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The activities of lung stretch and irritant receptors during cough
Neuroscience Letters, 90 (1988) 125 129
125
Elsevier Scientific Publishers Ireland Ltd. NSL 05421
The activities of lung stretch and irritant receptors during cough Shigeji M a t s u m o t o First Department o[' Physiology, Fukushima Medical College, Fukushhna (Japan)
(Received 30 November 1987: Revised version received 17 March 1988; Accepted 22 March 1988) Key words.
Slowlyadapting pulmonary stretch receptor: Inspiratory phase: Expiratory phase: Rapidly adapting pulmonary stretch receptor; Ammonia: Rabbit
In unilaterally vagotomized rabbits, changes in single vagal nerve fibers from the lung stretch and irritant receptors were studied during the cough reflex following ammonia vaponr administered into the lungs. The discharge rates of slowly adapting pulmonary stretch receptors (SARs) before the onset of cough and at the onset of cough did not change significantly. In contrast, the occurrence of cough after ammonia inhalation was usually preceded by vigorous stimulation of the rapidly adapting pulmonary stretch receptors (RARs). These results suggest that the genesis of cough provoked by ammonia is mainly mediated by afferent input from RARs.
A l t h o u g h it has been reported that a m m o n i a v a p o u r inhaled into the lungs stimulates a n u m b e r o f lung airway receptors, such as slowly adapting p u l m o n a r y stretch receptors (SARs), rapidly adapting p u l m o n a r y stretch receptors (RARs), cough receptors and type J receptors (afferent vagal C-fibers) [1, 8, l l], the cough reflex involves more complicated mechanisms. According to Bucher [2], there is a possible interaction between the S A R activity and the cough reflex. Recent evidence suggests that the genesis o f c o u g h needs the excitatory influence o f the Hering Breuer reflex [4, 5, 9]. This idea is based on the following results that sulphur dioxide (SO2), eliminating the activity o f S A R s but leaving the activity of R A R s , greatly diminishes the n u m b e r o f coughs elicited f r o m the tracheobronchial tree by a m m o n i a vapour. If cough induced by a m m o n i a would result from the mechanism suggested by Hanb,6ek et al. [5], one can expect that the occurrence o f cough following a m m o n i a inhalation is caused by the result o f increased S A R activity. To evaluate the mechanism o f producing c o u g h by a m m o n i a , the present study, therefore, investigated the firing patterns and discharge rates o f S A R s and R A R s at the onset o f coughing after a m m o n i a inhalation in unilaterally vagotomized rabbits.
Correspondence: S. Matsumoto, First Department of Physiology, Fukushima Medical College, t tikarigaoka-I, Fukushima City, Fukushima 961)-12,Japan.
0304-3940/88/$ 03.50 @ 1988 Elsevier Scientific Publishers Ireland Ltd.
t26 Twelve rabbits weighing between 2.5 and 3.5 kg were anesthetized with urethane (lg/kg, i.p.). The trachea was cannulated low in the neck and animals were breathing spontaneously through the tracheal cannula. The tracheal side-pressure was measured by using a differential transducer. The aortic nerves were sectioned in advance. Also, the recurrent laryngeal nerves were sectioned at the C3 or Ca level. To evoke the cough reflex, ammonia vapour (15% ammonia solution) was injected into the tracheal cannula for about 5 s. This procedure was performed twice on each preparation at intervals of about 15 rain. The left vagus nerve was exposed, sectioned in the middle of the neck and desheathed. A few fibers were separated and placed on a unipolar silver electrode and submerged under warm liquid paraffin (37-38°C). The action potentials from the vagus nerve fibers were recorded. The SAR and RAR afferents were initially identified by their firing pattern with maximum frequency in inspiration and minimum frequency in expiration and with the brief and irregular burst, respectively. The difference between the activities of SARs and RARs was further confirmed by their characteristic changes in the discharge rate of them: (1) the SARs had a lower inflation threshold than the RARs and (2) the RARs showed a rapid adaption by lung inflation, but the SARs showed a slow adaptation by the same procedure and decreased their activity during moderate lung deflation. The SAR and RAR action potentials were selected by a discriminator, monitored on an oscilloscope and recorded on a polygraph. The experiments were designed to examine the changes of SAR and RAR activity in response to cough after ammonia inhalation, and to compare these responses during normal breathing. For