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The mechanism of rapid shallow breathing due to histamine and phenyldiguanide in cats and rabbits
Physiology
Respiration
(1978) 32, 141LJ53
@ Elsevier/North-Holland
Biomedical
Press
THE MECHANISM OF RAPID SHALLOW BREATHING DUE TO HISTAMINE AND PHENYLDIGUANIDE IN CATS AND RABBITS’
G. MISEROCCHI,
T. TRIPPENBACH, M. MAZZARELLI, M. HAZUCHA
Deparrmeni
In anaesthetized
Abstract.
to histamine
aerosol
a J receptor
stimulant).
of Physio1og.v. McGill
cats and rabbits
(mainly
an irritant
time (TI) relationship
inspiratory
flow rate so that inspiration
VT US Tr relationship breaths central
occurred
(T?) accompanied respiratory
increased
central
and J receptors.
we analyzed
receptor
Both drugs caused
inspiratory
P.Q.. Canada
leftward
threshold
breathing
and i.v. injection displacement curve) without
following
exposure
of phenyldiguanide
(mainly
of the tidal volume a corresponding
was cut off at a lower VT and TI. The leftward
with a great
shortening
of the duration
of the expiratory
respiratory
frequency
displacement
of inspiration
phase (Tg). These parameters
was due to the augmented
of these endings
downwards
also caused
during
occluded the
that the irritant steeper in
in rabbits.
Histamine
Pulmonary
J receptors
Rapid shallow
stretch
receptors
breathing
Vagal cooling
Phenyldiguanide Pulmonary
to become
in
of the
monitored
tiring of fibers from stimulated
the TE OSTI relationship
(VT) us
increase
in absence of the phasic lung volume related vagal loop. It is suggested
Stimulation
cats and to be displaced
Montreal.
the rapid shallow
stimulant)
a marked
(Hering-Breuer
by a shortening
rhythm
Unicersiry.
N. JASPAR and
irritant
receptors
Vagus nerves
Histamine and phenyldiguanide are of interest to respiratory physiologists since these two substances have been shown to stimulate vagal irritants and J receptors, respectively (Paintal, 1973). Excitation of these two types of receptors results in a pattern of breathing which is rapid and shallow. This pattern has been recently analyzed (Winning and Widdicombe, 1976) in terms of a model describing some operational characteristics of the nervous control of the pattern of breathing. This mode1 is essentially based on the firing of pulmonary stretch receptors occurring Accepted for publication
’ Supported
24 August
by MRC of Canada
1977.
and MRC of Quebec. 141
142
G.
MISEROCCHI
et a/.
with each inspiration (Clark and von Euler, 1972). It was found that stimulation of irritant and/or J receptors resulted in a decrease of the Hering-Breuer threshold curve for inhibition of inspiratory activity. In the present paper tigated the phenomenon of rapid shallow breathing by extending to both cats and rabbits.
In addition,
we used the technique
we further invesour observations
of occluding
the airways
at the end expiratory volume to evaluate how afferents from stimulated J and irritant receptors affect the central respiratory rhythm in absence of phasic lung volume related information from pulmonary stretch receptors.
Methods Experiments were done in 11 cats (2.5-3 kg) and 8 rabbits (2.5 kg). Cats were anaesthetized i.p. with sodium pentobarbital (Nembutal, Abbot, 32 mg/kg). Rabbits were anesthetized with 2.5 ml/kg of a mixture consisting of 8.5 ml urethane (25?,,) plus 1.5 ml Nembutal (60 mg/ml). Experiments were done with the animals lying in the supine position, body temperature was maintained by aid of a heating pad. After tracheotomy and tracheal tube insertion, the vagus nerves were exposed in the neck and freed from the surrounding tissues. Catheters were placed into the right femoral artery and the right jugular vein, the latter being advanced into the right atrium. Tidal volume was obtained by electronic integration of the flow signal of a Fleisch # 00 pneumotachograph whose differential pressure was measured by a Sanborn 270 pressure transducer. Tracheal pressure was measured with a 267 Sanborn pressure transducer connected to a side arm of the tracheal cannula. Blood pressure was measured by connecting the femoral catheter to a Statham P23AA pressure transducer. The signals from the transducers were fed into a Honeywell oscillograph for amplification and recording. Histamine aerosol was administered by passing a flow of compressed air through a commercial generator containing a 5 ‘2” solution of histamine in saline. Phenyldiguanide (PDG) was delivered into the right atrium at a dose of 150 pg. To avoid tachyphylaxis, repeated injections of this drug were done at intervals of no less than 20-25 min (Dawes and Comroe, 1954). We used the vagal cooling technique in an attempt to identify the role of the different groups of receptors in the pattern of breathing observed. The literature indicates that both cold and anodal block cannot block fibers from pulmonary stretch receptors without affecting those from irritant receptors (both of which are myelinated) (Paintal, 1973). However, using both techniques it is possible to block most of the myelinated fibers without affecting the unmyelinated ones (J receptors) (Paintal, 1973). We chose the cold-block technique and used a temperature of 6 ’ C which should block all the myelinated fibers. About 1.5 cm of the vagi were placed into the grooves of stainless steel thermodes through which precooled water was passed at an average flow of 600 ml/min. Temperature of the thermodes was measured
RAPID SHALLOW
BREATHING IN CATS AND RABBITS
143
by aid of a thermometer whose bulb was in the thermode itself and assumed to be equal to that of’the nerve. The effects of histamine and PDG were studied in the same animal first with the vagi at body temperature, then cooled to 6 “C and then after vagotomy. In three cats the reflex effects of histamine and PDG were evaluated before and after carotid sinus denervation. Since in rabbits PDG caused an increase in FRC we compared the response to this drug with the pattern of breathing observed by raising the FRC by a similar amount under control conditions. This was obtained by having the animal breathe through a two-way valve,and by placing the expiratory line under water (expiratory threshold load, ETL) so as to increase alveolar pressure by an amount sufficient to raise the end expiratory level as with PDG. An end-expiratory pressure of about 2 cm Hz0 was used. In rabbits we also evaluated the pattern of breathing after eliciting the deflation reflex through a slight manual compression of the rib cage as recently done by D’Angelo rt al., 1976. This caused a reduction in FRC of about 2.5 ml. A similar maneuver in cats always failed to elicit a deflation reflex. Occlusion of the airways was done at the end-expiratory volume to evaluate the duration of inspiration and of expiration in absence of phasic lung volume related vagal afferents. Blood samples were taken from the arterial line during control conditions and during the rapid shallow breathing elicited either by histamine or PDG. Blood gases were analyzed with a Radiometer ~B53~L2 blood microsystem.
