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HIGHLIGHTED TOPICS
Airway Hyperresponsiveness: From Molecules to
Bedside
Departments of 1Physiology and 2Medicine, University of Kentucky Medical Center, Lexington, Kentucky 40536
Submitted 31 January 2003 ; accepted in final form 12 May 2003
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONDISCLOSURESACKNOWLEDGMENTSREFERENCES |
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10 min. The potentiating effect of
adenosine infusion was completely blocked by pretreatment with
8-cyclopentyl-1,3-dipropylxanthine (100 µg/kg), a selective antagonist of
the adenosine A1 receptor, but was not affected by
3,7-dimethyl-1-propargylxanthine (1 mg/kg), an A2-receptor
antagonist, or
3-ethyl-5-benzyl-2-methyl-4-phenylethynyl-6-phenyl-1,4-(±)-dihydropyridine-3,5-dicarboxylate
(2 mg/kg), an A3-receptor antagonist. This potentiating effect was
also mimicked by N6-cyclopentyladenosine (0.25
µg·kg-1·min-1 for
90 s), a selective agonist of the adenosine A1 receptor. In
conclusion, our results showed that infusion of adenosine significantly
elevated the sensitivity of pulmonary C-fiber afferents in rat lungs and that
this potentiating effect is likely mediated through activation of the
adenosine A1 receptor. airway hyperresponsiveness; dyspnea; lung afferents; adenosine receptor; chemical irritants
75% of the
afferent fibers in the vagal branches innervating the entire respiratory tract
(1,
7). These vagal
bronchopulmonary C-fiber afferents are sensitive to various inhaled irritants
and certain endogenous inflammatory mediators
(7,
27). Stimulation of these
afferents is known to elicit a number of reflex responses mediated through the
central nervous system and/or autonomic nervous system, including
bronchoconstriction, mucus hypersecretion, coughing, dyspneic sensation, and
bronchial vasodilatation (7,
27,
34). In addition, on
activation, these C-fiber endings can release various sensory neuropeptides
(e.g., tachykinins) that are known to generate potent effects on a number of
effector cells in the airways and are responsible for the neurogenic
inflammation resulting from sustained and/or intense stimulation of these
afferents (29,
44). Increasing evidence
suggests that hypersensitivity of bronchopulmonary C fibers plays a part in
the development of airway hyperresponsiveness associated with airway mucosal
injury and inflammation (27,
45). One of the endogenous chemical mediators possibly involved in the development of airway hyperresponsiveness is adenosine (27, 33). Adenosine is a naturally occurring purine nucleoside generated by the degradation of ATP in all metabolically active cells (4). Its production increases in response to insufficient energy supply, as during tissue ischemia or hypoxia (4, 13). Aside from having important functions as a constituent of nucleic acid and an essential component of intracellular messengers (38), adenosine is known to be a critical modulator of a vast array of physiological functions through its action on one or more of the four known receptor subtypes: A1, A2A, A2B, and A3 (20). The activation of these cell surface adenosine receptors generally functions in a protective role by decreasing energy demand and/or increasing energy supply (3, 4). Mainly because of these properties, adenosine is commonly used as a drug for the treatment of supraventricular tachycardia (10, 42). However, intravenous bolus injection of adenosine has been reported to cause dyspnea, chest discomfort, and bronchospasm in patients (42); these effects are believed to be signs of activation of bronchopulmonary C fibers (16, 27, 39). The adenosine-induced bronchoconstriction can be attenuated by muscarinic-receptor antagonists (8, 35), suggesting that it is mediated through the cholinergic reflex and that pulmonary afferent stimulation is probably involved (7, 27). Indeed, a recent study reported from our laboratory has shown that right atrial bolus injection of a therapeutic dose of adenosine evokes a consistent stimulatory effect on vagal pulmonary C-fiber terminals in rats (18). The response showed a long latency (3-18 s) and was frequently followed by a recurrent stimulation. This pattern of response suggests a distinct possibility of sensitization of these afferents.