evaluation of cough reflex on SAR activity, SAR impulses were counted during inspiration before the onset of cough as well as during expiration at the onset of cough, and the average activities of SARs were expressed as impulses/s. To evaluate the cough reflex on RAR activity, the RAR impulses were also counted during cough and expressed as impuises/s. When ammonia vapour was administered into the lungs, the SAR activity seen during the inspiratory phase before the onset of coughing only slightly increased whereas the discharge rate of SAR firing during expiration was not significantly affected by the onset of coughing (Fig. 1A). Similar results were obtained in all of the tested 14 different SAR fibers. The changes of SAR activity during inspiration and expiration, when cough occurred after ammonia inhalation, in 14 SAR fibers are summarized in Fig. I B,C. Before the onset of coughing, the discharge frequency of SARs firing during inspiration did not show any significant change as compared with that during normal breathing at rest. Similarly, the induction of cough following ammonia inhalation had no effect on the response of SAR activity during expiration. Fig. 2A illustrates a typical change of RAR activity after inhalation of ammonia vapour. Ammonia inhalation caused a strong but short-lasting excitation of RAR activity, and the response was followed by the cough reflex. After the occurrence of cough, the RAR activity tended to decrease. The results obtained in 5 ditferent RAR fibers are summarized in Fig. 2B. Note that vigorous stimulation of the RARs elicits the cough reflex.
127
Cough is easily provoked by mechanical stimulation at the carina as well as by administration of irritant gases into the lungs [10], since the RARs, which are sometimes called the cough receptors, are densely located at the carinal region [3, 10]. On the other hand, the number of coughs and intensity of the cough reflex, when ammonia vapour is injected into the lungs, are significantly suppressed by a block of the SAR activity due to SO2 [4, 5, 9]. These observations may imply that cough is triggered when the afferent input from either RARs or SARs reaches a critical level. Bucher [2] postulated that the activation of SARs inhibits the central inspiratory acA Impulses SAR activity ( imp~ec )
I_ 70
i =,
,
j
,
,
:
J
Ptrad-~
SBP
(mmHg) 100-
~
100-
~
80"
CL
C
80-
i,m
._E 60-
._E 6 0 -
"g 4 0 -
,~ /-,0-
~m
!
Control
!
After an'rnor~
v
I
Cor~ol
l,
Duringcough a f t e r ~
During inspiration before COLlgNflg
theonset of
During expiration at the onset of
coughlFlg
Fig. 1. Effects of cough following a m m o n i a inhalation on slowly adapting pulmonary stretch receptor activity. A: - , period of a m m o n i a inhalation. SAR, slowly adapting pulmonary stretch receptor: P,~,~h, tracheal side-pressure: 1, inspiration: E, expiration and SBP, systemic blood pressure. B: the changes of SAR activity during inspiration before the onset of coughing. Vertical bars are S.E.M. (n = 14). C: the changes of SAR activity during expiration at the onset of coughing. Vertical bars are S.E.M. (n = 14).
12~
tivity and which in turn promotes a strong expiration. However, there is evidence that augmentation of the SAR activity after ammonia inhalation does not elicit an inhibition of inspiratory activity responsible for the Hering-Breuer reflex [6, 7]. Furthermore, there are observations that the majority of SARs increase their activity following ammonia inhalation and a few fibers do not change or decrease the activity, suggesting that these different responses are due to 'heterogenous' changes of mechanical conditions in the lung units [6, 7]. In this study, the induction of cough after ammonia inhalation was usually preceded by vigorous stimulation of the RARs. Even though ammonia did not significantly alter the firing patterns and discharge rates of SARs during both inspiration and expiration, cough was seen at that period. Thus, it is more conceivable that the genesis of cough is mainly mediated through the afferent input from R A R s but does not require the activation of SARs.
A :I ,il
I
, il
20F
RAR
a~ti,,~ Io1-( oL; /
(mmi~)
I
--.
.....
-
.
..
!-,
.
.
.
.
.
0L W~0-B
.
.
.
.
,Jr•
'
4~
8O-
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Fig. 2. Effects of cough following ammonia inhalation on rapidly adapting pulmonary stretch re~ptor activity. A: --, period of ammonia inhalation. RAR, rapidly adapting pulmonary stretch receptor, Ptrach, tracheal side-pressure; I, inspiration; E, expiration and SBP, systemic blood pressure. B: the changes of RAR activity in response to cough after inhalation of ammonia vapour. Vertical bars are S.E.M. (n = 5).
