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Institute of Physiology, School of Medicine and Life Science, National Yang-Ming University, Taipei, Taiwan 11221, Republic of China
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
ACKNOWLEDGEMENTS
FOOTNOTES
REFERENCES
ABSTRACT 
Chen, H. F., B. P. Lee, and Y. R. Kou. Mechanisms of
stimulation of vagal pulmonary C fibers by pulmonary air embolism in
dogs. J. Appl. Physiol. 82(3):
765-771, 1997.
We investigated the involvement of the
cyclooxygenase metabolites and hydroxyl radical (· OH) in the
stimulation of vagal pulmonary C fibers (PCs) by pulmonary air embolism
(PAE). Impulses were recorded from PCs in 51 anesthetized, open-chest,
and artificially ventilated dogs. Fifty of 59 PCs were stimulated by
infusion of air into the right atrium (0.2 ml · kg
1 · min1
for 10 min). As a group (n = 59), PC
activity increased from a baseline of 0.4 ± 0.1 to a peak of 1.7 ± 0.2 impulses/s during the period from 1 min before to 2 min after
the termination of PAE induction. In PCs initially stimulated by PAE
induction, PAE was repeated after the intervening treatment (iv) with
saline (n = 9), ibuprofen (a
cyclooxygenase inhibitor; n = 11), or
dimethylthiourea (a · OH scavenger;
n = 12). The responses of PCs to PAE
were not altered by saline vehicle but were abolished by ibuprofen and significantly attenuated by dimethylthiourea. Although hyperinflation of the lungs reversed the PAE-induced bronchomotor responses, it did
not reverse the stimulation of PCs (n = 8). These results suggest that 1)
cyclooxygenase products are necessary for the stimulation of PCs by
PAE, whereas changes in lung mechanics are not, and
2) the functional importance of
cyclooxygenase products may be mediated in part through the formation
of · OH.
lung vagal sensory receptors; microembolism; reflex tachypnea; ibuprofen; dimethylthiourea; cyclooxygenase system; hydroxyl radical
INTRODUCTION PULMONARY MICROEMBOLISM is known to cause reflex
tachypnea (1, 4, 12). Vagal lung C-fiber afferents are
believed to play an important role in eliciting this respiratory
response (1, 4, 12). Indeed, previous electrophysiological studies have
demonstrated stimulation of vagal lung C-fiber nerve endings by emboli
such as starch particles, plastic spheres, or glass beads (2, 3, 21).
Although the physiological mechanisms of the stimulation remain
unclear, several investigators have postulated that chemical mediators
released locally in the lungs after microembolism may be responsible
for the stimulation of vagal pulmonary C fibers (2, 7, 18).
Pulmonary microembolism has been found to cause an increase in the
release of a variety of mediators, including cyclooxygenase products
and reactive oxygen metabolites (5, 9, 10, 18, 29). When the
cyclooxygenase system is activated, arachidonic acid is converted to
prostaglandin H2, which can be
subsequently metabolized to various types of prostaglandins and
thromboxane. Several cyclooxygenase products, when administered
exogenously, have been shown to stimulate vagal lung C-fiber nerve
endings (7, 13). On the other hand, superoxide anion, hydrogen
peroxide, and hydroxyl radical (· OH) are the major reactive
oxygen metabolites produced after pulmonary microembolization (18).
Among them, · OH, the reaction product of superoxide anion
and hydrogen peroxide, is the most reactive free radical produced in
the biological system (11). Recent studies have demonstrated that
· OH, generated by an ischemia-reperfusion process, can
activate visceral C-fiber nerve endings in the
gastrointestinal tract of cats (26) and in the heart of rats (28).
Taken together, these findings suggest the possibility that the
cyclooxygenase metabolites and · OH may be involved in the
stimulation of vagal lung C-fiber nerve endings induced by pulmonary
microembolism. However, experimental evidence to support this
possibility remains to be established.
The objective of the present study was to investigate the possible
involvements of the cyclooxygenase system and · OH in the stimulation of vagal pulmonary C fibers by pulmonary air embolism (PAE)
in anesthetized dogs. PAE was chosen as the model of microembolism in
this study because its effects are readily reversible within minutes
after termination of induction (15, 23). To accomplish our objective,
we compared the afferent responses of vagal pulmonary C fibers to PAE
before and after systemic administration of a saline vehicle, a
cyclooxygenase inhibitor [ibuprofen (Ibu)], or a
· OH scavenger [dimethylthiourea (DMTU)].
