and collected arterial blood for gas analysis just before the injection of phosphoramidon. We studied seven groups. There was no difference among the seven groups (Table 1).
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Effect of Phosphoramidon on Airway Plasma Extravasation Induced by Esophageal Stimulation with HCl (Fig. 1)
Phosphoramidon itself did not change the airway plasma extravasation. Infusion of 1 N HCl into the esophagus without phosphoramidon significantly increased plasma extravasation in the trachea. Phosphoramidon significantly potentiated the HCl-induced plasma extravasation in the trachea and main bronchi.
, Absence; +, presence.
* P < 0.05. ** P < 0.01.
Effect of Specific NK1-Receptor Antagonist FK-888 on the HCl-Induced Airway Plasma Extravasation in the Presence of Phosphoramidon (Fig. 2)
The NK1-receptor antagonist FK-888 significantly and in a dose-related manner inhibited the HCl-induced plasma extravasation potentiated by phosphoramidon. The inhibition was greater in the trachea than in the main bronchi.
Effect of Systemic Capsaicin Treatment on HCl-Induced Airway Plasma Extravasation in the Presence of Phosphoramidon (Fig. 3)
The plasma extravasation potentiated by phosphoramidon was significantly inhibited in the capsaicin-treated animals.
Effect of Bilateral Vagotomy on HCl-Induced Airway Plasma Extravasation in the Presence of Phosphoramidon (Fig. 4)
The plasma extravasation potentiated by phosphoramidon was significantly inhibited in the trachea of the vagotomized animals.
Effect of Bilateral Vagotomy on Substance P-Induced Airway Plasma Extravasation in the Presence of Phosphoramidon
The plasma extravasation was not different between the vagotomized and sham-operated animals (Fig. 5). The heart rate and arterial blood pressure were not different (Fig. 6) and arterial blood-gas analysis was not different between the animals (groups 6 and 7 in Table 1).
) and sham-operated
animals (
) before and after intravenous SP injection. All values are means ± SE; n = 5 guinea pigs for
each experiment.
DISCUSSION
In guinea pigs in which cholinergic and adrenergic nerves were pharmacologically blocked, we found that 1) esophageal stimulation by HCl caused airway plasma extravasation, 2) the extravasation was potentiated by inhibiting NEP, and 3) the potentiation was inhibited by the tachykinin antagonist FK-888 (NK1-receptor antagonist). We also found that the HCl-induced plasma extravasation was completely inhibited in the capsaicin-treated guinea pig. The pH of the adventitia of the esophagus was 7.0 in all groups 10 min after HCl infusion, and no histological change was seen in the airway adventitia, muscularis, lamina propria, or epithelium. So the plasma extravasation was not associated with the leakage from the intraesophageal HCl.
There are four types of neural pathways in the guinea pig airways and lungs: adrenergic, cholinergic, NANC inhibitory nerve, and NANC excitatory nerve. In the present study, we pretreated the animals with atropine and propranolol to avoid both adrenergic and cholinergic nerve effects (5), leaving active only the NANC inhibitory and NANC excitatory nerves. The NANC excitatory nerve in the airways contains neuropeptides, tachykinins (substance P and neurokinin A), and calcitonin gene-related peptide (CGRP). Substance P and CGRP mainly cause airway plasma extravasation, and neurokinin A causes airway smooth muscle contractions. It is known that NEP exists in the lung and airways in many animals, including humans (17, 35), and that NEP cleaves substance P and neurokinin A at the acting site of the peptides (13, 29). Previous studies suggest that the cleavage of substance P and/or neurokinin A is blocked by inhibiting the NEP activity (7, 19, 36). In the present study, esophageal stimulation by HCl causes airway plasma extravasation in the trachea, and the HCl-induced extravasation was potentiated in the trachea and main bronchi by NEP inhibitor phosphoramidon. This suggests that the airway plasma extravasation was induced by the release of tachykinin-like substances in the airways.
