ClinicalScience(1986) 71, 519-526
519
Respiratory and cardiovascular effects of central and peripheral
intravenous injections of capsaicin in man: evidence for
pulmonary chemosensitivity
A. J. WINNING, R. D. HAMILTON, S. A. SHEA AND A. GUZ
Department oJMedicine, Charing Cross and Westminster Medical School, London
(Received I7December 198Y16April 1986; accepted 30 May 1986)
Summary
1. The respiratory and cardiovascular effects of
capsaicin injection into the superior vena cava and
an arm vein were studied in three normal subjects.
2. No changes were seen in tidal volume, inspiratory time or expiratory time after capsaicin injection. Instantaneous heart rate, systolic blood
pressure and diastolic blood pressure remained
unchanged.
3. Central and peripheral intravenous injections
of capsaicin but not control solution above a
threshold of 0.5 ,ug/kg produced dose-dependent
sensations sequentially in the chest, face, rectum
and extremities. The chest sensation, a ‘raw, burning’ feeling, occurred 3-4 s after central capsaicin
injection. No subject reported feeling breathless. In
one subject the maximum tolerable dose of capsaicin (4 &kg) produced paroxysmal coughing 3.9 s
after a central injection.
4. In two of the subjects capsaicin injection was
repeated after inhalation of a 5% bupivacaine aerosol (aerodynamic mass median diameter 4.8 pm),
sufficient to block the cough reflex to a 5% citric
acid aerosol. Prior inhalation of local anaesthetic
aerosol abolished the chest sensation after capsaicin
injection; the other sensations were unaffected.
5. This study demonstrates that stimulation of
receptors accessible from the pulmonary vascular
bed does not evoke the pulmonary chemoreflex in
conscious man but can produce coughing. It provides evidence for the existence of a nociceptive
system of nerve endings in the lung parenchyma that
can be blocked by inhaled local anaesthetic aerosol.
Correspondence: Dr A. J. Winning, Department of
Medicine, Charing Cross Hospital, Fulham Palace Road,
London W6 8RE
Key words: capsaicin, local anaesthetic aerosol, pulmonary chemoreflex, sensation.
Abbreviations: BP, blood pressure; ECG, electrocardiogram; PDG, phenyldiguanide; SVC, superior
vena cava.
Introduction
In animals a variety of drugs injected into the right
heart elicit the pulmonary chemoreflex [l].This
vagally dependent reflex of bradycardia, hypotension and apnoea, followed by rapid shallow breathing, is initiated within 2-3 s of the injection,
suggesting that the receptors mediating the response
are located in the pulmonary vascular bed. Pulmonary C-fibres are believed to account for the
reflex [2-41. However, different drugs evoke the reflex in different animal species. It is evoked in rabbits
by phenyldiguanide (PDG) [5],in cats by PDG [5],
lobeline [6],5-hydroxytryptamine [2] and capsaicin
[6], and in dogs by capsaicin [7] but not usually by
PDG [ 1,8].
The classical pulmonary chemoreflex has not
been demonstrated in man. Intravenous injection of
lobeline produces hyperventilation resulting from
stimulation of carotid and aortic body chemoreceptors preceded by cough [9]. Stern et al. [lo] found
that coughing occurred within 1.4 s of lobeline
injection into the main pulmonary artery but not in
response to left heart injection. Peripheral intravenous injection of lobeline was reported to produce ventilatory depression within the arm-lung
circulation time in 17 of 20 normal subjects studied
by Bevan & Murray [ l l ] ; in 10 of these subjects
there was an accompanying transient bradycardia
and hypotension. Coughing occurred in most sub-
A. J. Winning et al.
520
jects but coincided with the onset of hyperventilation 12-18 s after injection. In addition, some
subjects reported burning or flushing sensations
localized to the mid-sternum or throat.
The evidence for the existence of lung chemoreflexes in man was further examined by Jain et al.
[12]. They showed that PDG acted on the carotid
body alone to produce stimulation of breathing.