METHODS Fifty-one dogs (8.5-20.0 kg) were anesthetized with an intravenous
injection of thiopental sodium (20 mg/kg; Abbott), followed by a combination of chloralose (50 mg/kg iv; Sigma Chemical) and urethan (500 mg/kg iv; Sigma Chemical). Supplemental doses of chloralose (15 mg · kg After a midline incision was made in the neck, a short tracheal cannula
was inserted just below the larynx, and a midline thoracotomy was
performed. The lungs were ventilated (model 607, Harvard) with 65%
O2 at a frequency of 16-20
cycles/min and a tidal volume
(VT) of 12-15 ml/kg; both
were kept constant during each experiment.
CO2 was mixed with the inspired
gas when necessary to maintain end-tidal
CO2 concentration at ~5%. The
expiratory outlet of the respirator was placed under 3-4
cmH2O to maintain a near normal
functional residual capacity. Respiratory flow was measured with a
pneumotachograph (Fleisch no. 1) and a flow transducer (model 17212, Gould). The flow signal was integrated to give
VT. Tracheal pressure (Ptr;
i.e., transpulmonary pressure in open-chest preparation) and
CO2 concentration were measured
via side taps of the tracheal cannula by a pressure transducer
(MP45-28, Validyne) and a capnograph (model 9000, Biochem),
respectively. Total lung resistance
(RL) and dynamic lung
compliance (Cdyn) were determined by using the subtraction method (20).
All physiological signals were recorded by a thermal array recorder
(model TA11, Gould) and also recorded on tape (model DR-890,
Neurocorder) for later analysis.
1 · h1)
and urethan (150 mg · kg1 · h1)
were administered to maintain abolition of the corneal and withdrawal reflexes during the course of the experiments. The femoral artery was
cannulated for measurment of arterial blood pressure. Catheters (PE-240) were inserted into the right atrium and left ventricle via the femoral vein and carotid artery, respectively. During the
recording of vagal action potentials, the dogs were paralyzed with pancuronium bromide (0.05 mg/kg iv; Organon Teknica).
Periodically, the effect of pancuronium was allowed to wear off so that
the depth of anesthesia could be checked.
1 · min1)
into the right atrial catheter by an infusion pump (model 101, Nan Jou)
for a 10-min period. The infusion rate thus ranged from 1.7 to 4 ml/min, depending on the body weight of each individual animal. Each
study of PAE challenge consisted of a 5-min baseline period, a 10-min
period during PAE induction, followed by a 5-min recovery period after
the end of air infusion.
Experimental procedures.
A total of 64 pulmonary C fibers were recorded from 51 dogs. In five
pulmonary C fibers, impulses were continuously recorded over two
consecutive 20-min periods to serve as the time control. The remaining
59 pulmonary C fibers were first studied for their control responses to
PAE. Subsequently, the challenge of PAE was repeated in 9, 11, and 12 pulmonary C fibers at 10 min after pretreatment with saline vehicle,
Ibu (20 mg/kg), and DMTU (50 mg/kg), respectively, to investigate the
involvements of the cyclooxygenase system and · OH. In
another eight pulmonary C fibers, PAE challenge was repeated and a
brief hyperinflation of the lungs (4 × VT) was performed at the
termination of the second PAE induction to examine whether the
increased activity of pulmonary C fibers was associated with the
changes in RL and Cdyn after
embolization. Ibu (Sigma Chemical) and DMTU (Aldrich), dissolved in
isotonic saline, were slowly injected into the right atrium over a
2-min period. These doses of Ibu and DMTU have been previously shown to
abolish the pulmonary responses to embolization (5) and the cardiac
vagal C-fiber responses to reactive oxygen metabolites (27),
respectively. Before each 20-min period of continuous recording or each
challenge of PAE, the animal's lungs were hyperinflated (4 × VT) to establish a constant
volume history. To confirm that pulmonary C fibers remained active,
right atrial injection of capsaicin (5 µg/kg) was performed at 10 min
after the end of PAE induction. Because air emboli last for ~20 min
(23), at least 20 min were allowed to elapse between two challenges of
PAE. Animals received one to three challenges of PAE to obtain control
responses, depending on the number of pulmonary C fibers studied in
each individual animal, but received only one challenge of PAE after
pretreatment with saline, Ibu, or DMTU. Results were discarded for
those pulmonary C fibers that became inactive during the test
and/or were unresponsive to capsaicin at the end of the test
period.
Data analysis and statistics.
Neural activity of pulmonary C fibers and mean arterial blood pressure
were measured at 1-s intervals.