129
1 Armstrong, D.J. and Luck, J.C., A comparative study of irritant and type J receptors in the cat, Resp. Physiol., 21 (1974) 47 60. 2 Bucher, K., Pathophysiology and pharmacology of cough, Pharmacol. Rev., 10 (1958) 43 58. 3 Fillenz, M. and Widdicombe, J., Receptors of the lungs and airways. In E. Neil (Ed.), Handbook of Sensory Physiology. Enteroreceptors, Vol. 3, Springer, New York, 1972, pp. 8b 112. 4 Han&(:ek, J., Widdicombe, J.G. and Korpas, J., Stretch receptors of the lung and their effect on lung defensive reflexes. Prog. Int. Congr. Sci., 28th, Budapest, 1980, 460 pp. 5 Han&(zek, J., Davies, A. and Widdieombe, J.G., Influence of lung stretch receptors on the cough reflex in rabbits, Respiration, 45 (1984) 161 168. 6 Kohl, J. and Koller, E.A., Stretch receptor activity during irritant-induced tachypnoea in the rabbit, Pfliigers Arch., 386 (1980) 231 237. 7 Matsumoto, S., Effects of ammonia on lung stretch receptor activity in the rabbit, Jpn. J. Physiol., 37 (1988) 911 921. 8 Mills, J.E., Sellick, H. and Widdicombe, J.G., Activity of lung irritant receptors in pulmonary microembolism, anaphylaxis and drug-induced bronchoconstrictions, J. Physiol. (Lond.), 203 (1969) 337 357. 9 Sant'Ambrogio, G., Sant'Ambrogio, F.B. and Davies, A., Coughing to irritant of the tracheo-bronchial and the larynx after sulphur dioxide inhalation in rabbits and dogs, Physiologist, Abstract 23 (1980) 28. 10 Widdicombe, J.G., Respiratory reflexes from the trachea and bronchi of the cat, J. Physiol. (LondJ, 123 (1954) 55 70. 11 Widdicombe, J.G., Receptors in the trachea and bronchi of the cat, J. Physiol. (Lond.), 123 (1954) 71 101.
125
Elsevier Scientific Publishers Ireland Ltd. NSL 05421
The activities of lung stretch and irritant receptors during cough Shigeji M a t s u m o t o First Department o[' Physiology, Fukushima Medical College, Fukushhna (Japan)
(Received 30 November 1987: Revised version received 17 March 1988; Accepted 22 March 1988) Key words.
Slowlyadapting pulmonary stretch receptor: Inspiratory phase: Expiratory phase: Rapidly adapting pulmonary stretch receptor; Ammonia: Rabbit
In unilaterally vagotomized rabbits, changes in single vagal nerve fibers from the lung stretch and irritant receptors were studied during the cough reflex following ammonia vaponr administered into the lungs. The discharge rates of slowly adapting pulmonary stretch receptors (SARs) before the onset of cough and at the onset of cough did not change significantly. In contrast, the occurrence of cough after ammonia inhalation was usually preceded by vigorous stimulation of the rapidly adapting pulmonary stretch receptors (RARs). These results suggest that the genesis of cough provoked by ammonia is mainly mediated by afferent input from RARs.
A l t h o u g h it has been reported that a m m o n i a v a p o u r inhaled into the lungs stimulates a n u m b e r o f lung airway receptors, such as slowly adapting p u l m o n a r y stretch receptors (SARs), rapidly adapting p u l m o n a r y stretch receptors (RARs), cough receptors and type J receptors (afferent vagal C-fibers) [1, 8, l l], the cough reflex involves more complicated mechanisms. According to Bucher [2], there is a possible interaction between the S A R activity and the cough reflex. Recent evidence suggests that the genesis o f c o u g h needs the excitatory influence o f the Hering Breuer reflex [4, 5, 9]. This idea is based on the following results that sulphur dioxide (SO2), eliminating the activity o f S A R s but leaving the activity of R A R s , greatly diminishes the n u m b e r o f coughs elicited f r o m the tracheobronchial tree by a m m o n i a vapour. If cough induced by a m m o n i a would result from the mechanism suggested by Hanb,6ek et al. [5], one can expect that the occurrence o f cough following a m m o n i a inhalation is caused by the result o f increased S A R activity. To evaluate the mechanism o f producing c o u g h by a m m o n i a , the present study, therefore, investigated the firing patterns and discharge rates o f S A R s and R A R s at the onset o f coughing after a m m o n i a inhalation in unilaterally vagotomized rabbits.