Results Ej$xt qf‘hi~tami~e aerosol Administration of histamine aerosol caused in all the animals rapid and shallow breathing within 30-90 sec. In 75”/, of the animals this pattern was preceded by a period of high tidal volumes and inspiratory flow rates. Our analysis will be restricted to the rapid and shallow breathing that remained essentially unchanged as long as the histamine aerosol was administered to the animal. Figures IA and 2A show that histamine aerosol (closed triangles) caused a marked leftward displacement of the VT US TI relationship as compared to the control condition (open circles) both in cats and rabbits. These approximate relationships were obtained by joining the coordinates of unloaded to those of occluded breaths. Since histamine aerosol did not cause any consistent change in the inspiratory flow rate the inspiration was cut off at a smaher VT and at a shorter Tr (tables 1 and 2). Figure IB shows that in cats the expiratory us inspiratory duration relationship with histamine aerosol was displaced to the left and had a steeper slope as compared to control values. In fig. 2C the same relationships for rabbits show that the histamine data are displaced downwards, as compared to control values, but with little change in slope. In both cats and rabbits histamine caused a shortening of TE and T8 (dura-
144
G. MISEROCCHI
ri id.
(set)
-0.09~0.03*
-0.1
receptors,
I *0.01*
from stretch
on TP and T$ only.
** At 6°C owing to the block of fibers
P < 0.05.
-1.97k1.36
-3.33*0.45*
Vagotomy
effects were considered
ml)
0.74*0.15*
- 0.35 + 0.03*
0.05 + 0.06
0.01 kO.04
-0.14+0.04*
0.02 + 0.04
kO.03
aerosol,
kO.13
+0.12*
respectively.
-0.3
-0.58+0.05* -0.19+0.06*
- 1.54 f 0.34*
1.01 ko.31:
0.12*0.02*
0.11+0.08
0
-0.28*0.08*
0.60 f 0.2*
-0.23kO.18
(set)
AT&
1.7*
Accordingly,
-34
-34
-23.32*
6*
5.07*
5.07*
4.06*
6.59*
timing
+12.17*
f
+5
at 6°C and vagotomy
4.76+2
33.3 I f 2.08* 7.08 f 1.45*
49.08f2*
- 15.56+
5
-21.29&
- 17.23 f
14.19*
20.28 f
2.03*
load(ETL)
(mm Hg)
APB
threshold
k SE)
16.93 i 1.83*
- 0.45 + 0.97
-0.12k1.65
14.41&4.32*
- 11.56f3*
- 13.14*2.03*
(cjmin)
Af
(mean
PDG i.v., expiratory
to 6 C and after vagotomy.
histamine
equal to Ti’ andTg,
-0.02kO.04
-0.07~0.05
-0.14*0.04*
0
-0.12f0.02*
ml)**
TI and TE became
-0.47*0.02*
= 5.1 20.82
- 1.17+0.16
Effect of DPG compared with control (AFRC
-2.12+0.91*
- 3.48 f 1.06*
* Significance:
-0.01+0.01
= 5.5 + 1.25 ml)
-0.02+0.01
Effect of PDG compared wiih ETL (AFRC = 0.4kO.4)
-1.21+1.51
Effect of ETL (AFRC
-2.72kO.45’
Effect of deflation (AFRC
= -2.21+0.19
AT: W)
-0.15*0.13
Vagi intact 6°C
Vagi intact
Vagi intact
Vagi intact
0.27&0.15
-0.22&0.09*
and vagotomy;
0.6 kO.91
-0.09+0.02
0.35 k 0.06*
ATE (set)
of: cooling and PDG also after cooling
-0.05~0.05
-0.3
in rabbits
2
k1.21
-2.12k1.06
Effect of histamine**
1.21+ 1.81
4.54 f 0.60*
Effect of cooling and vagotomy**
ATI
AVT
(ml)
6-C
Vagotomy
and on blood pressure
reflex with vagi intact and for histamine
parameters
and deflation
respiratory
Vagi intact
to vagotomy
6°C
to 6°C
Vagi intact
Condition
Effect on various
TABLE
K m
G.
146
MISEROCCHI
et a/.
tion of expiration during occluded breaths). Statistics for the respiratory parameters considered are shown in tables 1 and 2 for cats and rabbits, respectively. Histamine
aerosol
did not
cause
any
appreciable
change
in FRC
which
was
125 +2 (SE) in cats and 105 + 3 ml in rabbits. FRC was measured from the negative pressure generated in the airways during occluded breaths and the corresponding decompression volume according to Boyle’s law. Histamine caused a decrease in systemic blood pressure of 39.65 + 14.07 (SE) and 17.23 f4.06 mm Hg in cats and rabbits, respectively. lCf]kct of’irzjection
of’phenyldiguanide
Injection of phenyldiguanide (PDG) in cats caused a sudden decrease in VT and inspiratory flow rate leading to apnea at the expiratory level. Apnea lasted approximately 2 seconds followed by rapid shallow breathing. Our analysis has been extended to the pattern observed within 15 set from resumption of breathing. Over that period of time the response was waning, being reduced to about 502, of its maximum. The latter occurred within 4-5 set after resumption of breathing. Figure 1 (A, B) shows that in cats the effect of PDG (open triangles) was similar to that of histamine. Injection of PDG in rabbits caused apnea at the end-inspiratory level and during the following rapid and shallow breathing there was a tendency for the
TIME (set)
INSPIRATORY
1.6 z c :
1.2 -
*..;i’ .:)’ A.‘r
z w 0.8 0
1 0.4
I 0.8
I 1.2
INSPIRATORY
I 1.6 TIME
I 2.4
2
(WC)
Fig. 1. Anesthetized cats. A: VT us TI relationships obtained by joining with a straight line the coordinates of unloaded to those of loaded breaths, The true relationship that one could obtain by applying elastic loads to the animal,
would show a slight upward
concavity
which has been neglected
the mean values for all the animals studied. Control conditions (0); i.v. injection of 150 fig of phenyldiguanide (a). B : TE vs TI relationship of unloaded
to those of loaded
breaths.
exposure obtained
Same conditions
here. Points represent
to histamine aerosol (A); by joining the coordinates as in A.