RL and Cdyn were measured on a
breath-by-breath basis. Baseline data of these physiological parameters
were calculated as the average values over the 30-s period immediately
preceding the PAE induction. Peak responses were measured as the peak
values averaged over a 30-s period after the PAE induction. Pulmonary C
fibers were judged to be activated by PAE when the peak response
exceeded its baseline activity by at least 0.5 impulses/s. These
physiological parameters were analyzed by using a computer equipped
with an analog-to-digital convertor (model DASA 4600, Gould) and
software (version 1.0, BioCybernatics). Results obtained from the
computer analysis were routinely checked with those obtained by manual
calculation for accuracy. Results were analyzed by a paired
t-test and one-way or two-way
repeated-measures analysis of variance followed by Tukey's test when
appropriate. P < 0.05 was considered
significant. All data are presented as means ± SE.
RESULTS
The baseline activity of the 64 vagal pulmonary C fibers studied (0.4 ± 0.1 impulses/s, n = 64) was
irregular and sparse. Pulmonary C fibers were stimulated by
hyperinflating the lungs up to 3 or 4 VT; they were also stimulated
within 1-3 s by right atrial injections of capsaicin (Fig.
1A)
but not by left ventricular injections (Fig.
1B). The locations of
these pulmonary C fibers within the lung structure were identified by
direct palpation. The conduction velocity of the afferent fibers
conducting impulses from 30 of these pulmonary C fibers was 1.2 ± 0.1 m/s (range 0.6-2.0 m/s). The physiological properties of these
pulmonary C fibers are consistent with those previously reported in
dogs (6, 7, 14, 16) and in other species (7).
1 · min1
for 10 min) into right atrium. This pulmonary C fiber had its nerve
endings located in right cardiac lobe and had a conduction velocity of
1.4 m/s. AP, action potential; 
, respiratory flow; Ptr, tracheal pressure; ABP, arterial blood pressure.
To study the changes in activity of pulmonary C fibers that occurred
spontaneously under our experimental conditions, impulses of five
pulmonary C fibers were recorded over two consecutive 20-min periods.
Neural activity of these pulmonary C fibers did not change
significantly during the two periods of continuous recording (Fig.
2A).
Induction of PAE stimulated 50 of the 59 pulmonary C fibers studied. The stimulation started 1.9 ± 0.1 min (0.9-2.7 min) after the onset of air infusion (Fig. 2B). When stimulated, these pulmonary C fibers fired irregularly, and the evoked discharge was not in phase with the ventilatory cycle (Fig. 1, C and D). On average, the evoked discharge of these pulmonary C fibers progressively increased from a baseline of 0.4 ± 0.1 impulses/s to a peak of 1.7 ± 0.2 impulses/s (n = 59) during the period from 1 min before to 2 min after the termination of PAE induction (Fig. 2B). They then gradually declined to their baseline activity within 5-10 min after the termination of PAE induction.
Of the 50 pulmonary C fibers stimulated by the first induction of PAE,
9, 11, and 12 pulmonary C fibers received a second challenge of PAE
after the animals had pretreated with saline vehicle, Ibu, and DMTU,
respectively. Ten minutes after pretreatment with saline or these
chemicals, the baseline activity of pulmonary C fibers did not change
significantly (Figs. 2B, 3, and
4). In the vehicle-treated group, a repeated challenge of
PAE induced afferent responses of very similar amplitude and time
course in the same pulmonary C fibers compared with their control
responses (Fig. 2B). In contrast, a
repeated challenge of PAE was unable to stimulate any of the pulmonary
C fibers tested in the Ibu-treated group, and the overall stimulation
of pulmonary C fibers induced by PAE was totally inhibited by the
pretreatment (Fig.
3A). In the DMTU-treated group, a repeated challenge of PAE induced a milder
stimulation in each of the pulmonary C fibers tested, and the overall
stimulation of pulmonary C fibers was markedly suppressed by the
pretreatment (Fig. 3B). Because the
time at which peak activity occurred varied among pulmonary C fibers,
the peak response was measured in each pulmonary C fiber, and the
average data are shown in Fig. 4.
Statistical analysis revealed that the average peak responses of
pulmonary C fibers to PAE were not altered by pretreatment with saline
(Fig. 4A) but were abolished by
pretreatment with Ibu (Fig. 4B) and
attenuated by pretreatment with DMTU (Fig. 4C). At the end of the test period,
all the pulmonary C fibers in saline-, Ibu-, and DMTU-treated groups
could still respond to the right atrial injection of capsaicin (Table
1). In 10 other pulmonary C
fibers that were stimulated by the first induction of PAE and received
pretreatment with saline, Ibu, or DMTU, they became inactive during the
second challenge of PAE and were unresponsive to capsaicin at the end
of the test period. Presumably, these 10 pulmonary C fibers had lost
their viability.