Lobeline produced similar carotid chenioreceptor
stimulation but this was preceded in some subjects
by a variable apnoea with or without cough. No
accompanying circulatory effects were seen in any
subject. Lobeline, but not PDG, produced a sensation of fumes in the throat or burning over the
manubrium.
Capsaicin ( 8-methyl-N-vanillyl-6-nonenamide)
is
the active principle in the fruit of various species of
Capsicum and is the pungent agent in chilli pepper
and paprika. At a dose of 5 pglkg it produces acute
activation of afferent C-fibre endings in the respiratory tract in dogs [8] and in doses 10" times greater
results in degeneration of these fibres in guinea pigs
and rats [ 131. Such capsaicin pretreatment induces
desensitization of the airway mucosa to a variety of
mechanical and chemical stimulants [ 141. Capsaicin
is a relatively selective C-fibre stimulant in the lungs
of animals, having little effecr on the discharge of
pulmonary stretch receptors [4, 51. However, it has
been shown to potentiate the existing discharge of
rapidly adapting fibres in the cat [15], but the effect
was small compared with the striking stimulation of
pulmonary C-fibres produced by a similar dose of
drug.
In man, capsaicin has been applied to the skin
[16] and buccal mucosa [17], where it causes pain
and a burning sensation. When inhaled, capsaicin
produces dose-dependent coughing [ 18, 191, which
is abolished by prior application of local anaesthetic
to the larynx; it also results in bronchoconstriction
[ 191. A similar capsaicin-induced contraction of
human bronchus has been shown iti vitro [20].
In the present study we have examined the effects
of peripheral and central intravenous injections of
capsaicin in normal subjects. A local anaesthetic
aerosol, which we have recently shown to abolish
the pulmonary chemoreflex in dogs [21], was used
to determine whether effects resulting from capsaicin injection originated from receptors in the pulmonary vascular bed. The results of this study have
been presented in preliminary form [22].
Methods
The study was performed on three normal healthy
subjects (Table 1) on no regular medication. Since
this represented the first occasion to our knowledge
that capsaicin had been intravenously administered
to man, the study was confined to the authors. Subjects were therefore fully conversant with the
pharmacology of the drug and the purpose of the
investigation. The protocol for the study was approved by the Ethical Committee of Charing Cross
Hospital.
Design of the study
To allow central intravenous injections to be
made, a catheter was inserted under local anaesthesia into a peripheral vein in the antecubital fossa
and advanced under fluoroscopic control until its
tip lay in the superior vena cava (SVC). This was
performed on subject 1 on two occasions on separate days, and in subject 2 on a single occasion. In
order that further studies could be performed on
the subjects without the need for a central venous
catheter, peripheral venous injections were made
on a separate day via a catheter inserted into an arm
vein. This was performed in subject 2 on two occasions and in subjects 1 and 3 on a single occasion.
Capsaicin or control solutions were rapidly injected
through the catheters allowing for the volume of the
catheter dead space. A n event marker was
depressed at the start and released at the end of
injection to allow accurate timing of responses; all
injections took less than 1 s. A stock solution of
TABLE
1. Details of age, sex, airway firtiction, bronchial reactiviry and smoking history for
the sirbjects
FEV,, Forced expiratory volume in 1 s; PD,,, provocative dose of methacholine causing
a 35% fall in specific airways conductance (normal range for this laboratory is geometric
mean 5.4 pmol, geometric standard deviation 1.7 pmol [23]); pack years, product of
daily cigarette pack consumption and number of years smoked.
Subject
1
2
3
Age
(years)
Sex
54
37
29
M
M
M
FEV,
("Aof predicted)
114
104
95
PD,,
(pnol)
Cigarette consumption
(pack years)
4.1
27.2
39.1
0
0
1
Pulmonary chemosemitivity to capsaicin
capsaicin (80-85% pure, Sigma)made up to 10 mg/
ml in 90% ethanol was diluted in a solution of 30%
ethanol in saline (150 mmol/l NaCI) to provide
doses of 0.1, 0.5, 1.0, 2.0 and 4.0 pg/kg in 1 ml of
solution. At the beginning of the experiment, 0.25,
0.5 and 1.0 ml of 30% ethanol in saline were given
as controls. However, due to concern about the
effects of the cumulative dose of alcohol, 1 ml of
saline was used as the control for the remainder of
the experiment. Venous blood was taken from the
other arm for the measurement of blood alcohol
levels.