In light of the existing background information and unanswered questions, this study was carried out to determine 1) whether the sensitivity of single pulmonary C fibers is altered by intravenous infusion of a low dose of adenosine and, 2) if so, which subtype(s) of adenosine receptor is involved.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONDISCLOSURESACKNOWLEDGMENTSREFERENCES |
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Animal preparation. Male Sprague-Dawley rats (330-435 g) were
initially anesthetized with an intraperitoneal injection of 
-chloralose
(100 mg/kg) and urethane (500 mg/kg); smaller (1/10th of the initial
dose) supplemental doses of the same anesthetics were given intravenously,
whenever necessary, to maintain abolition of the pain reflex elicited by paw
pinch. The right femoral artery, left jugular vein, and right femoral vein
were cannulated for recording arterial blood pressure (ABP) and injecting and
infusing various chemical agents, respectively. The tip of the femoral
arterial catheter was advanced into the abdominal aorta; the jugular venous
catheter was advanced until its tip was slightly above the right atrium. The
trachea was cannulated just below the larynx, and the lungs were artificially
ventilated with a respirator (model 7025, UGO Basile, Comerio-Varese, Italy).
Tidal volume (VT) and respiratory frequency were set at 8-10 ml/kg
and 44-50 breaths/min, respectively, to mimic those of unilaterally
vagotomized rats. Tracheal pressure (Ptr) was measured via a side port of the
tracheal cannula. The expiratory outlet of the respirator was placed under 3
cmH2O pressure to maintain a near-normal functional residual
capacity. Body temperature was maintained at 36°C throughout the
experiment by a heating pad placed under the animal lying in a supine
position. Animals were killed at the end of the experiments by an intravenous
injection of an overdose of pentobarbital sodium.
Recording of pulmonary C-fiber activity. Single-unit pulmonary C-fiber activity was recorded as previously described (18). Briefly, the right cervical vagus nerve was separated from the carotid artery and sectioned rostrally. The caudal end of the cut vagus nerve was placed on a small dissection platform and desheathed; a thin filament was teased away from the nerve trunk and placed on a platinum-iridium hook electrode. Action potentials were amplified (model P511K, Grass), monitored by an audio monitor (model AM8RS, Grass), and displayed on an oscilloscope (model 2211, Tektronix). The thin filament was further split until the afferent activity from a single unit was electrically isolated. Both vagi were ligated just above the diaphragm to eliminate the electrical signals arising from abdominal visceras. The afferent activity of a single unit was first sought by hyperinflation (3-4 times VT) and then identified by the immediate (<1-s delay) response to bolus injection of capsaicin (0.5-1 µg/kg) into the right atrium. Finally, the general locations of pulmonary C fibers were identified by their responses to gentle pressure on the lungs with a blunt-ended glass rod. The signals of the afferent activities, Ptr (model MP 45-28, Validyne), and ABP (model P23AA, Statham) were recorded on a thermal writer (model TW11, Gould) and on a videocassette recorder (model 500H, Vetter). Fiber activity (FA) was analyzed continuously by a computer for each 0.5-s interval.
Experimental protocols. Four series of experiments were carried
out. In study series 1, the effect of intravenous infusion of
adenosine on pulmonary C-fiber responses to chemical stimuli was examined. To
minimize potential cumulative effects of adenosine, a low dose of adenosine
was infused for a relatively short duration (40 µg ·
kg-1 · min-1 iv for 90 s).