There are three types of tachykinin receptors: NK1, NK2, and NK3. The NK1 receptor exhibits the greatest affinity for substance P and exists on the bronchial smooth muscle and bronchial blood vessels. The NK2 receptor exhibits the greatest affinity for neurokinin A and is found on the bronchial smooth muscle (1). The NK3 receptor exhibits the greatest affinity for neurokinin B and appears to be localized at the bronchial parasympathetic ganglia (30). Thus, in the airway plasma extravasation, endogenously released tachykinins may act on NK1 receptors. Therefore, we used the NK1-receptor antagonist FK-888 (9) to study the effect of endogenously released tachykinins to cause airway plasma extravasation. In the present study, the potentiation of HCl-induced airway plasma extravasation in the presence of phosphoramidon was inhibited by tachykinin antagonist FK-888 in a dose-related manner. Furthermore, our study showed that, in the systemic capsaicin-treated guinea pigs, phosphoramidon failed to potentiate airway plasma extravasation induced by stimulation of esophagus with HCl. Systemic capsaicin treatment causes the release of tachykinins and finally depletes tachykinins in the peripheral nerves (14, 16a, 25). From these results, we suggest that esophageal stimulation by HCl causes the release of tachykinin-like substances, resulting in plasma extravasation in the airways.
There may be several pathways involved in the release of tachykinin-like substances in the airways when the esophagus is stimulated by HCl. Because we focused on the neural pathways, we blocked communication between the esophagus and airways by ligating the upper and lower parts of the esophagus. Thus we can ignore the effect of the aspiration of HCl into the airways in this study. Previous studies show that there is a vagally mediated reflex pathway between the esophagus and airways (27, 28, 37). An atropine-sensitive vagally mediated neural pathway has been shown (2). We used atropine and propranolol to block the effects of adrenergic and cholinergic nerves. Our results, therefore, showed that NANC nerves, especially the NANC excitatory nerve, are involved in the airway plasma extravasation induced by esophageal HCl stimulation.
In the present study, the plasma extravasation potentiated by phosphoramidon was significantly inhibited in the trachea in the bilaterally vagotomized animals. Because local tracheal hemodynamic changes due to vagotomy may cause a general inhibition of extravasation, we also studied whether or not the extravasation to exogenously applied substance P is inhibited by vagotomy. Vagotomy did not affect the airway plasma extravasation to substance P and the cardiovascular parameters. These results suggest that tachykinin release is mediated or modulated by the vagal reflex. One possible mechanism, then, is that of a vagally mediated pathway, where an impulse from the acid receptor in the esophagus (11) is transmitted to the airways to release tachykinins. If so, afferent C fibers may act as efferent fibers that release tachykinins in the vagal reflex. Another possible mechanism is that mediators released from NANC inhibitory and/or NANC excitatory nerves may modulate the release of tachykinins. However, in the vagotomized guinea pigs, the tracheal plasma extravasation induced by esophageal stimulation with HCl in the presence of phosphoramidon was significantly higher than that by sham stimulation in nonvagotomized guinea pigs (Figs. 1 and 4; P < 0.05). This suggests that there are other nerve pathways or mechanisms communicating between the esophagus and airways. Two possible pathways are 1) a local axon reflex pathway (4) and 2) a spinal reflex pathway. Because peptide-containing sensory nerve fibers in the airways originate from vagal and dorsal root ganglia (24, 38), the vagus nerve is not the only nerve supplying the airways and/or lungs with tachykinins. But a previous study argues against a significant spinal contribution to the tachykinergic innervation of guinea pig trachea (22). Therefore, we could suggest alternative possible mechanisms. 1) Because of the intimate association between esophagus and trachea, it is possible that the tachykinins released in the esophagus diffuse to the trachea or are carried to the trachea via local circulation. 2) Similarly, the local circulation may also lead to changes in the pH of the tracheal interstitium. In the present study, the plasma extravasation potentiated by phosphoramidon in the trachea was higher than in the main bronchi, although it was not statistically significant. Because substance P containing nerves are distributed highest at the level of large intrapulmonary bronchi (22), we speculate that 1) higher activity of NEP may exist in the trachea than in the main bronchi or that 2) the neural and/or vascular communications may be more intimate between esophagus to trachea than esophagus to main bronchi.