Correspondence: S. Matsumoto, First Department of Physiology, Fukushima Medical College, t tikarigaoka-I, Fukushima City, Fukushima 961)-12,Japan.
0304-3940/88/$ 03.50 @ 1988 Elsevier Scientific Publishers Ireland Ltd.
t26 Twelve rabbits weighing between 2.5 and 3.5 kg were anesthetized with urethane (lg/kg, i.p.). The trachea was cannulated low in the neck and animals were breathing spontaneously through the tracheal cannula. The tracheal side-pressure was measured by using a differential transducer. The aortic nerves were sectioned in advance. Also, the recurrent laryngeal nerves were sectioned at the C3 or Ca level. To evoke the cough reflex, ammonia vapour (15% ammonia solution) was injected into the tracheal cannula for about 5 s. This procedure was performed twice on each preparation at intervals of about 15 rain. The left vagus nerve was exposed, sectioned in the middle of the neck and desheathed. A few fibers were separated and placed on a unipolar silver electrode and submerged under warm liquid paraffin (37-38°C). The action potentials from the vagus nerve fibers were recorded. The SAR and RAR afferents were initially identified by their firing pattern with maximum frequency in inspiration and minimum frequency in expiration and with the brief and irregular burst, respectively. The difference between the activities of SARs and RARs was further confirmed by their characteristic changes in the discharge rate of them: (1) the SARs had a lower inflation threshold than the RARs and (2) the RARs showed a rapid adaption by lung inflation, but the SARs showed a slow adaptation by the same procedure and decreased their activity during moderate lung deflation. The SAR and RAR action potentials were selected by a discriminator, monitored on an oscilloscope and recorded on a polygraph. The experiments were designed to examine the changes of SAR and RAR activity in response to cough after ammonia inhalation, and to compare these responses during normal breathing. For evaluation of cough reflex on SAR activity, SAR impulses were counted during inspiration before the onset of cough as well as during expiration at the onset of cough, and the average activities of SARs were expressed as impulses/s. To evaluate the cough reflex on RAR activity, the RAR impulses were also counted during cough and expressed as impuises/s. When ammonia vapour was administered into the lungs, the SAR activity seen during the inspiratory phase before the onset of coughing only slightly increased whereas the discharge rate of SAR firing during expiration was not significantly affected by the onset of coughing (Fig. 1A). Similar results were obtained in all of the tested 14 different SAR fibers. The changes of SAR activity during inspiration and expiration, when cough occurred after ammonia inhalation, in 14 SAR fibers are summarized in Fig. I B,C. Before the onset of coughing, the discharge frequency of SARs firing during inspiration did not show any significant change as compared with that during normal breathing at rest. Similarly, the induction of cough following ammonia inhalation had no effect on the response of SAR activity during expiration. Fig. 2A illustrates a typical change of RAR activity after inhalation of ammonia vapour. Ammonia inhalation caused a strong but short-lasting excitation of RAR activity, and the response was followed by the cough reflex. After the occurrence of cough, the RAR activity tended to decrease. The results obtained in 5 ditferent RAR fibers are summarized in Fig. 2B. Note that vigorous stimulation of the RARs elicits the cough reflex.
127
Cough is easily provoked by mechanical stimulation at the carina as well as by administration of irritant gases into the lungs [10], since the RARs, which are sometimes called the cough receptors, are densely located at the carinal region [3, 10]. On the other hand, the number of coughs and intensity of the cough reflex, when ammonia vapour is injected into the lungs, are significantly suppressed by a block of the SAR activity due to SO2 [4, 5, 9]. These observations may imply that cough is triggered when the afferent input from either RARs or SARs reaches a critical level. Bucher [2] postulated that the activation of SARs inhibits the central inspiratory acA Impulses SAR activity ( imp~ec )
I_ 70
i =,
,
j
,
,
:
J
Ptrad-~
SBP
(mmHg) 100-
~
100-
~
80"
CL
C
80-
i,m
._E 60-
._E 6 0 -
"g 4 0 -
,~ /-,0-
~m
!
Control
!