Capsaicin was injected in increasing doses till the
sensations resulting from the injection became
intolerable; the maximum tolerable dose of drug
was used for all subsequent capsaicin injections.
Capsaicin and control solutions were given single
blind in a randomized order. Thus, subjects
received two doses of each solution containing 0.1,
0.5 and 1.0 pg/kg of capsaicin and between four
and nine doses of the 2 or 4 pg/kg solution.
All measurements were made on subjects supine,
blindfolded, wearing soundproof headphones in a
room separate from the recording apparatus. This
ensured a minimum of visual and auditory stimulation and allowed injections to be made without the
subjects’knowledge.
Cardiovascular and respiratory measurements
Each injection of capsaicin or control solution
was preceded by a control period, during which
baseline cardiovascular and respiratory measurements were made. The solution was then injected
into the central or peripheral vein without the subjects’ knowledge and measurements were continued.
Tidal volume (V,), inspiratory time (Ti) and
expiratory time (T,) were measured breath by
breath without a mouthpiece by respiratory inductance plethysmography (Respitrace, Ambulatory
Monitoring, New York, U.S.A.).This was calibrated
against a spirometer using a multiple linear regression technique (modified from Loveridge et al.
[24]).An electrocardiogram (ECG) and instantaneous heart rate (f,) were recorded. Blood pressure
(BP) was measured within 30 s of injection with an
ultrasonic blood pressure monitor and inflatable
cuff (Arteriosonde 1225, Roche, New Jersey,
U.S.A.). All variables were displayed on an oscilloscope, recorded on a multi-channel chart recorder
and stored on tape together with a time code for
subsequent analysis. A balanced, two-way analysis
of variance was performed on f, averaged over a
breath, V,, Ti and T, for the five breaths before and
after central injections of capsaicin and saline solutions.
521
Sensations
After each injection, when the cardiovascular
and respiratory measurements had been made, the
subjects were asked to describe what sensations, if
any, they had experienced and the sequence in
which they occurred. Additional experiments were
performed to allow accurate timing of the occurrence of any such sensations. Subjects used an
agreed set of key words, which were spoken as a
sensation occurred, to describe the origin of that
sensation. This precluded respiratory measurements during these studies. A video recording of the
experiment, with sound and a time code, was made
to allow accurate measurement of subject responsetimes.
Local anaesthetic aerosol and infision
A peripheral venous injection of the maximum
acceptable dose of capsaicin was repeated after a
10 min inhalation of a local anaesthetic aerosol in
subjects 1 and 2. This aerosol (mass medium
diameter 4.8 pm; geometric standard deviation 1.6
pm; Malvern Laser particle size analyser) was
generated from an aqueous solution of 5% (w/v)
bupivacaine hydrochloride (Marcain, Duncan
Flockhart) by an ultrasonic nebulizer (35B, Devilbiss, Middlesex, U.K.) as previously described [25].
On a separate day, a central injection of a similar
dose of capsaicin was given to subject 1 and a peripheral injection to subject 2 after an intravenous
infusion of bupivacaine (0.75 mg/kg over 10 min)
into the other arm. After each capsaicin injection
timing of the associated sensations was performed
as described above. A venous blood sample was
taken for analysis of plasma bupivacaine (modified
from Reynolds & Beckett [26])and the cough reflex
to inhalation of a 5% (w/v) citric acid aerosol [25]
was tested.
Circulation time
To determine the circulation times from the sites
of injection to the ear lobe, cardiogreen dye
(HW&D, Baltimore, U.S.A.) was injected as a bolus
into the central or peripheral catheters and its
arrival at the ear detected with an ear oximeter
(Hewlett-Packard, Wokingham, U.K.). The
SVC-ear lobe or arm-ear lobe circulation time was
determined at the end of every study in all subjects.
Results
General effects of capsaicin injection
Central intravenous injection of capsaicin but not
control solution produced dose-dependent sensa-
A . J. Winning et al.