In summary, our results suggest that 1) tachykinin-like substances are released to cause plasma extravasation in the airways by intraesophageal HCl stimulation; and 2) there are neural pathways communicating between the esophagus and airways, including the vagus nerve; and/or 3) there are vascular pathways communicating between the esophagus and airways via local circulation modulating the plasma extravasation.
ACKNOWLEDGEMENTS
This work was supported by Scientific Grants-in-Aid for Scientific Research (C) 02670343 and 06670622 from the Ministry of Education, Science, and Culture of Japan.
FOOTNOTES
Address for reprint requests: H. Kohrogi, First Dept. of Internal Medicine, Kumamoto Univ. School of Medicine, 1-1-1 Honjo, Kumamoto 860, Japan.
Received 17 July 1996; accepted in final form 29 October 1996.
REFERENCES
| 1. | Advenier, C., E. Naline, G. Drapeau, and D. Regoli. Relative potencies of neurokinins in guinea pig trachea and human bronchus. Eur. J. Pharmacol. 139: 133-137, 1987. [Medline] |
| 2. |
Andersen, L. I.,
A. Schmidt,
and
A. Bundgaard.
Pulmonary function and acid application in the esophagus.
Chest
90:
358-363,
1986.
|
| 3. | Baker, A. P., L. M. Hillegass, D. A. Holden, and W. J. Smith. Effect of kallidin, substance P, and other basic polypeptides on the production of respiratory macromolecules. Am. Rev. Respir. Dis. 115: 811-817, 1977. [Medline] |
| 4. | Barnes, P. J. Asthma as an axon reflex. Lancet 1: 242-245, 1986. [Medline] |
| 5. |
Belvisi, M. G.,
D. F. Rogers,
and
P. J. Barnes.
Neurogenic plasma extravasation: inhibition by morphine in guinea pig airways in vivo.
J. Appl. Physiol.
66:
268-272,
1989.
|
| 6. | Bertrand, C., P. Geppetti, J. Baker, I. Yamawaki, and J. A. Nadel. Role of neurogenic inflammation in antigen-induced vascular extravasation in guinea pig trachea. J. Immunol. 150: 1479-1485, 1993. [Abstract] |
| 7. | Borson, D. B., R. Corrales, S. Varsano, M. Gold, N. Viro, G. Caughey, J. Ramachandran, and J. A. Nadel. Enkephalinase inhibitors potentiate substance P-induced secretion of 35SO24 macromolecules from ferret trachea. Exp. Lung Res. 12: 21-36, 1987. [Medline] |
| 8. |
Fujii, K.,
H. Kohrogi,
H. Iwagoe,
J. Hamamoto,
N. Hirata,
T. Yamaguchi,
O. Kawano,
and
M. Ando.
Evidence that PGF2-induced contraction of isolated guinea pig bronchi is mediated in part by release of tachykinins.
J. Appl. Physiol.
79:
1411-1418,
1995.
|
| 9. | Fujii, T., M. Murai, H. Morimoto, Y. Maeda, M. Yamaoka, D. Hagiwara, H. Miyake, N. Ikari, and M. Matsuo. Pharmacological profile of a high affinity dipeptide NK1 receptor antagonist, FK888. Br. J. Pharmacol. 107: 785-789, 1992. [Medline] |
| 11. | Harding, R., and D. A. Titchen. Chemosensitive vagal endings in the oesophagus of the cat. J. Physiol. (Lond.) 247: 52-53, 1975. |
| 12. | Honda, I., H. Kohrogi, T. Yamaguchi, M. Ando, and S. Araki. Enkephalinase inhibitor potentiates substance P- and capsaicin-induced bronchial smooth muscle contractions in humans. Am. Rev. Respir. Dis. 143: 1416-1418, 1991. [Medline] |
| 13. | Hooper, N. M., A. J. Kenny, and A. J. Turner. The metabolism of neuropeptides. Neurokinin A (substance K) is a substrate for endopeptidase-24.11 but not for peptidyl dipeptidase A (angiotensin-converting enzyme). Biochem. J. 231: 357-361, 1985. [Medline] |
| 14. | Hua, X.-Y., E. Theodorsson-Norheim, E. Brodin, J. M. Lundberg, and T. Hökfelt. Multiple tachykinins (neurokinin A, neuropeptide K, and substance P) in capsaicin-sensitive sensory neurons in the guinea pig. Regul. Pept. 13: 1-19, 1985. [Medline] |