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Induction of PAE did not significantly affect the mean arterial blood
pressure (before vs. 10 min after the onset of PAE induction, 122.8 ± 2.9 vs. 118.1 ± 3.6 mmHg; n = 59). However, induction of PAE consistently caused an increase in
RL and a decrease in Cdyn (Figs.
5 and 6). At
1.5-2.5 min after the onset of embolization, RL began to increase, which
reached its peak 5-9 min after the onset of embolization and
remained elevated for the remaining test period. In a similar time
course, Cdyn was decreased by the induction of PAE (Fig. 5). The
PAE-induced increase in RL was not significantly altered by pretreatment with saline vehicle or DMTU
(Fig. 5, A and
C) but was attenuated by
pretreatment with Ibu (Fig. 5B). In
the remaining eight pulmonary C fibers that were stimulated by the
first induction of PAE, a brief hyperinflation of the lungs (4 × VT) was performed at the
termination of the second PAE induction. Hyperinflation of the lungs
largely restored RL and Cdyn to
their baseline values, whereas it did not reverse the PAE-induced
stimulation (Fig. 6).
DISCUSSION
Results of the present study demonstrated that a majority of vagal pulmonary C fibers studied (85%) were stimulated by PAE and that the stimulation was not due to the progressive changes in fiber activity that occurred spontaneously under our experimental conditions because not any detectable response was found in the five pulmonary C fibers tested as the time control (Fig. 2A). This is the first experimental evidence that air emboli lodged in the pulmonary vessels can stimulate pulmonary C fibers. These results are in general agreement with those reported by other investigators using emboli such as starch particles, plastic spheres, or glass beads (2, 3, 21). In addition, we have demonstrated that when two challenges of PAE separated by at least 20 min were induced, afferent responses similar in both intensity and time course were produced in the same pulmonary C fibers. The reproducibility of the afferent responses to PAE, therefore, allowed us to investigate the effects of Ibu or DMTU on the PAE-induced stimulation of pulmonary C fibers.
We found that pretreatment with Ibu totally abolished the afferent
responses of pulmonary C fibers to PAE and that DMTU attenuated the
responses of pulmonary C fibers by 62.2%. These results suggest that
both the cyclooxygenase system and · OH may play important roles in the stimulation of pulmonary C fibers by PAE. In fact, these
two factors have also been shown to participate in the process of the
activation of afferent C-fiber nerve endings in other organs. In cats,
the afferent responses of sympathetic visceral C-fiber nerve endings to
abdominal ischemia are attenuated by either cyclooxygenase blockade
(17) or inhibition of · OH production (26). In rats, cardiac
vagal C-fiber nerve endings are stimulated by an ischemia and
reperfusion of the heart (28). The activation of these cardiac vagal
afferents at the onset of ischemia is totally prevented by
cyclooxygenase blockade, whereas the activation at reperfusion is
completely abolished by inhibition of · OH production (28). Hence, it appears that these two factors are important activators for a
variety of afferent C-fiber nerve endings. The exact sources of these
two factors are not well understood. However, it is known that the
lungs are a rich source of arachidonate products and the enzymes
necessary for their metabolism (5, 18). Furthermore, circulating
leukocytes and possibly lung cells have been suggested to be possible
sources for the production of oxygen radicals after embolization (9,
18, 29). Indeed, both in vivo and in vitro studies have demonstrated
activation of the cyclooxygenase pathway and leukocytes after PAE by
measurment of concentrations of 6-ketoprostaglandin F1
and thromboxane
B2 and by leukocyte counts in the
plasma (10, 18, 29).
Our results suggest that there is an overlap of functional contributions of the cyclooxygenase system and · OH to the afferent responses of pulmonary C fibers to PAE. Similar findings have also been reported in the study of other physiological responses. Longhurst and co-workers (17) and Stahl and co-workers (26) reported that more than half of the visceral C-fiber responses to abdominal ischemia are reduced by either cyclooxygenase blockade or inhibition of · OH production. In studies of tissue injury in the lungs (19), heart (24), and brain (30), the responses produced under various pathological conditions could be prevented by either cyclooxygenase inhibitors or by oxygen radical scavengers. One plausible explanation for the overlap of functional contributions is that the cyclooxygenase system and · OH are interrelated in their biochemical pathways. For example, it has been shown that significant amounts of oxygen radicals are formed during the metabolism of arachidonic acid via cyclooxygenase (8, 24, 30). Furthermore, some cyclooxygenase products have been demonstrated to induce adherence and aggregation of leukocytes (25), which are known to be the prime factor for the increased release of oxygen radicals after PAE (18, 29). Thus cyclooxygenase blockade by Ibu could possibly inhibit not only the production of prostaglandins and thromboxanes but also the generation of · OH associated with the cyclooxygenase pathway. However, scavenging · OH by DMTU presumably affects only the latter. Another plausible explanation is that cyclooxygenase products and · OH are interrelated in their physiological effects. For example, some investigators (18, 26) have postulated that one mediator must act synergistically with the other to manifest either's functional contribution to the responses. Therefore, eliminating either of these two participants would prevent or attenuate the overall response. Collectively, it would be assumed that the cyclooxygenase system is essential for the activation of pulmonary C fibers by PAE and that its functional importance is mediated in part through the involvement of · OH in our experimental model.