522
in one subject. There is no apparent apnoea nor
change in V, orfc.
The mean values for averaged over a breath,
together with V,, 7; and T,, are shown in Fig. 2 for
the five breaths before and after central injections
of saline and capsaicin solutions in subjects 1 and 2.
In order to assess the stability of these variables
before injection, the coefficients of variation (sn as a
percentage of the mean value) were calculated for
each run in each subject. The ranges of the coeffi-
tions which occurred sequentially in the chest, face,
rectum and extremities. The threshold dose for
these sensations was 0.5 ,ug/kg in both subjects; the
maximum tolerable dose was 2 ,ug/kg in subject 1
and 4 ,ug/kg in subject 2. Neither subject was aware
of the moment of injection. Peripheral injections of
capsaicin but not control solutions produced a similar though less intense sequence of sensations. This
was preceded by a local pain in the arm as the drug
was injected, which became intolerable as the dose
of capsaicin was increased. However, the maximum
tolerable dose was the same for both central and
peripheral injections. Blood alcohol levels for all
three subjects were less than 10 mg/100 ml. No
subject complained of chest tightness, wheezing o r
any other effects of drug or control injection. No
cardiac arrhythmia or systemic hypotension was
noted during this study and subjects have subsequently remained well.
Curdiovasculur and respiratory efsects
Fig. l ( a )shows an example of the effect of central capsaicin injection on the ventilation and ECG
..
- 600
0
-.0
.
O
o
400
o
1 SAL
(a)
:
V, 0.5 litre[
I
0'
ECG
,
L
t
10 s
4
CT
CAPS
41e
ECG
3
CAPS
2
V, 0.5 l
O
i
t
r
e
[
t
0
LSD
CAPS
9
O
0
I
(C)
o
.
0 .
10 s
.
1
'
2
I
3
I
I
4
1 : '
5
1
I
2
3
I
4
'
5
Breath no.
ECG
10 s
Pre
4
CAPS
4
CT
FIG. 1. Effect of central and peripheral capsaicin
injections in subject 2. ( a ) Capsaicin, 2 ,ug/kg, injected into the SVC. ( b )Capsaicin, 4 pg/kg, injected
into the SVC. (c) Capsaicin, 4 ,ug/kg, injected into
an arm vein. T h e arrows indicate the point of capsaicin injection (CAPS) and the circulation time
( C T ) from the site of injection to the ear lobe for
cardiogreen dye.
Post
FIG.2. Effect of central injections of capsaicin ( 0 )
and saline ( 0 )on the heart rate (f,) averaged over a
breath, together with tidal volume ( V, ), inspiratory
time ( T i ) and expiratory time (TJ,for the five
breaths before and after injection. Each point
represents mean data for seven injections of either
saline o r capsaicin (2 ,ug/kg) in subjects 1 and 2.
Fisher's least significant difference at the P= 0.05
level is shown for capsaicin (LSD CAPS) and saline
(LSD SAL) injections.
Pulmonary chemosensitivity to capsaicin
cients of variation for f,, V,, Ti and T, were 1-5%,
4-39%, 7-33% and 5-43% respectively. A
balanced analysis of variance was used to compare
data for these variables before and after saline and
capsaicin injections. There was no significant difference in the mean levels off, (saline pre 69.3, post
68.8 beats/min, P > 0.5; capsaicin pre 72.0, post
73.6 beats/min, P > 0.5), V, (saline pre 480, post
495 ml, P > 0.6; capsaicin pre 544, post 525 ml,
P> O S ) , Ti (saline pre 1.9, post 2.0 s, P > 0.6; capsaicin pre 2.0, post 2.0 s, P> 0.8) or T, (saline pre
2.5, post 3.1 s, P> 0.1; capsaicin pre 3.1, post 3.1 s,
P> 0.9).In order to detect changes from baseline in
individual breaths after injection, Fisher’s least
significant difference at the P= 0.05 level was used
(Fig. 2). The only values significantly different from
the mean levels before injection were those off, for
the fifth breath after capsaicin and T, for the fifth
breath after saline. Both these breaths occur considerably after the circulation time to the ear
(Table 2).