RAPID SHALLOW
Fig. 2. Anesthetized from the detlation
rabbits.
reflex (n)
BREATHING
A: same conditions and
of an added
IN CATS AND RABBITS
147
and symbols as in lig. IA with the addition
expiratory
threshold
load (0).
in A but when plotting absolute volumes on the ordinate.
of results
B: same conditions
C: same as fig.
shown
I B.
animal to go back to its normal FRC. In fig. 2A the VT I’STI relationship obt~~ined in rabbits with PDG (open triangles) shows results similar to those obtained with histamine. In fig. 2B the same relationship was replotted using absolute volumes. Figure 2C shows that in rabbits PDG caused, similarly to histamine, a downward displacement of the TE I‘STI relationship. Statistics for the effect of PDG as compared to control conditions is given in tables I and 2 for cats and rabbits, respectively. Figure 2A shows that ETL (closed circles) affected the VT PS Tr relationship only by causing a shortening of Tf. Figure 2B shows the same results when plotting absolute volumes. Figure 2C shows that ETL caused a great lengthening of TE and T$ tht,s displacing greatly upwards the TE us Tt relationship. Statistical analysis on the effect of ETL, as compared to control conditions, is given in table 2. Table 2 also reports the statistical analysis referring to the comparison between the effects of ETL and PDG. This comparison, of course, would show a greater frequency effect of PDG. Figure 2A, B, shows that the response to a deflation reflex (open squares) was different from that to histamine and PDG in that Tf’ remained essentially unchanged (table 2). Conversely, the deflation reflex caused shortening of T# so that the TE us TI relationship was essentially similarly affected by the deflation reflex as it was by histamine and PDG (fig. 2C).
Figure 3A and B and table I show that in cats cooling the vagus nerves to 6 C caused a lengthening of T? but no substantial change in Tg. Vagotomy, as compared to 6 j C, caused a slight lengthening of T?; neither of these changes, however, were
148
G. MISEROCCHI
2.6 -
et d.
A
CATS 0 I
2.4
A
-
CONTR. HiST
POG
:.>*A$+ .. ...&
_--
*._---
0.6 1
Fig. 3. Anesthetized (0);
histamine
I
“AGl INTmx
6’
cats. A : effect on the duration
aerosol
0.8
“AGOT.
the same conditions
B: effect on the duration as in A. Points represent
Y&GOT.
“AGi INTACT
of inspiration
(A) and of 150 blcgi.v. injection
to 6 C and after vagotomy.
v
during occluded
of phenyldiguanide of expiration
during
(a)
breaths
(TP) of: control
with vagi intact,
occluded
breaths
the mean values of all the animals
cooled
(TE) under
studied.
statistically significant. Figure 4A and B and table 2 show the corresponding results for rabbits. Vagal cooling caused a slight lengthening of 1-P but a definite shortening of Tfi. Vagotomy, as compared to cooling, caused a slight lengthening of T?, but a marked lengthening of Tg. Results show that after cooling and thus also after vagotomy, in both cats and rabbits, the effect of histamine on Tf and T# was no longer significant. In cats this applied also to PDG. In rabbits the effect of PDG at 6 “C and after vagotomy was compared to control values since after block of the myelinated fibers the effect of ETL disappeared (table 2). Figure 4 shows that after cooling to 6 C, the shortening effect of PDG on Tf disappeared, whereas that on T?! was still present although greatly reduced. After vagotomy PDG still caused a significant decrease in T! but this decrease was not significantly
.
fl4TICT
#“TACT
Fig. 4. Anesthetized
rabbits.
A, B: same as fig. 3, A, 3. With vagi intact data referring to the deflation
reflex (0)
were also plotted.
to ETL (0)
and
RAPID
SHALLOW
BREATHING
IN CATS AND
RABBITS
149
different from the one occurring at 6,-C. The deflation reflex disappeared after cooling and vagotomy. Vagal cooling caused in both cats and rabbits an increase in blood pressure (tables 1 and 2) which was further increased by vagotomy. Histamine caused a significant decrease in blood pressure during vagal blockade in both cats and rabbits. A further decrease was observed after vagotomy in cats. In cats PDG caused a reduction in blood pressure both with vagi cooled and after vagotomy. In both conditions the response was less than with vagi intact. In rabbits the hypotensive effect of PDG was unaffected by either vagal cooling or vagotomy. In three cats we found that during the response to histamine or PDG the respiratory parameters were similarly affected before and after sinus denervation, suggesting that under conditions of irritant and J receptor stimulation, baroreceptor discharge did not significantly affect respiration. Blood gases
In cats during rapid shallow breathing elicited by both histamine and PDG, there was an increase in Pa,, 2 from 25.4? 1.I (SE) to 29.2kO.7 mm Hg and a decrease in Paol from 97.8f 1 to 69.7+ 1.2 mm Hg. This could be related to an almost 500/, decrease in VT, the increased frequency being not enough to counterbalance the drop in alveolar ventilation. In rabbits the decrease in VT was less and accordingly, we did not find significant changes in blood gases during rapid shallow breathing with histamine and PDG. ETL in rabbits increased Paco2 from 3lk2.1 (SE) to 36+2.5 mm Hg and decreased Paoz from 75 f 1 to 59.7+2 mm Hg.
Discussion Mechanism of rapid shallow breathing
The present results clarify the mechanism by which rapid shallow breathing is generated after histamine aerosol or injection of PDG. This pattern was observed as a leftward displacement of the VT c’sTI relationship without a corresponding increase in inspiratory flow rate. This displacement implies a decrease in the volume threshold for inhibition of inspiratory activity (Clark and von Euler, 1972). A shorter expiratory time corresponded with a decreased inspiratory time (Clark and von Euler, 1972). These conclusions are similar to those recently reached by Winning and Widdicombe (1976). A leftward displacement of the VT 6s TI relationship has been described by Miserocchi and Milic-Emili (1975) as being caused by hypercapnia, however, in the latter condition, there was, unlike under histamine or PDG stimulation, a great increase in the inspiratory flow rate. In cats we found that under steady conditions of rapid shallow breathing, end tidal P~co~ increased so that we cannot exclude a role played by CO, on displacing the VT us TI relationship to the left. However, due to CO, stimulation, the mean inspiratory flow should have increased, but it was not observed in our study. The relative hypoxia developed in anesthetized cats during
150
G. MISEROCHHI
et af.