After an'rnor~
v
I
Cor~ol
l,
Duringcough a f t e r ~
During inspiration before COLlgNflg
theonset of
During expiration at the onset of
coughlFlg
Fig. 1. Effects of cough following a m m o n i a inhalation on slowly adapting pulmonary stretch receptor activity. A: - , period of a m m o n i a inhalation. SAR, slowly adapting pulmonary stretch receptor: P,~,~h, tracheal side-pressure: 1, inspiration: E, expiration and SBP, systemic blood pressure. B: the changes of SAR activity during inspiration before the onset of coughing. Vertical bars are S.E.M. (n = 14). C: the changes of SAR activity during expiration at the onset of coughing. Vertical bars are S.E.M. (n = 14).
12~
tivity and which in turn promotes a strong expiration. However, there is evidence that augmentation of the SAR activity after ammonia inhalation does not elicit an inhibition of inspiratory activity responsible for the Hering-Breuer reflex [6, 7]. Furthermore, there are observations that the majority of SARs increase their activity following ammonia inhalation and a few fibers do not change or decrease the activity, suggesting that these different responses are due to 'heterogenous' changes of mechanical conditions in the lung units [6, 7]. In this study, the induction of cough after ammonia inhalation was usually preceded by vigorous stimulation of the RARs. Even though ammonia did not significantly alter the firing patterns and discharge rates of SARs during both inspiration and expiration, cough was seen at that period. Thus, it is more conceivable that the genesis of cough is mainly mediated through the afferent input from R A R s but does not require the activation of SARs.
A :I ,il
I
, il
20F
RAR
a~ti,,~ Io1-( oL; /
(mmi~)
I
--.
.....
-
.
..
!-,
.
.
.
.
.
0L W~0-B
.
.
.
.
,Jr•
'
4~
8O-
~' z,O.
Conlra
~er,mmmr/a
Fig. 2. Effects of cough following ammonia inhalation on rapidly adapting pulmonary stretch re~ptor activity. A: --, period of ammonia inhalation. RAR, rapidly adapting pulmonary stretch receptor, Ptrach, tracheal side-pressure; I, inspiration; E, expiration and SBP, systemic blood pressure. B: the changes of RAR activity in response to cough after inhalation of ammonia vapour. Vertical bars are S.E.M. (n = 5).
129
1 Armstrong, D.J. and Luck, J.C., A comparative study of irritant and type J receptors in the cat, Resp. Physiol., 21 (1974) 47 60. 2 Bucher, K., Pathophysiology and pharmacology of cough, Pharmacol. Rev., 10 (1958) 43 58. 3 Fillenz, M. and Widdicombe, J., Receptors of the lungs and airways. In E. Neil (Ed.), Handbook of Sensory Physiology. Enteroreceptors, Vol. 3, Springer, New York, 1972, pp. 8b 112. 4 Han&(:ek, J., Widdicombe, J.G. and Korpas, J., Stretch receptors of the lung and their effect on lung defensive reflexes. Prog. Int. Congr. Sci., 28th, Budapest, 1980, 460 pp. 5 Han&(zek, J., Davies, A. and Widdieombe, J.G., Influence of lung stretch receptors on the cough reflex in rabbits, Respiration, 45 (1984) 161 168. 6 Kohl, J. and Koller, E.A., Stretch receptor activity during irritant-induced tachypnoea in the rabbit, Pfliigers Arch., 386 (1980) 231 237. 7 Matsumoto, S., Effects of ammonia on lung stretch receptor activity in the rabbit, Jpn. J. Physiol., 37 (1988) 911 921. 8 Mills, J.E., Sellick, H. and Widdicombe, J.G., Activity of lung irritant receptors in pulmonary microembolism, anaphylaxis and drug-induced bronchoconstrictions, J. Physiol. (Lond.), 203 (1969) 337 357. 9 Sant'Ambrogio, G., Sant'Ambrogio, F.B. and Davies, A., Coughing to irritant of the tracheo-bronchial and the larynx after sulphur dioxide inhalation in rabbits and dogs, Physiologist, Abstract 23 (1980) 28. 10 Widdicombe, J.G., Respiratory reflexes from the trachea and bronchi of the cat, J. Physiol. (LondJ, 123 (1954) 55 70. 11 Widdicombe, J.G., Receptors in the trachea and bronchi of the cat, J. Physiol. (Lond.), 123 (1954) 71 101.