A paired t-test was used to compare values for
systolic and diastolic blood pressures before and
after saline and capsaicin injections. There was no
significant difference in the systolic (saline pre 123,
post 125 mmHg, P> 0.4; capsaicin pre 126, post
127 mmHg, P> 0.6) or diastolic (saline pre 83, post
84 mmHg, P > 0.6; capsaicin pre 87, post 88
mmHg, P> 0.6) blood pressures.
Thus, there was no demonstrable apnoea, bradycardia or hypotension after injection or evidence of
any change in the variables studied within the circulation time. However, in subject 2, 4 pg/kg capsaicin produced paroxysmal coughing 3.9 s after the
end of a central injection (Fig. lb). Where peripheral venous injections were made, the occurrence
of local arm pain made the analysis of ventilatory
records difficult on occasion. However, where this
analysis was possible no cardiovascular or respiratory effects were seen within the arm-ear lobe circulation time. Fig. l ( c ) shows the effect of
peripheral capsaicin injection in subject 2.
523
Sensations
Central and peripheral injections of capsaicin
above the threshold dose produced transient, ‘hot,
flushing’ sensations in the chest, face, rectum and
extremities. These were discrete, sequential sensations, each lasting for several seconds. An additional characteristic quality of the chest sensation
was a ‘raw, burning feeling’ which limited the dose
of capsaicin that could be centrally injected.
Repeated capsaicin injection did not result in tachyphylaxis of any of these sensations. No subject
reported feeling breathless. The key words used to
time this sequence of sensations were ‘chest’, ‘face’,
‘rectum’, ‘hands’ and ‘feet’. The timing of the sensations after capsaicin injections in any subject was
highly reproducible. The appearance time of the
chest sensation and the circulation time to the ear
for each injection site for the three subjects are
shown in Table 2. The sensation in the face
occurred shortly after the circulation time to the ear
and the other sensations later. On no occasion did
control injections result in any sensation.
Effects of local anaesthetic aerosol and infusion
Prior inhalation of local anaesthetic aerosol in
two subjects abolished the chest sensation after capsaicin injection; the other sensations were unaffected. The cough reflex to citric acid aerosol was
abolished in both subjects. Plasma bupivacaine
levels after aerosol were 0.96 pg/ml and 1.01 pg/ml
in subjects 1 and 2 respectively. Intravenous bupivacaine infusion had no effect on any of the sensations after capsaicin injections in these subjects.
Plasma bupivacaine levels after infusion were 1.94
yg/ml and 1.41 y g / d for the two subjects.
Discussion
The present study demonstrates that intravenous
capsaicin injection to the maximum tolerable dose
does not elicit a pulmonary chemoreflex in con-
TABLE
2. Appearance time of the chest sensation after central and peripheral intravenous
injections of capsaicin and the corresponding circulation time to the ear of cardiogreen dye
Each value represents one determination.
Subject
Central injection
SVC-ear
circulation time
Chest
sensation
Arm-ear
circulation time
(4
(4
(4
(4
4,4
373
-
8
9
8,7,8
16,12,14
13,13,14
11
29,24
20
Chest
sensation
1
2
3
Peripheral injection
-
524
A. J. Wiririirig et al.
scious man at a time when it produces an intense
chest sensation. This result is in contrast to that in
anaesthetized dogs [7,27] in which a similar dose of
capsaicin produces a marked apnoea, bradycardia
and hypotension. However, this dose of capsaicin
represents the threshold for the reflex effect in the
dog and the use of anaesthesia may potentiatc its
effect. The possibility therefore exists that a similar
dose in anaesthetized man may elicit the reflex; it is
unlikely that a higher dose could be given to conscious subjects.