rapid shallow breathing should, on the other hand, not have affected the VT us Tr relationship (Gamier, 1976; Miserocchi, 1976). Results from sinus denervation experiments suggest that, at least in cats, a decrease in baroreceptor discharge was unlikely to be responsible for the observed changes in respiratory pattern. A possible explanation for this displacement may reside in an effect of histamine and PDG on vagal activity at FRC resulting in shortening of T? and Tg. Widdicombe (1961) found that inhalation of histamine aerosol caused sensitization of pulmonary stretch receptors. However, an increased firing from these receptors should cause a slight decrease in T? (D’Angelo and Agostoni, 1975) but a lengthening of Tg (Lourenco et al., 1966; Bartoli et al., 1973; D’Angelo and Agostoni, 1975). PDG, on the contrary, was proved not to influence pulmonary stretch receptors discharge (Dawes and Comroe, 1954). Thus, our findings with histamine and PDG may be explained by irritants and/or J receptor stimulation. Vagal cooling and vagotomy
Block of afferent myelinated fibers of the vagus resulted in a consistent lengthening of T? in cats but in a very slight one in rabbits. Conversely, it caused a much more marked shortening of Tg in rabbits than in cats. These results are consistent with the general view that in anaesthetized animals the effect of stretch receptors is that of shortening T! but lengthening T$. Vagotomy, as compared to vagal block, caused a further lengthening of T?, greater in cats than in rabbits, but a lengthening of Tg much more marked in rabbits than in cats. These results show that some effect of unmyelinated afferents was present in our animals under control conditions. This effeci was a shortening one on the duration of the respiratory phases and confirms data by Fishman et al. (1973) and by Phillipson (1974) in awake dogs and by D’Angelo et al. (1976) in anesthetized dogs, cats and rabbits. Data from figures 3 and 4 indicate that a basic difference exists between cats and rabbits in that vagal afferents affect the central respiratory rhythm mainly through a modulation of the inspiratory time in cats and of the expiratory time in rabbits. Our results show that in both cats and rabbits the response to histamine and PDG was significantly diminished following vagal cooling to 6 ‘C. As far as histamine is concerned this is in line with other findings in rabbits (Karczewski and Widdicombe, 1969; Glogowska and Widdicombe, 1973). Moreover, vagal single-fiber recording showed that histamine acts mainly on irritant receptors (Mills et a/., 1969; Sellick and Widdicombe, 1971; Armstrong and Luck, 1974) although some stimulating effect on J receptors was also found (Paintal, 1973). As for phenyldiguanide, there are conflicting results in the literature. Dawes et al. (195 1) mentioned that in cats after cooling the vagi to 2-3 “C the response to PDG was little affected. In rabbits Karczewski and Widdicombe (1969) found that the response to PDG, in terms of tidal volume and frequency, was more markedly reduced with vagal cooling to 8-10°C than it was in Dawes’ cats. Guz and Trenchard (1971) found that in rabbits the response to PDG was enhanced when myelinated fibers were blocked through a direct current applied to the vagus. We found that in cats vagal
RAPID SHALLOW BREATHING IN CATS AND RABBITS
151
cooling to 6 “C abolished the tidal volume and frequency response to PDG, whereas, in rabbits the response was greatly reduced but still statistically significant. The former results are at variance with those of Dawes et al. (195 I), whereas, the latter are qualitatively in agreement with those of Karczewski and Widdicombe (1969). Quantitatively, the smaller reduction found by these authors in the response to PDG after vagal block, as compared to us, could be explained by the fact that they used a higher blocking tem~rature. After vagotomy the reflex response to histamine was abolished in both cats and rabbits. This is in agreement with lmdings in rabbits by Karczewski and Widdicombe (1969) and Glogowska and Widdicombe (1973). The postvagotomy response to PDG was abolished in cats confirming data from Dawes et al. (195 1). In rabbits we found that PDG after vagotomy still caused a significant shortening of the expiratory time. In these animals after vagotomy, Guz and Trenchard (1971) found no response to PDG, whereas Karczewski and Widdicombe (1969) found that a small response was still present. Our results agree with the latter finding. In this connection it should be noted that in our rabbits the postvagotomy effect of PDG was essentially due to a reduction of expiratory time and the latter was not different from that caused by PDG during vagal cooling to 6 “C. The fact that the frequency response to PDG was greater with vagi blocked than after vagotomy may be explained considering that the basic frequency of breathing was higher during vagal block than after vagotomy and that there is a hyperbolic relationship between frequency and total duration of the respiratory cycle. In conclusion, also in rabbits we failed to observe a response to PDG as being due to J receptor stimulation when myelinated fibers were blocked. This might suggest that the reflex effect of a change in J receptor discharge is dependent on intact myelinated fibers, although some reduction of this reflex effect should be expected because of the limitation of the maximum transmissible frequency of unmyelinated fibers from stimulated J receptors due to the cold block (Paintal, 1973). Conversely, one could also think that in our animals most of the response to PDG was mediated via irritant receptor stimulation. The results in rabbits are of interest since the tachypnea due to PDG occurs at an increased FRC, i.e. in a condition where the lengthening effect of pulmonary stretch receptors discharge on the expiratory time should be markedly increased. This might suggest that on the one hand J receptor stimulation results in an inhibition of the lengthening effect on TE due to pulmonary stretch receptor discharge and that the latter, on the other hand, is essential for the shortening effect of J receptor stimulation to be seen. This phenomenon is, at present, rather obscure. Deflation rejlex
In our rabbits a comparison could also be done between the pattern of breathing elicited by the deflation reflex and that caused by histamine aerosol. The main difference between the two was that, while histamine greatly affected both the VT US TI and TE USTr relationship; the deflation reflex essentially affected the second.
152
G. MISEROCCHI
et uf.