Several mechanisms have been postulated to explain how pulmonary microembolism stimulates pulmonary C fibers, including 1) a direct stimulation by the released mediators (2, 7, 18), 2) a mechanical stimulation by an increase in interstitial fluid volume (18, 22), and 3) a mechanical stimulation by airway constriction (2). Therefore, the involvement of cyclooxygenase products and · OH may possibly arise from their direct actions on pulmonary C fibers or their ability to induce further releases of other chemical mediators to stimulate pulmonary C fibers. It is also plausible that neither cyclooxygenase products nor · OH directly mediates the PAE-induced stimulation of pulmonary C fibers. However, baseline levels of cyclooxygenase products and · OH (27) might nonspecifically raise the sensitivity of C-fiber nerve endings. Consequently, administration of Ibu and DMTU might lower the baseline levels of these metabolites and thereby make pulmonary C fibers less responsive to PAE-related stimulus. The possibility of an increase in interstitial fluid volume should also be considered because both cyclooxygenase products and · OH after embolization can increase vascular permeability (18). In the present study, PAE elicited an increase in RL and a decrease in Cdyn, a finding consistent with that reported in our previous study (15). However, pretreatment with Ibu totally abolished the afferent responses of pulmonary C fibers, whereas it only partially attenuated the bronchomotor responses to PAE. Furthermore, pretreatment with DMTU attenuated the afferent responses of pulmonary C fibers while yielding no effect on the bronchomotor responses to PAE. Moreover, hyperinflation of the lungs restored the increase in RL and the decrease in Cdyn to their baseline values, but it did not reverse the PAE-induced stimulation of pulmonary C fibers. These observations suggest that the bronchomotor responses to PAE may be due to constriction and/or closure of small airways and regional atelectasis in the lungs (20) and that the cyclooxygenase system, but not · OH, is involved in these responses. In addition, the dissociation of the relationship between the afferent and bronchomotor responses to PAE may imply that the involvements of cyclooxygenase products and · OH in the stimulation of pulmonary C fibers are not likely mediated through bronchoconstriction.
Armstrong and Miller (3) initially attempted to study the mechanisms underlying the stimulation of pulmonary C fibers by pulmonary microembolism. They demonstrated that platelet depletion prevented the increased activity of pulmonary C fibers after glass-bead microembolization in rabbits (3), suggesting a central role for platelet aggregation. Although not specifically identified as the mediator(s) involved in this electrophysiological study (3), many mediators such as cyclooxygenase metabolites, oxygen radicals, histamine, and serotonin could be released as a consequence of platelet aggregation (18). In their studies, Armstrong and co-workers (1, 4) showed that the reflex tachypneic response to glass-bead microembolization in rabbits was totally prevented by platelet depletion and partially attenuated by pretreatment with a serotonin-receptor antagonist. The tachypneic response to microembolization in rabbits has been shown to be a reflex elicited by the stimulation of pulmonary C fibers (12). Therefore, their findings may indirectly suggest that the C-fiber stimulation after embolization is mediated in part by the effects of serotonin associated with platelet aggregation. In this study, we made no attempt to investigate the involvement of serotonin because pulmonary C fibers are relatively insensitive to serotonin in dogs (7). However, these findings (1, 4) that indomethacin or aspirin (two other cyclooxygenase inhibitors) completely abolished the reflex tachypneic response to glass-bead microembolization also reflect the importance of the cyclooxygenase system in eliciting this respiratory reflex in their embolic model.
ACKNOWLEDGEMENTS
We are grateful to Drs. L.-Y. Lee and M. A. Kirkpatrick for their valuable comments on the manuscript.
FOOTNOTES
Address reprint requests to Y. R. Kou.
Received 12 August 1996; accepted in final form 29 October 1996.
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