Because of the nature of this study the number of
subjects was limited. We were, therefore, concerned
to ensure that a small effect of capsaicin injection
was not missed eithcr by our method of measurement o r data analysis. Our subjects were studied
under conditions of minimal visual or auditory
stimulation and injections were made without the
subject’s knowledge. Our method for measuring the
subdivisions of ventilation, respiratory inductance
plethysmography, is an accurate and sensitive technique for detecting changes in the pattern of resting
breathing [24]. However, the coefficients of variation of VT, T, and T, for the control state before
injection indicate the considerable variation in resting breathing. Such variability has been well
described [25, 28, 291. T h e smallest significant
change in a variable that will be detected by analysis
of variance after capsaicin injection is given by
Fisher’s least significant difference. In the present
study this is 113 ml for V,, 0.53 s for T, and 1.10 s
for T,. Changes smaller than this would not be
detected. In contrast, the coefficients of variation
for f, were small, indicating the stability of this
variable. Since Fisher’s least significant difference
was 4.1 beats/min, any change after injection could
be readily detected. No such changes were seen
within the circulation time to the ear. Thus,
although small changes in ventilation could have
remained undetected by our analysis, the crucial
feature of our study is the complete absence of a
change in heart rate.
The use of an intra-arterial method of measuring
BP, essential for the detection of transient changes,
was considered unjustified in this study. It is, therefore, possible that a transient change in BP might be
missed by our method of recording. However, a
decrease in BP without a concomitant decrease in f,
has never been reported after capsaicin injection in
animals [6-81.
Evidence for the existence of a reflex from the
pulmonary circulation in man has come from previous studies employing intravenous lobeline.
Though Bevan & Murray [ 111 described transient
bradycardia and hypotension within the arm-lung
circulation time in some of their subjects, the evidence for the accompanying changes in breathing
pattern is unconvincing. In contrast, Jain el al. [ 121
reported the occurrence of apnoea in the majority
of their subjects with no accompanying cardiovascular effects. Though we were unable to demonstrate a pulmonary chemoreflex in our subjects,
central injection of capsaicin produced paroxysmal
coughing within 3.9 s. A similar result has also been
observed after lobeline injection [9, 10, 121. Such a
result would be consistent with its originating from
receptors located at the pulmonary artery bifurcation [ 101 or from juxtapulmonary capillary receptors in the lung [30]. Inhaled capsaicin has recently
been reported to cause coughing, which was
abolished by application of local anaesthetic to the
larynx [18]. However, since coughing occurred in
subject 2 well before the circulation time to the ear,
its origin from receptors in the larynx, a structure
supplied by branches of the external carotid artery,
is unlikely.
Although methods to quantify the intensity of
sensations are well described [311, the transient
nature and the unfamiliarity of the sensation produced by capsaicin injection makes the use of such
methods invalid. Therefore, no such attempt was
made in this study. The sensations resulting from
capsaicin injection are similar to those previously
described as occurring in the chest and throat after
lobeline injection [ 11, 121. However, precise timing
of these sensations has not been previously
reported. T h e short latency of the chest sensation
suggests that it originates from stimulation of receptors accessible from the pulmonary vascular bed;
unmyelinated fibres have recently been demonstrated in the alveolar wall in man [32]. Since Paintal
1331 has proposed that juxtapulmonary capillary
receptors may be an important source of dyspnoeic
sensation from the lung, it is relevant that such
intense stimulation of these receptors never produced the sensation of breathlessness in any of our
subjects. These receptors have the characteristics of
visceral nociceptive endings in animals [34] and our
demonstration that capsaicin injection produces
intense chest discomfort supports the belief that
such a system exists in the human lung. It may
account for similar sensations experienced after the
inhalation of irritant gases or aerosols. Although
these receptors are believed to be primarily activated by tissue damage, the accumulation of interstitial fluid, and by release of mediators [34], we
know of no disease state which produces a chest
sensation similar to that found in the present study.
In constrast to disease, capsaicin o r other irritants
may produce mass activation of these receptors.
Confirmation that the chest sensations after capsaicin injection originated from receptors in the
lung parenchyma is provided by the results with
local anaesthetic aerosol inhalation. Prior admini-
Pulmonary chemosensitivity to capsaicin
stration of bupivacaine aerosol but not infusion
abolished the chest sensation alone. As tachyphylaxis was not observed in the present study, this
result was not due to repeated administration of
capsaicin. We have recently demonstrated that
inhalation of this aerosol abolishes the pulmonary
chemoreflex to capsaicin in dogs [21].