This might suggest different groups of myelinated fibers involved in response to histamine and deflation. Recently D’Angelo et al. (1976) reported that the classic rapidly adapting irritant receptors cannot be responsible for the deflation reflex. On the contrary, these authors reported that other receptors having myelinated Fibers showed a definite increase of firing during expiration, phenomenologically related to the shortening of expiratory time occurring during the reflex (D’Angelo et al., 1976). These receptors were similar to those described by Luck (1970) in rabbits, by Knowlton and Larrabee (1946) in cats, by Keller and Ferrer (1970) in guinea pigs, and to those defined as ‘intermediate receptors’ by Widdicombe (1954) in cats. Receptors involved in the response to histamine, on the contrary, might be the classic rapidly adapting ones which proved to greatly increase their activity when exposed to this drug (Sellick and Widdicombe, 1971; Mills el ai., 1969). In s~~~ar~~~,the rapid shallow breathing occurring after administration~f histamine aerosol or phenyldiguanide iv. seems to be due, both in cats and rabbits, to a marked decrease of the volume threshold for the inhibition of inspiratory activity (seen as a leftward displacement of the VT vs TI relationship) without a consistent increase in the output of the respiratory centers. The decrease in the volume threshold for inhibition of inspiratory activity is likely to be due to a stimulation of irritant and J receptor endings in the lung.
References Armstrong, D. J. and J. C. Luck (1974). A comparative study of irritant and type-J receptors in the cat. Respir. Physiol. 21 : 47-60.
Bartoli, A., E. Bystrzycka, A. Guz, S. K. Jain. M. 1. M. Noble and D. Trenchard (1973). Studies of the pulmonary vagal control of central respiratory rhythm in the absence of breathing movements. J. Ph~!~io~.(L.mdon) 230: 449465.
Clark, F. J. and C. von Euler (1972). On the regulation ofdepth and rate of breathing. J. PhyJiol. (London) 222: 267-295. D’Angelo, E. and E. Agostoni (1975). Tonic vagal influences on inspiratory duration. Respir. Physiol. 24: 287-302.
D’Angelo, E., G. Miserocchi and E. Agostoni (1976). Effect of ribcage or abdomen compression at iso-lung volume on breathing pattern. Respir. Physiol. 28: 161-177. Dawes, G. S., J. C. Mott and J. G. Widdicombe (1951). Respiratory and cardiovascular reflexes from the heart and lungs. J. Physiof. (condor) 115:258-291. Dawes, G. S. and J. H. Comroe, Jr. (1954). Chemoreflexes from the heart and lungs. Physiol. Rev. 34: 167-201.
Fishman, N. H., E. A. Phillipson and J. A. Nadel (1973). Effect of differential vagal cold blockade on breathing pattern in conscious dogs. J. Appl. Physiol. 34: 754-758. Gautier, H. (1976). Pattern of breathing during hypoxia or hypercapnia of the awake or anesthetized cat. Respir. Physiol. 21: 193-206.
Glogowska, M. and J. G. Widdicombe (1973). The role of vagal reflexes in experimental lung oedema, bronchoconstriction and inhalation of halothane. Respir. Physiof. 18 : I 16128. Guz, A. and D. Trenchard (1971). The role of nonmyelinat~ vagal afferent Bbres from the lungs in the genesis of tachypnoea in the rabbit. J. Physiol. (London) 213: 345-371.
RAPID SHALLOW
Karczewski,
W. A. and J. G. Widdicombe
circulatory responses 201; 271-291. Knowlton,
to intravenous
G. C. and M. G. Larrabee
Physiol. Keller.
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(1969). The role of the vagus histamine
and phenyldiguanide
(1946). A unitary
153
IN CATS AND RABBITS
analysis
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of pulmonary
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volume
and
(London/
receptors.
Am. J.
147: 100-l 14.
E. A. and P. Ferrer
(1970). Studies
reflex. Rrspir.
on the role of the lung deflation
Ph,,sio/.
IO:
172 183. Lourenco,
R. V., N. S. Cherniack,
respiratory
center during
Luck, J. C. (1970). Afferent
J. R. Maim and A. P. Fishman
the obstructed
breathing.
(1966).
Nervous
J. App/. Ph~~siol. 21
: 527-533.
vagal libres with an expiratory
discharge
in the rabbit.
output
J. Ph~siol.
from the (London)
211: 63-71. Mills, J. E., H. Sellick and J. G. Widdicombe embolism, Miserocchi,
anaphylaxis
G. and J. Milic-Emili
the timing Miserocchi, Paintal,
of breathing
Respir.
of breathing.
E. A.
J. A&.
receptors
dust and histamine
aerosol.
Winning,
stimuli and of vagal afferents
to
25: 71-88. afferents
in the control
and their reflex effects. Physiol. pattern
(1971). Stimulation J. Appl. Physiol.
Widdicombe. J. G. (1954). Respiratory 105-I 15. pulmonary
micro-
203: 337-357.
of depth and
independent
Rev. 53: 159-227.
of lung inflation
in conscious
dogs.
37: 1833189.
Sellick, H. and J. G. Widdicombe
Widdicombe.
in pulmonary
(London)
26: 101~1 I I.
(I 974). Vagal control of breathing
Physiol.
Phj+o/.
and central chemosensitive
Physiol.
A. S. (1973). Vagal sensory
Phillipson,
of hypercapnic
cats. Respir.
receptors
J. Physiol.
bronchoconstriction.
(1975). Contribution
in anesthetized
G. (1976). Role of peripheral
frequency
(1969). Activity of lung irritant
and drug induced
J. G. (1961). oedema,
A. J. and J. G. Widdicombe
cats. Respir. Physiol.
of pulmonary
and breathing
27: 253-266.
receptors
by cigarette
smoke, carbon
: 15-19.
reflexes excited by inflation
The activity
atelectasis
of lung irritant 31
against
stretch
of the lungs. J. Ph_vsiol. (London) receptors
a resistance.
during
J. PhJsiol.
123:
bronchoconstriction,
(London)
(1976). The effect of lung reflexes on the pattern
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in
Respiration
(1978) 32, 141LJ53
@ Elsevier/North-Holland
Biomedical
Press
THE MECHANISM OF RAPID SHALLOW BREATHING DUE TO HISTAMINE AND PHENYLDIGUANIDE IN CATS AND RABBITS’
G. MISEROCCHI,
T. TRIPPENBACH, M. MAZZARELLI, M. HAZUCHA
Deparrmeni
In anaesthetized
Abstract.
to histamine
aerosol
a J receptor
stimulant).
of Physio1og.v. McGill
cats and rabbits
(mainly
an irritant
time (TI) relationship
inspiratory
flow rate so that inspiration
VT US Tr relationship breaths central
occurred
(T?) accompanied respiratory
increased
central
and J receptors.
we analyzed
receptor
Both drugs caused
inspiratory
P.Q.. Canada
leftward
threshold
breathing
and i.v. injection displacement curve) without
following
exposure
of phenyldiguanide
(mainly
of the tidal volume a corresponding
was cut off at a lower VT and TI. The leftward
with a great
shortening
of the duration
of the expiratory
respiratory
frequency
displacement
of inspiration
phase (Tg). These parameters
was due to the augmented
of these endings
downwards
also caused
during
occluded the
that the irritant steeper in
in rabbits.