Two chemical stimulants of C-fiber afferents, capsaicin (0.25 or 0.5 µg/kg)
and lactic acid (9 or 18 mg/kg), were applied separately during the last 10 s
of the adenosine infusion. In study series 2, the effect of adenosine
infusion at the same dose on the pulmonary C-fiber response to lung inflation
was examined. The lungs were inflated (30 cmH2O Ptr for 10 s)
during the last 10 s of adenosine infusion. In study series 3, the
effects of adenosine were compared before and after pretreatments with the
selective antagonists of adenosine A1, A2, and
A3 receptors, 8-cyclopentyl-1,3-dipropylxanthine (DPCPX),
3,7-dimethyl-1-propargylxanthine (DMPX), and
3-ethyl-5-benzyl-2-methyl-4-phenylethynyl-6-phenyl-1,4-(±)-dihydropyridine-3,5-dicarboxylate
(MRS-1191), respectively. In three separate groups of animals, pulmonary
C-fiber responses to capsaicin before and during infusion of adenosine were
established. Then DPCPX (100 µg/kg), DMPX (1 mg/kg), or MRS-1191 (2 mg/kg)
was slowly injected (2 min) intravenously as a bolus. C-fiber responses
to capsaicin before and during adenosine infusion were repeated at 10 and
20 min after pretreatment of these adenosine receptor antagonists. The doses
of these antagonists were selected on the basis of the following observations
reported in anesthetized rats: 1) DPCPX blocks
A1-receptor-mediated bradycardia without affecting
A2-receptor-mediated hypotension
(22); 2) DMPX
abolishes the A2-receptor agonist-induced hypotension
(23); and 3) MRS-1191
produces a high degree of antagonistic effect on the A3 receptor
without exhibiting any of the A1-receptor antagonistic properties
(28). In study series
4, the effect of N6-cyclopentyladenosine (CPA, 0.25
µg · kg-1 · min-1
for 90 s), a selective adenosine A1-receptor agonist, on the
pulmonary C-fiber response to capsaicin was determined. This dose of CPA was
chosen on the basis of our preliminary observation that CPA at a higher dose
(0.5-2 µg · kg-1 ·
min-1 for 90 s) markedly elevated the baseline FA and
decreased the baseline heart rate (HR) and ABP. In study series 1-4,
10 min elapsed between administrations of chemical stimuli.
Materials. All chemicals were obtained from Sigma Chemical (St.
Louis, MO). A mixture of 2% -chloralose and 10% urethane was dissolved
in a 2% borax solution. Capsaicin was dissolved in a stock solution at 250
µg/ml in a vehicle of 10% Tween 80, 10% ethanol, and 80% isotonic saline.
The hemisulfate salt of adenosine was chosen over adenosine free base because
of its higher solubility in saline, whereas adenosine in both forms at the
same molar dose produced very similar cardiovascular and C-fiber responses
(18). CPA and DMPX were
dissolved in saline at 1 and 0.8 mg/ml, respectively. MRS-1191 was dissolved
in DMSO at 5 mg/ml. DPCPX was first dissolved in DMSO and then diluted in
saline to a concentration of 0.1 mg/ml before use; the final concentration of
DMSO was 2%, and the total volume of DMSO used in each rat was <10 µl.
L(+)-Lactic acid (30% solution, wt/vol) was diluted with distilled
water, and other chemical agents were diluted with saline to the desired
concentration just before the experiments. No detectable effect of the
vehicles of these chemical agents on pulmonary C fibers was found in our
preliminary experiments.
Statistical analysis. A one- or two-way repeated-measures analysis of variance was used for the statistical analysis. When the two-way analysis of variance showed a significant interaction, pairwise comparisons were made with a post hoc analysis (Newman-Keuls test). Values are means ± SE. P < 0.05 was considered significant.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONDISCLOSURESACKNOWLEDGMENTSREFERENCES |
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At control, the right atrial bolus injection of a low dose of capsaicin
(0.25 or 0.5 µg/kg) abruptly evoked a mild and short burst of discharge
(Fig. 1); the difference
between the peak FA averaged over a 2-s duration after capsaicin injection and
the baseline FA averaged over a 10-s duration (
FA) was 2.64 ±
0.67 impulses/s. During adenosine infusion, the stimulatory effect of the same
dose of capsaicin on these C fibers was augmented by more than fivefold
(FA = 16.27 ± 3.11 impulses/s, n = 13, P <
0.05). Peak activity and duration of firing of the C fibers increased
(Fig. 2). The responses to
capsaicin returned toward control levels (FA = 1.44 ± 0.52
impulses/s) when the fibers were tested again 10 min after termination of
the adenosine infusion (Fig.