The present study provides no support for the
existence of a pulmonary chemoreflex in concious
man. However, it demonstrates that stimulation of
receptors accessible from the pulmonary vascular
bed produces paroxysmal coughing, the latency of
which is suggestive of a reflex nature. Furthermore,
it provides evidence for the existence of a nociceptive system of nerve endings in the human lung
parenchyma which can be blocked by an inhaled
local anaesthetic aerosol.
525
8. Coleridge, J.G.C. & Coleridge, H.M. (1984)Afferent
vagal C fibre innervation of the lungs and airways and
its functional significance. Reviews of Physiology, Biochemistry ond Pharmacology,99,l-110.
9. Eckenhoff, J.E. & Comroe, J.H., Jr (1951)Blocking
action of tetra-ethylammonium on lobeline-induced
thoracic pain. Proceedings of the Society for Experimental Biology and Medicine, 76,725-726.
10. Stern, S., Bruderman, I. & Braun, K. (1966)Localization of lobeline-sensitive receptors in the pulmonary
circulation in man. American Heart Journal, 71,
651-655.
11. Bevan, J.A. & Murray, J.F. (1963)Evidence for a
ventilation modifying reflex from the pulmonary circulation in man. Proceedings of the Societyfor Experimental Biology and Medicine, 114,393-396.
12. Jain, S.K., Subramanian, S., Julka, D.B. & Guz, A.
(1972)Search for evidence of lung chemoreflexes in
man: study of respiratory and circulatory effects of
phenyldiguanide and lobeline. Clinical Science, 42,
163-177.
13. Lundberg, J.M., Brodin, E. & Saria, A. (1983)Effects
and distribution of vagal capsaicin-sensitive substance P neurons with soecial reference to the
Acknowledgments
trachea and lungs. Acta IJhysiologica Scandinavica,
119,243-252.
14. Lundberg, J.M. & Saria, A. (1983)Capsaicin-induced
We thank Ms Christine Knott, Anaesthetic Unit, St
desensitization of the airway mucosa to cigarette
Thomas's Hospital Medical School, London, for
smoke, mechanical and chemical irritants. Nature
measurement of plasma bupivacaine, Dr M. Ashun,
(London),302,251-253.
Pharmacy Department, Charing Cross Hospital, for
15. Armstrong, D.J. & Luck, J.C. (1974)A comparative
help with the preparation of capsaicin and bupivastudy of irritant and type J receptors in the cat. Respiration Physiology, 21,47-60.
caine solutions, and Dr W. Kox, Department of
16. Jancso, N., Jancso-Gabor, A. & Szolcsanyi, J. (1968)
Anaesthetics, Charing Cross Hospital, for assistThe role of sensory nerve endings in neurogenic
ance with the insertion of central venous catheters.
inflammation induced in human skin and in the eye
and paw of the rat. British Joicrnul of Phurmacology
and Chemotherapy, 32,32-41.
17. Szolcsanyi, J. (1977)A pharmacological approach to
References
elucidation of the role of different nerves and receptor endings in mediation of pain. Journal of Physiology(Paris),73,257-259.
1. Dawes, G.S. & Comroe, J.H., Jr (1954)Chemo18. Collier, J.G. & Fuller, R.W. (1984)Capsaicin inhalareflexes from the heart and lungs. Physiological
tion in man and the effects of sodium cromoglycate.
Reviews, 34, 167-201.
British JournalofPharmacology, 81, 113-117.
2. Paintal, AS. (1955)Impulses in vagal afferent fibres
19. Fuller, R. W., Dixon, C.M.S. & Barnes, P.J. (1985)
from specific pulmonary deflation 'receptors. The
Bronchoconstrictor response to inhaled capsaicin in
response of these receptors to phenyl diguanide,
humans. Journal of Applied Physiology, 58,
potato starch, 5-hydroxytryptamine and nicotine, and
1080-1084.
their role in respiratory and cardiovascular reflexes.
20. Lundberg, J.M., Martling, C.-R. & Saria, A. (1983)
Quurterly Journal of Experimental Physiology, 40,
89-111.