Histamine
Pulmonary
J receptors
Rapid shallow
stretch
receptors
breathing
Vagal cooling
Phenyldiguanide Pulmonary
to become
in
of the
monitored
tiring of fibers from stimulated
the TE OSTI relationship
(VT) us
increase
in absence of the phasic lung volume related vagal loop. It is suggested
Stimulation
cats and to be displaced
Montreal.
the rapid shallow
stimulant)
a marked
(Hering-Breuer
by a shortening
rhythm
Unicersiry.
N. JASPAR and
irritant
receptors
Vagus nerves
Histamine and phenyldiguanide are of interest to respiratory physiologists since these two substances have been shown to stimulate vagal irritants and J receptors, respectively (Paintal, 1973). Excitation of these two types of receptors results in a pattern of breathing which is rapid and shallow. This pattern has been recently analyzed (Winning and Widdicombe, 1976) in terms of a model describing some operational characteristics of the nervous control of the pattern of breathing. This mode1 is essentially based on the firing of pulmonary stretch receptors occurring Accepted for publication
’ Supported
24 August
by MRC of Canada
1977.
and MRC of Quebec. 141
142
G.
MISEROCCHI
et a/.
with each inspiration (Clark and von Euler, 1972). It was found that stimulation of irritant and/or J receptors resulted in a decrease of the Hering-Breuer threshold curve for inhibition of inspiratory activity. In the present paper tigated the phenomenon of rapid shallow breathing by extending to both cats and rabbits.
In addition,
we used the technique
we further invesour observations
of occluding
the airways
at the end expiratory volume to evaluate how afferents from stimulated J and irritant receptors affect the central respiratory rhythm in absence of phasic lung volume related information from pulmonary stretch receptors.
Methods Experiments were done in 11 cats (2.5-3 kg) and 8 rabbits (2.5 kg). Cats were anaesthetized i.p. with sodium pentobarbital (Nembutal, Abbot, 32 mg/kg). Rabbits were anesthetized with 2.5 ml/kg of a mixture consisting of 8.5 ml urethane (25?,,) plus 1.5 ml Nembutal (60 mg/ml). Experiments were done with the animals lying in the supine position, body temperature was maintained by aid of a heating pad. After tracheotomy and tracheal tube insertion, the vagus nerves were exposed in the neck and freed from the surrounding tissues. Catheters were placed into the right femoral artery and the right jugular vein, the latter being advanced into the right atrium. Tidal volume was obtained by electronic integration of the flow signal of a Fleisch # 00 pneumotachograph whose differential pressure was measured by a Sanborn 270 pressure transducer. Tracheal pressure was measured with a 267 Sanborn pressure transducer connected to a side arm of the tracheal cannula. Blood pressure was measured by connecting the femoral catheter to a Statham P23AA pressure transducer. The signals from the transducers were fed into a Honeywell oscillograph for amplification and recording. Histamine aerosol was administered by passing a flow of compressed air through a commercial generator containing a 5 ‘2” solution of histamine in saline. Phenyldiguanide (PDG) was delivered into the right atrium at a dose of 150 pg. To avoid tachyphylaxis, repeated injections of this drug were done at intervals of no less than 20-25 min (Dawes and Comroe, 1954). We used the vagal cooling technique in an attempt to identify the role of the different groups of receptors in the pattern of breathing observed. The literature indicates that both cold and anodal block cannot block fibers from pulmonary stretch receptors without affecting those from irritant receptors (both of which are myelinated) (Paintal, 1973). However, using both techniques it is possible to block most of the myelinated fibers without affecting the unmyelinated ones (J receptors) (Paintal, 1973). We chose the cold-block technique and used a temperature of 6 ’ C which should block all the myelinated fibers. About 1.5 cm of the vagi were placed into the grooves of stainless steel thermodes through which precooled water was passed at an average flow of 600 ml/min. Temperature of the thermodes was measured
RAPID SHALLOW
BREATHING IN CATS AND RABBITS
143
by aid of a thermometer whose bulb was in the thermode itself and assumed to be equal to that of’the nerve. The effects of histamine and PDG were studied in the same animal first with the vagi at body temperature, then cooled to 6 “C and then after vagotomy. In three cats the reflex effects of histamine and PDG were evaluated before and after carotid sinus denervation. Since in rabbits PDG caused an increase in FRC we compared the response to this drug with the pattern of breathing observed by raising the FRC by a similar amount under control conditions. This was obtained by having the animal breathe through a two-way valve,and by placing the expiratory line under water (expiratory threshold load, ETL) so as to increase alveolar pressure by an amount sufficient to raise the end expiratory level as with PDG. An end-expiratory pressure of about 2 cm Hz0 was used. In rabbits we also evaluated the pattern of breathing after eliciting the deflation reflex through a slight manual compression of the rib cage as recently done by D’Angelo rt al., 1976. This caused a reduction in FRC of about 2.5 ml. A similar maneuver in cats always failed to elicit a deflation reflex. Occlusion of the airways was done at the end-expiratory volume to evaluate the duration of inspiration and of expiration in absence of phasic lung volume related vagal afferents. Blood samples were taken from the arterial line during control conditions and during the rapid shallow breathing elicited either by histamine or PDG. Blood gases were analyzed with a Radiometer ~B53~L2 blood microsystem.