| 15. | Ing, A. J., M. C. Ngu, and A. B. X. Breslin. Chronic persistent cough and gastro-oesophageal reflux. Thorax 46: 479-483, 1991. [Abstract] |
| 16. | Irwin, R. S., J. K. Zawacki, F. J. Curley, C. L. French, and P. J. Hoffman. Chronic cough as the sole presenting manifestation of gastroesophageal reflux. Am. Rev. Respir. Dis. 140: 1294-1300, 1989. [Medline] |
| 16a. | Jancsó, G., J. E. Kiraly, and A. Jancsó-Gábor. Pharmacologically induced selective degeneration of chemosensitive primary sensory neurons. Nature 270: 741-743, 1977. [Medline] |
| 17. | Johnson, A. R., J. Ashton, W. W. Schulz, and E. G. Erdös. Neutral metalloendopeptidase in human lung tissue and cultured cells. Am. Rev. Respir. Dis. 132: 564-568, 1985. [Medline] |
| 18. | Keast, J. R., J. B. Furness, and M. Costa. Distribution of peptide-containing neurons and endocrine cells in the rabbit gastrointestinal tract, with particular reference to the mucosa. Cell Tissue Res. 248: 565-577, 1987. [Medline] |
| 19. | Kohrogi, H., P. D. Graf, K. Sekizawa, D. B. Borson, and J. A. Nadel. Neutral endopeptidase inhibitors potentiate substance P and capsaicin-induced cough in awake guinea pigs. J. Clin. Invest. 82: 2063-2068, 1988. |
| 20. | Kohrogi, H., J. A. Nadel, B. Malfroy, C. Gorman, R. Bridenbaugh, J. S. Patton, and D. B. Borson. Recombinant human enkephalinase (neutral endopeptidase) prevents cough induced by tachykinins in awake guinea pigs. J. Clin. Invest. 84: 781-786, 1989. |
| 21. | Kohrogi, H., T. Yamaguchi, O. Kawano, I. Honda, M. Ando, and S. Araki. Inhibition of neutral endopeptidase potentiates bronchial contraction induced by immune response in guinea pigs in vitro. Am. Rev. Respir. Dis. 144: 636-641, 1991. [Medline] |
| 22. | Kummer, W., A. Fischer, R. Kurkowski, and C. Heym. The sensory and sympathetic innervation of guinea-pig lung and trachea as studied by retrograde neuronal tracing and double-labelling immunohistochemistry. Neuroscience 49: 715-737, 1992. [Medline] |
| 23. | Llorens, C., and J.-C. Schwartz. Enkephalinase activity in rat peripheral organs. Eur. J. Pharmacol. 69: 113-116, 1981. [Medline] |
| 24. | Lundberg, J. M., T. Hökfelt, C. R. Martling, A. Saria, and C. Cuello. Substance P-immunoreactive sensory nerves in the lower respiratory tract of various mammals including man. Cell Tissue Res. 235: 251-261, 1984. [Medline] |
| 25. | Lundberg, J. M., and A. Saria. Capsaicin-induced desensitization of airway mucosa to cigarette smoke, mechanical and chemical irritants. Nature 302: 251-253, 1983. [Medline] |
| 26. |
Lundberg, J. M.,
A. Saria,
E. Brodin,
S. Rosell,
and
K. Folkers.
A substance P antagonist inhibits vagally induced increase in vascular permeability and bronchial smooth muscle contraction in the guinea pig.
Proc. Natl. Acad. Sci. USA
80:
1120-1124,
1983.
|
| 27. | Mansfield, L. E., H. H. Hameister, H. S. Spaulding, N. J. Smith, and N. Glab. The role of the vagus nerve in airway narrowing caused by intraesophageal hydrochloric acid provocation and esophageal distention. Ann. Allergy 47: 431-434, 1981. [Medline] |
| 28. | Mansfield, L. E., and M. R. Stein. Gastroesophageal reflux and asthma: a possible reflux mechanism. Ann. Allergy 41: 224-226, 1978. [Medline] |
| 29. |
Matsas, R.,
I. S. Fulcher,
A. J. Kenny,
and
A. J. Turner.
Substance P and [leu]enkephalin are hydrolyzed by an enzyme in pig caudate synaptic membranes that is identical with the endopeptidase of kidney microvilli.