1).
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Bolus injection of capsaicin (0.25 or 0.5 µg/kg) triggered an immediate
bradycardia (HR = 134.2 ± 26.8 beats/min) and a lower blood
pressure (MABP = 23.1 ± 4.2 mmHg). We previously demonstrated
that these cardiovascular responses could be completely eliminated in intact
animals by vagotomy or selective inactivation of C-fiber afferents after
perineural capsaicin treatment of both vagi
(23), suggesting that these
responses were probably elicited by capsaicin stimulation of bronchopulmonary
C-fiber afferents in the contralateral lung. During adenosine infusion, these
cardiovascular depressor responses to the same dose of capsaicin were also
significantly augmented (HR = 260.6 ± 14.5 beats/min, n
= 11, P < 0.05; MABP = 51.2 ± 7.1 mmHg, n =
11, P < 0.05; Fig.
2) and prolonged (Fig.
1).
The potentiating effect of adenosine infusion was not limited to the
response to capsaicin. The response of these pulmonary C fibers to right
atrial injection of lactic acid (9 or 18 mg/kg) was also markedly enhanced
during adenosine infusion (FA = 4.54 ± 0.52 and 12.42 ±
2.02 impulses/s at control and during adenosine infusion, respectively,
n = 10, P < 0.05). The augmented response to lactic acid
was also reversible 10 min after termination of the adenosine infusion
(Figs. 3 and
4).
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All pulmonary C fibers had very weak or no response to lung inflation
during eupneic breathing. At control, the FA generated by lung
inflation (i.e., the difference between the FA during lung inflation and
baseline activity, each averaged over 10 s) was 0.70 ± 0.19 impulses/s.
During adenosine infusion, the lung inflation-elicited FA was
significantly augmented to 2.44 ± 0.55 impulses/s (n = 16,
P < 0.05). The potentiating response to lung inflation also
completely returned to the control level 10 min after termination of the
adenosine infusion (Figs. 3 and
4).
Pretreatment with DPCPX (100 µg/kg iv), the adenosine
A1-receptor antagonist, did not affect the pulmonary C-fiber
response to capsaicin (0.25 or 0.5 µg/kg): FA = 1.44 ± 0.52
and 1.28 ± 0.86 impulses/s before and after DPCPX, respectively
(n = 9, P > 0.05). However, it completely blocked the
potentiating effect of adenosine infusion on the C-fiber response to the same
dose of capsaicin: FA = 9.73 ± 2.44 and 1.22 ± 0.60
impulses/s before and after DPCPX, respectively (n = 9, P
< 0.05; Figs. 5,
6,
7). DPCPX also completely
blocked the augmenting effect of adenosine on capsaicin-induced cardiovascular
depressor responses that were presumably elicited by stimulation of C-fiber
afferents in the left lung (Fig.
6). In sharp contrast, pretreatment with DMPX (1 mg/kg iv,
n = 6; Figs. 5 and
7), the adenosine
A2-receptor antagonist, or MRS-1191 (2 mg/kg iv, n = 7;
Figs. 7 and
8), the adenosine
A3-receptor antagonist, had no significant effect on the
potentiating effect of adenosine in all the pulmonary C fibers tested.
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To further verify that the adenosine A1 receptor is involved in
the sensitizing effect of adenosine, we investigated whether CPA, the
selective agonist of the adenosine A1 receptor, affected the
pulmonary C-fiber response to capsaicin. Infusion of a low dose of CPA (0.25
µg · kg-1 · min-1
iv for 90 s) had no detectable effect on the baseline activities of pulmonary
C fibers, nor did it significantly affect the baseline MABP and HR. However,
the FA evoked by the same dose of capsaicin (0.25 or 0.5 µg/kg) was
significantly increased from 5.2 ± 0.98 impulses/s at control to 10.6
± 0.91 impulses/s during CPA infusion (n = 8, P <
0.05; Fig. 9). Similarly, the
capsaicin-induced cardiovascular depressor responses were also augmented in
four of six rats studied, but the differences were not statistically
significant (HR = 100.2 ± 45.8 and 160.5 ± 34.8 beats/min
at control and during CPA infusion, respectively, P > 0.05;
MABP = 35.5 ± 5.19 and 46.2 ± 4.29 mmHg at control and
during CPA infusion, respectively, P > 0.05).