Results Ej$xt qf‘hi~tami~e aerosol Administration of histamine aerosol caused in all the animals rapid and shallow breathing within 30-90 sec. In 75”/, of the animals this pattern was preceded by a period of high tidal volumes and inspiratory flow rates. Our analysis will be restricted to the rapid and shallow breathing that remained essentially unchanged as long as the histamine aerosol was administered to the animal. Figures IA and 2A show that histamine aerosol (closed triangles) caused a marked leftward displacement of the VT US TI relationship as compared to the control condition (open circles) both in cats and rabbits. These approximate relationships were obtained by joining the coordinates of unloaded to those of occluded breaths. Since histamine aerosol did not cause any consistent change in the inspiratory flow rate the inspiration was cut off at a smaher VT and at a shorter Tr (tables 1 and 2). Figure IB shows that in cats the expiratory us inspiratory duration relationship with histamine aerosol was displaced to the left and had a steeper slope as compared to control values. In fig. 2C the same relationships for rabbits show that the histamine data are displaced downwards, as compared to control values, but with little change in slope. In both cats and rabbits histamine caused a shortening of TE and T8 (dura-
144
G. MISEROCCHI
ri id.
(set)
-0.09~0.03*
-0.1
receptors,
I *0.01*
from stretch
on TP and T$ only.
** At 6°C owing to the block of fibers
P < 0.05.
-1.97k1.36
-3.33*0.45*
Vagotomy
effects were considered
ml)
0.74*0.15*
- 0.35 + 0.03*
0.05 + 0.06
0.01 kO.04
-0.14+0.04*
0.02 + 0.04
kO.03
aerosol,
kO.13
+0.12*
respectively.
-0.3
-0.58+0.05* -0.19+0.06*
- 1.54 f 0.34*
1.01 ko.31:
0.12*0.02*
0.11+0.08
0
-0.28*0.08*
0.60 f 0.2*
-0.23kO.18
(set)
AT&
1.7*
Accordingly,
-34
-34
-23.32*
6*
5.07*
5.07*
4.06*
6.59*
timing
+12.17*
f
+5
at 6°C and vagotomy
4.76+2
33.3 I f 2.08* 7.08 f 1.45*
49.08f2*
- 15.56+
5
-21.29&
- 17.23 f
14.19*
20.28 f
2.03*
load(ETL)
(mm Hg)
APB
threshold
k SE)
16.93 i 1.83*
- 0.45 + 0.97
-0.12k1.65
14.41&4.32*
- 11.56f3*
- 13.14*2.03*
(cjmin)
Af
(mean
PDG i.v., expiratory
to 6 C and after vagotomy.
histamine
equal to Ti’ andTg,
-0.02kO.04
-0.07~0.05
-0.14*0.04*
0
-0.12f0.02*
ml)**
TI and TE became
-0.47*0.02*
= 5.1 20.82
- 1.17+0.16
Effect of DPG compared with control (AFRC
-2.12+0.91*
- 3.48 f 1.06*
* Significance:
-0.01+0.01
= 5.5 + 1.25 ml)
-0.02+0.01
Effect of PDG compared wiih ETL (AFRC = 0.4kO.4)
-1.21+1.51
Effect of ETL (AFRC
-2.72kO.45’
Effect of deflation (AFRC
= -2.21+0.19
AT: W)
-0.15*0.13
Vagi intact 6°C
Vagi intact
Vagi intact
Vagi intact
0.27&0.15
-0.22&0.09*
and vagotomy;
0.6 kO.91
-0.09+0.02
0.35 k 0.06*
ATE (set)
of: cooling and PDG also after cooling
-0.05~0.05
-0.3
in rabbits
2
k1.21
-2.12k1.06
Effect of histamine**
1.21+ 1.81
4.54 f 0.60*
Effect of cooling and vagotomy**
ATI
AVT
(ml)
6-C
Vagotomy
and on blood pressure
reflex with vagi intact and for histamine
parameters
and deflation
respiratory
Vagi intact
to vagotomy
6°C
to 6°C
Vagi intact
Condition
Effect on various
TABLE
K m
G.
146
MISEROCCHI
et a/.
tion of expiration during occluded breaths). Statistics for the respiratory parameters considered are shown in tables 1 and 2 for cats and rabbits, respectively. Histamine
aerosol
did not
cause
any
appreciable
change
in FRC
which
was
125 +2 (SE) in cats and 105 + 3 ml in rabbits. FRC was measured from the negative pressure generated in the airways during occluded breaths and the corresponding decompression volume according to Boyle’s law. Histamine caused a decrease in systemic blood pressure of 39.65 + 14.07 (SE) and 17.23 f4.06 mm Hg in cats and rabbits, respectively. lCf]kct of’irzjection
of’phenyldiguanide
Injection of phenyldiguanide (PDG) in cats caused a sudden decrease in VT and inspiratory flow rate leading to apnea at the expiratory level. Apnea lasted approximately 2 seconds followed by rapid shallow breathing. Our analysis has been extended to the pattern observed within 15 set from resumption of breathing. Over that period of time the response was waning, being reduced to about 502, of its maximum. The latter occurred within 4-5 set after resumption of breathing. Figure 1 (A, B) shows that in cats the effect of PDG (open triangles) was similar to that of histamine. Injection of PDG in rabbits caused apnea at the end-inspiratory level and during the following rapid and shallow breathing there was a tendency for the
TIME (set)
INSPIRATORY
1.6 z c :
1.2 -
*..;i’ .:)’ A.‘r
z w 0.8 0
1 0.4
I 0.8
I 1.2
INSPIRATORY
I 1.6 TIME
I 2.4
2
(WC)
Fig. 1. Anesthetized cats. A: VT us TI relationships obtained by joining with a straight line the coordinates of unloaded to those of loaded breaths, The true relationship that one could obtain by applying elastic loads to the animal,
would show a slight upward
concavity
which has been neglected
the mean values for all the animals studied. Control conditions (0); i.v. injection of 150 fig of phenyldiguanide (a). B : TE vs TI relationship of unloaded
to those of loaded
breaths.
exposure obtained
Same conditions
here. Points represent
to histamine aerosol (A); by joining the coordinates as in A.