Proc. Natl. Acad. Sci. USA
80:
3111-3115,
1983.
|
| 30. |
Myers, A. C.,
and
B. J. Undem.
Electrophysiological effects of tachykinins and capsaicin on guinea-pig bronchial parasympathetic ganglion neurones.
J. Physiol. (Lond.)
470:
665-679,
1993.
|
| 31. | Nilsson, G., K. Dahlberg, E. Brodin, F. Sundler, and K. Strandberg. Distribution and constrictor effect of substance P in guinea pig in tracheobronchial tissues. In: Substance P, edited by U. S. von Euler, and B. Pernow. New York: Raven, 1977, p. 75-81. |
| 32. | Ronco, P., H. Pollard, M. Galceran, M. Delauche, J. C. Schwartz, and P. Verroust. Distribution of enkephalinase (membrane metallopeptidase, E.C.3.4.24.11) in rat organs: detection using a monoclonal antibody. Lab. Invest. 58: 210-217, 1988. [Medline] |
| 33. | Saria, A., and J. M. Lundberg. Evans blue fluorescence: quantitatve and morphological evaluation of vascular permeability in animal tissues. J. Neurosci. Methods. 8: 41-49, 1983. [Medline] |
| 34. | Saria, A., C.-R. Martling, Z. Yan, E. Theodorsson-Norheim, R. Gamse, and J. M. Lundberg. Release of multiple tachykinins from capsaicin-sensitive sensory nerves in the lung by bradykinin, histamine, dimethylphenyl piperazinium, and vagal nerve stimulation. Am. Rev. Respir. Dis. 137: 1330-1335, 1988. [Medline] |
| 35. |
Sekizawa, K.,
J. Tamaoki,
P. D. Graf,
C. B. Basbaum,
D. B. Borson,
and
J. A. Nadel.
Enkephalinase inhibitor potentiates mammalian tachykinin-induced contraction in ferret trachea.
J. Pharmacol. Exp. Ther.
243:
1211-1217,
1987.
|
| 36. | Shore, S. A., N. P. Stimler-Gerard, S. R. Coats, and J. M. Drazen. Substance P-induced bronchoconstriction in the guinea pig: enhancement by inhibitors of neutral metalloendopeptidase and angiotensin-converting enzyme. Am. Rev. Respir. Dis. 137: 331-336, 1988. [Medline] |
| 37. | Spaulding, H. S., L. E. Mansfield, M. R. Stein, J. C. Sellner, and D. E. Gremillion. Further investigation of the association between gastroesophageal reflux and bronchoconstriction. J. Allergy Clin. Immunol. 69: 516-521, 1982. [Medline] |
| 38. | Springall, D. R., A. Cadieux, H. Oliveira, H. Su, D. Royston, and J. M. Polak. Retrograde tracing shows that CGRP-immunoreactive nerves of rat trachea and lung originate from vagal and dorsal root ganglia. J. Auton. Nerv. Syst. 20: 155-166, 1987. [Medline] |
| 39. | Uchida, Y., A. Nomura, M. Ohtsuka, S. Hasegawa, K. Goto, S. Kimura, Y. Sugita, and Y. Uchiyama. Neurokinin A as a potent bronchoconstrictor. Am. Rev. Respir. Dis. 136: 718-721, 1987. [Medline] |
| 40. | Walsh, D. A., M. Salmon, R. Featherstone, J. Wharton, M. K. Church, and J. M. Polak. Differences in the distribution and characteristics of tachykinin NK1 binding sites between human and guinea pig lung. Br. J. Pharmacol. 113: 1407-1415, 1994. [Medline] |
This article has been cited by other articles:
|
|
 |
|
  I. M. Lang, S. T. Haworth, B. K. Medda, D. L. Roerig, H. V. Forster, and R. Shaker Airway responses to esophageal acidification Am J Physiol Regulatory Integrative Comp Physiol, January 1, 2008; 294(1): R211 - R219. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. N Patterson, B. T Johnston, J. E S Ardill, L. G Heaney, and L. P A McGarvey Increased tachykinin levels in induced sputum from asthmatic and cough patients with acid reflux Thorax, June 1, 2007; 62(6): 491 - 495. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K Fujino, S G de la Fuente, Y Takami, T Takahashi, and C R Mantyh Attenuation of acid induced oesophagitis in VR-1 deficient mice Gut, January 1, 2006; 55(1): 34 - 40. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. D. T. Q. S. Lopes, G. S. Alvarenga, R. Quiles, M. B. Dorna, J. E. Vieira, M. Dolhnikoff, and M. A. Martins Pulmonary responses to tracheal or esophageal acidification in guinea pigs with airway inflammation J Appl Physiol, September 1, 2002; 93(3): 842 - 847. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Daoui, B. D'Agostino, L. Gallelli, X. Emonds Alt, F. Rossi, and C. Advenier Tachykinins and airway microvascular leakage induced by HCl intra-oesophageal instillation Eur. Respir. J., August 1, 2002; 20(2): 268 - 273. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D.-N. Wu, K. Yamauchi, H. Kobayashi, Y. Tanifuji, C. Kato, K. Suzuki, and H. Inoue Effects of Esophageal Acid Perfusion on Cough Responsiveness in Patients With Bronchial Asthma* Chest, August 1, 2002; 122(2): 505 - 509. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. J. Oh and D. Weinreich Chemical Communication Between Vagal Afferent Somata in Nodose Ganglia of the Rat and the Guinea Pig In Vitro J Neurophysiol, June 1, 2002; 87(6): 2801 - 2807. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. K. Field Asthma and Gastroesophageal Reflux : Another Piece in the Puzzle? Chest, April 1, 2002; 121(4): 1024 - 1027. [Full Text] [PDF]
|
|
|
|
|
|
M. D. Crowell, E. N. Zayat, B. E. Lacy, A. Schettler-Duncan, and M. C. Liu The Effects of an Inhaled {beta}2-Adrenergic Agonist on Lower Esophageal Function : A Dose-Response Study Chest, October 1, 2001; 120(4): 1184 - 1189. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. S. THEODOROPOULOS, D. K. LEDFORD, R. F. LOCKEY, D. L. PECORARO, J. A. RODRIGUEZ, M. C. JOHNSON, and H. W. BOYCE Jr. Prevalence of Upper Respiratory Symptoms in Patients with Symptomatic Gastroesophageal Reflux Disease Am. J. Respir. Crit. Care Med., July 1, 2001; 164(1): 72 - 76. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D.-N. Wu, Y. Tanifuji, H. Kobayashi, K. Yamauchi, C. Kato, K. Suzuki, and H. Inoue Effects of Esophageal Acid Perfusion on Airway Hyperresponsiveness in Patients With Bronchial Asthma Chest, December 1, 2000; 118(6): 1553 - 1556. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. M. HARDING, M. R. GUZZO, and J. E. RICHTER The Prevalence of Gastroesophageal Reflux in Asthma Patients without Reflux Symptoms Am. J. Respir. Crit. Care Med., July 1, 2000; 162(1): 34 - 39. [Abstract] [Full Text]
|
|
|
|
|
|
T. Ishikawa, S.-I. Sekizawa, F. B. Sant'Ambrogio, and G. Sant'Ambrogio Larynx vs. esophagus as reflexogenic sites for acid-induced bronchoconstriction in dogs J Appl Physiol, April 1, 1999; 86(4): 1226 - 1230. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S.-I. Sekizawa, T. Ishikawa, F. B. Sant'Ambrogio, and G. Sant'Ambrogio Vagal esophageal receptors in anesthetized dogs: mechanical and chemical responsiveness J Appl Physiol, April 1, 1999; 86(4): 1231 - 1235. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. K. Field A Critical Review of the Studies of the Effects of Simulated or Real Gastroesophageal Reflux on Pulmonary Function in Asthmatic Adults Chest, March 1, 1999; 115(3): 848 - 856. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Visit Other APS Journals Online |