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONDISCLOSURESACKNOWLEDGMENTSREFERENCES |
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The mechanism by which the intravenous infusion of such a low dose of
adenosine dramatically enhances the sensitivity of pulmonary C-fiber responses
to chemical stimulants and lung inflation is not clear. However, it is known
that the physiological functions of adenosine are mediated through activation
of specific cell surface-associated receptors. Several different adenosine
receptor subtypes (A1, A2A, A2B, and
A3) have been characterized on the basis of biochemical
(21), functional
(46), and receptor-cloning
studies (47). It is well
documented that the adenosine A1 receptor acts predominantly to
inhibit adenylate cyclase and voltage-dependent Ca2+
channels via its coupling with the G proteins, most likely
Gi/Go proteins, whereas adenosine A2A and
A2B receptors are linked to activation of adenylate cyclase via
Gs proteins (13).
Middle-kauff and colleagues
(31,
32) demonstrated that
adenosine inhibited the slow afterhyperpolarizations (AHPs) that developed
after action potentials in a large percentage (50%) of vagal afferent C
neurons and, consequently, increased the neuronal excitability of these
afferents. This inhibition of AHPs by adenosine is probably caused by the
adenosine A2A-receptor-mediated stimulation of cAMP production in
rabbits (31) or the adenosine
A1-receptor-mediated attenuation of the voltage-dependent
Ca2+ currents in rats
(32). In bullfrog sympathetic
ganglion neurons, the slow AHP has been shown to result primarily from
activation of a Ca2+-dependent K+ current
(IKCa)
(36); inhibition of
IKCa has been suggested to be one of the mechanisms of
nociceptor sensitization (40).
However, whether adenosine-induced sensitization of vagal pulmonary C-fiber
terminals is mediated through inhibition of IKCa remains
to be determined.
Several clinical observations strongly suggest an association of adenosine and the onset of an asthmatic attack in patients. For example, increase in the mucosal concentration of adenosine and appearance of the adenosine A1 receptor have been demonstrated in the airways of asthmatic patients (43). The basal level of adenosine in the bronchoalveolar lavage fluid was also found to be significantly higher in asthmatic patients than in normal subjects (11). Consistent with these reports, the level of adenosine in plasma nearly doubles and increases in parallel with brochoconstriction after allergen challenge in asthmatic patients (30). In addition, when adenosine is administered to patients for treatment of supraventricular tachycardia, the drug is known to trigger an asthmatic attack (5, 9). Similarly, dipyridamole, a drug that increases the extracellular concentration of adenosine and is used for myocardial perfusion scintigraphy, can also cause asthmatic attacks in asthmatic patients (6, 41). In a rabbit model of asthma simulating the human condition of the disease, adenosine has been shown to cause bronchoconstriction and airway hyperresponsiveness, which are mediated via the adenosine A1 receptor (2, 12). Furthermore, in a recent study, Nyce and Metzger (33) demonstrated that the airway constriction triggered by adenosine is dramatically attenuated by using antisense oligodeoxynucleotide targeting the adenosine A1 receptor.
Although the mechanism underlying the involvement of adenosine in airway hyperresponsiveness is not clear, the data obtained in this study seem to suggest a potential role of pulmonary C-fiber activation and/or sensitization. It is well documented that stimulation of vagal pulmonary C-fiber afferents can elicit reflex bronchoconstriction mediated through the cholinergic pathways (7, 27, 34). In addition, this stimulation can also evoke local release of tachykinins from the sensory terminals, which may in turn cause smooth muscle contraction (29, 44). Our results clearly show that the sensitivity of pulmonary C fibers is markedly enhanced by adenosine. Thus a sufficient level of C-fiber stimulation by inhaled irritants (e.g., cigarette smoke) will elicit a more intense bronchoconstriction via cholinergic and tachykininergic pathways.