Substance P and capsaicin-induced contraction of
human bronchi. Actu Physiologica Scandinavica,
3. Paintal, AS. (1969)Mechanism of stimulation of
119,49-53.
type J pulmonary receptors. Jozirnal of Physiology
21. Hamilton, R.D. & Winning, A.J. (1986)Reversible
(London),203,511-532.
blockade of the pulmonary chemoreflex and airway
4. Coleridge, H.M., Coleridge, J.G.C. & Luck, J.C.
reflexes in dogs by local anaesthetic aerosol
(1965)Pulmonary afferent fibres of small diameter
(Abstract). Journal OJ Physiology (London), 371,
stimulated by capsaicin and by hyperinflation of the
1 1 1P.
lungs. Journal of Physiology (London), 179,
22. Winning, A.J., Hamilton, R.D., Shea, S.A., Kox, W. &
248-262.
Guz, A. (1985)The effects of stimulating lung affer5. Dawes, G.S., Mott, J.C. & Widdicombe, J.G. (1951)
ents in man with intravenous capsaicin (Abstract).
Respiratory and cardiovascular reflexes from the
CliniculScience, 69,34P-35P.
heart and lungs. JournalofPhysiology(London),
115,
23. Chung, K.F. & Snashall, P.D. (1984)Methacholine
258-291.
dose-response curves in normal and asthmatic man:
6. Bevan, J.A. (1962)Action of lobeline and capsaicin
effect of starting conductance and pharmacological
on afferent endings in the pulmonary artery of the
antagonism. ClinicalScience, 66,665-673.
cat. CirculationResearch, 10,792-797.
7. Coleridge, H.M., Coleridge, J.G.C. & a d d , C. (1964) 24. Loveridge, B., West, P.,Anthonisen, N.R. & Kryger,
M.H. (1983)Single-position calibration of the resRole of the pulmonary arterial baroreceptors in the
piratory inductance plethysmograph. Journal of
effects produced by capsaicin in the dog. Journal of
Applied Physiology, 55,1031-1034.
Physiology(London),170.27 2-285.
526
A . J. Winning et al.
25. Winning, A.J., Hamilton, R.D., Shea, S.A., Knott, C.
& Guz, A. (1985)The effect of airway anaesthesia on
the control of breathing and the sensation of breathlessness in man. Clinical Science, 68,215-225.
26. Reynolds, F. & Beckett, A.H. (1968)The determination of bupivacaine, lignocaine and mepivacaine in
human blood. Journal of Pharmacy and Pharmace
logy, 20,704-708.
27. Porszasz, J., Such, G. & Porszasz-Gibiszer, K. (1957)
Circulatory and respiratory chemoreflexes. I. Analysis of the site of action and receptor types of capsaicin. Acta Physiologica Academiae Scieniiarum
Hungaricae, 12,189-205.
28. Newsom Davis, J. & Stagg, D. (1975) Interrelationship of the volume and time components of individual breaths in resting man. Journal of Physiology
(London),245,481-498.
29. Gribbin, H.R., Bruce, E.N. & Goldman, M.D. (1985)
Timing of tidal volume during resting breathing in
naive subjects. ClinicalScience, 68,34P.
30. Paintal, AS. (1973)Vagal sensory receptors and their
reflex effects. Physiological Reviews, 53, 159-227.
31. Adams, L., Chronos, N., Lane, R. & Guz, A. (1985)
The measurement of breathlessness induced in normal subjects: validity of two scaling techniques. Clinical Science, 69,7-16.
32. Fox, B., Bull, T. & Guz, A. (1980) Innervation of
alveolar walls in the human lung: an electron microscopy study. JournalofAnatomy, 131,683-692.
33. Paintal, A.S. (1968) Respiratory reflex mechanisms
and respiratory sensations. Indian Journal of Medical
Research, 56, 1-1 1.
34. Widdicombe, J.G. (1981) Regulation of Breathing.
In: Lung Biology in Health and Disease, vol. 17, pp.
429-472. Ed. Hornbein, T.F. Dekker, New York.