Alternatively, it is possible that the adenosine-induced airway hyperresponsiveness is mediated through an indirect mechanism, in part via activation of adenosine receptors expressed on intermediary inflammatory cells (30, 38). For example, adenosine may cause mast cell degranulation and subsequent release of various inflammatory mediators (14, 38). Increased levels of mast cell granule-derived mediators such as histamine, prostanoids, and tryptase in bronchoalveolar lavage fluid have been reported after adenosine challenge in asthmatic patients (37). Some of these mediators (e.g., histamine and prostaglandin E2) are known to exert profound sensitizing and stimulatory effects on the pulmonary C-fiber sensory terminals (15, 17, 24, 26). The cellular mechanism underlying the hypersensitivity of the C-fiber afferent endings induced by these mediators is not totally understood but is probably related to changes in the conductance of specific ion channels and/or the resting membrane potential mediated by the activation of certain specific receptor proteins (e.g., prostanoid EP2 receptor) located on the membranes of nerve terminals (24, 25, 27). It is known that the adenosine receptor subtype involved in the modulation of mast cell activity may vary depending on the mast cell phenotype. Given this and the well-documented functional heterogeneity of mast cells from different animal species (13), a possible influence of these factors should not be overlooked in identifying the receptor subtypes and the mediators involved in the adenosine-induced sensitization of pulmonary C fibers.
Two chemical stimulants of pulmonary C fibers (capsaicin and lactic acid) and lung inflation were used in the present study to test the sensitivity of these C-fiber afferents. Capsaicin, a pungent active ingredient of hot pepper, has been used extensively as a tool for identifying C-fiber afferents arising from the respiratory tract because of its well-documented potent and selective effect on these afferent endings (7, 27). Lactic acid, a "fixed acid" produced endogenously in large quantity during anaerobic tissue metabolism, has been shown to dose dependently stimulate pulmonary C-fiber afferents in anesthetized rats (19). Under certain pathophysiological conditions such as local tissue ischemia and inflammation in the airways, excessive production of adenosine and lactic acid could occur simultaneously. Furthermore, although bronchopulmonary C fibers are usually quiescent during eupneic breathing, lung inflation provides a mild physiological stimulus of these afferent endings. Because an increase in VT occurs commonly during hyperventilation caused by hypoxia or severe exercise, a concomitant increase in adenosine production in response to these physiological stresses may then augment C-fiber stimulation and reflex responses.
In summary, this study shows that infusion of a low dose of adenosine markedly potentiates the sensitivity of pulmonary C fibers to chemical stimulants and lung inflation. This sensitizing effect is probably mediated through activation of the adenosine A1 receptor. However, whether the sensitization is caused by a direct effect of adenosine on the C-fiber sensory terminals or is secondary to an adenosine-induced release of certain inflammatory mediators that, in turn, enhance the sensitivity of C-fiber endings remains to be determined. Whatever the cause, this sensitizing effect on pulmonary C-fiber afferents probably plays a role in adenosine-induced airway hyperresponsiveness.
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DISCLOSURES |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONDISCLOSURESACKNOWLEDGMENTSREFERENCES |
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ACKNOWLEDGMENTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONDISCLOSURESACKNOWLEDGMENTSREFERENCES |
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FOOTNOTES |
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The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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TOPABSTRACTMETHODSRESULTSDISCUSSIONDISCLOSURESACKNOWLEDGMENTSREFERENCES |
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, Control response; 
, response during infusion of
adenosine (40 µg · kg-1 ·
min-1 iv for 90 s). Capsaicin (0.25 or 0.5 µg/kg) was
injected into the right atrium at time 0. FA was measured in 0.5-s
intervals in each fiber. Values are means ± SE of 9 pulmonary C
fibers.
Significant difference (P < 0.05) between corresponding
data before and after pretreatment with DPCPX.