RAPID SHALLOW
Fig. 2. Anesthetized from the detlation
rabbits.
reflex (n)
BREATHING
A: same conditions and
of an added
IN CATS AND RABBITS
147
and symbols as in lig. IA with the addition
expiratory
threshold
load (0).
in A but when plotting absolute volumes on the ordinate.
of results
B: same conditions
C: same as fig.
shown
I B.
animal to go back to its normal FRC. In fig. 2A the VT I’STI relationship obt~~ined in rabbits with PDG (open triangles) shows results similar to those obtained with histamine. In fig. 2B the same relationship was replotted using absolute volumes. Figure 2C shows that in rabbits PDG caused, similarly to histamine, a downward displacement of the TE I‘STI relationship. Statistics for the effect of PDG as compared to control conditions is given in tables I and 2 for cats and rabbits, respectively. Figure 2A shows that ETL (closed circles) affected the VT PS Tr relationship only by causing a shortening of Tf. Figure 2B shows the same results when plotting absolute volumes. Figure 2C shows that ETL caused a great lengthening of TE and T$ tht,s displacing greatly upwards the TE us Tt relationship. Statistical analysis on the effect of ETL, as compared to control conditions, is given in table 2. Table 2 also reports the statistical analysis referring to the comparison between the effects of ETL and PDG. This comparison, of course, would show a greater frequency effect of PDG. Figure 2A, B, shows that the response to a deflation reflex (open squares) was different from that to histamine and PDG in that Tf’ remained essentially unchanged (table 2). Conversely, the deflation reflex caused shortening of T# so that the TE us TI relationship was essentially similarly affected by the deflation reflex as it was by histamine and PDG (fig. 2C).
Figure 3A and B and table I show that in cats cooling the vagus nerves to 6 C caused a lengthening of T? but no substantial change in Tg. Vagotomy, as compared to 6 j C, caused a slight lengthening of T?; neither of these changes, however, were
148
G. MISEROCCHI
2.6 -
et d.
A
CATS 0 I
2.4
A
-
CONTR. HiST
POG
:.>*A$+ .. ...&
_--
*._---
0.6 1
Fig. 3. Anesthetized (0);
histamine
I
“AGl INTmx
6’
cats. A : effect on the duration
aerosol
0.8
“AGOT.
the same conditions
B: effect on the duration as in A. Points represent
Y&GOT.
“AGi INTACT
of inspiration
(A) and of 150 blcgi.v. injection
to 6 C and after vagotomy.
v
during occluded
of phenyldiguanide of expiration
during
(a)
breaths
(TP) of: control
with vagi intact,
occluded
breaths
the mean values of all the animals
cooled
(TE) under
studied.
statistically significant. Figure 4A and B and table 2 show the corresponding results for rabbits. Vagal cooling caused a slight lengthening of 1-P but a definite shortening of Tfi. Vagotomy, as compared to cooling, caused a slight lengthening of T?, but a marked lengthening of Tg. Results show that after cooling and thus also after vagotomy, in both cats and rabbits, the effect of histamine on Tf and T# was no longer significant. In cats this applied also to PDG. In rabbits the effect of PDG at 6 “C and after vagotomy was compared to control values since after block of the myelinated fibers the effect of ETL disappeared (table 2). Figure 4 shows that after cooling to 6 C, the shortening effect of PDG on Tf disappeared, whereas that on T?! was still present although greatly reduced. After vagotomy PDG still caused a significant decrease in T! but this decrease was not significantly
.
fl4TICT
#“TACT
Fig. 4. Anesthetized
rabbits.
A, B: same as fig. 3, A, 3. With vagi intact data referring to the deflation
reflex (0)
were also plotted.
to ETL (0)
and
RAPID
SHALLOW
BREATHING
IN CATS AND
RABBITS
149
different from the one occurring at 6,-C. The deflation reflex disappeared after cooling and vagotomy. Vagal cooling caused in both cats and rabbits an increase in blood pressure (tables 1 and 2) which was further increased by vagotomy. Histamine caused a significant decrease in blood pressure during vagal blockade in both cats and rabbits. A further decrease was observed after vagotomy in cats. In cats PDG caused a reduction in blood pressure both with vagi cooled and after vagotomy. In both conditions the response was less than with vagi intact. In rabbits the hypotensive effect of PDG was unaffected by either vagal cooling or vagotomy. In three cats we found that during the response to histamine or PDG the respiratory parameters were similarly affected before and after sinus denervation, suggesting that under conditions of irritant and J receptor stimulation, baroreceptor discharge did not significantly affect respiration. Blood gases
In cats during rapid shallow breathing elicited by both histamine and PDG, there was an increase in Pa,, 2 from 25.4? 1.I (SE) to 29.2kO.7 mm Hg and a decrease in Paol from 97.8f 1 to 69.7+ 1.2 mm Hg. This could be related to an almost 500/, decrease in VT, the increased frequency being not enough to counterbalance the drop in alveolar ventilation. In rabbits the decrease in VT was less and accordingly, we did not find significant changes in blood gases during rapid shallow breathing with histamine and PDG. ETL in rabbits increased Paco2 from 3lk2.1 (SE) to 36+2.5 mm Hg and decreased Paoz from 75 f 1 to 59.7+2 mm Hg.
Discussion Mechanism of rapid shallow breathing
The present results clarify the mechanism by which rapid shallow breathing is generated after histamine aerosol or injection of PDG. This pattern was observed as a leftward displacement of the VT c’sTI relationship without a corresponding increase in inspiratory flow rate. This displacement implies a decrease in the volume threshold for inhibition of inspiratory activity (Clark and von Euler, 1972). A shorter expiratory time corresponded with a decreased inspiratory time (Clark and von Euler, 1972). These conclusions are similar to those recently reached by Winning and Widdicombe (1976). A leftward displacement of the VT 6s TI relationship has been described by Miserocchi and Milic-Emili (1975) as being caused by hypercapnia, however, in the latter condition, there was, unlike under histamine or PDG stimulation, a great increase in the inspiratory flow rate. In cats we found that under steady conditions of rapid shallow breathing, end tidal P~co~ increased so that we cannot exclude a role played by CO, on displacing the VT us TI relationship to the left. However, due to CO, stimulation, the mean inspiratory flow should have increased, but it was not observed in our study. The relative hypoxia developed in anesthetized cats during
150
G. MISEROCHHI
et af.
rapid shallow breathing should, on the other hand, not have affected the VT us Tr relationship (Gamier, 1976; Miserocchi, 1976). Results from sinus denervation experiments suggest that, at least in cats, a decrease in baroreceptor discharge was unlikely to be responsible for the observed changes in respiratory pattern. A possible explanation for this displacement may reside in an effect of histamine and PDG on vagal activity at FRC resulting in shortening of T? and Tg. Widdicombe (1961) found that inhalation of histamine aerosol caused sensitization of pulmonary stretch receptors. However, an increased firing from these receptors should cause a slight decrease in T? (D’Angelo and Agostoni, 1975) but a lengthening of Tg (Lourenco et al., 1966; Bartoli et al., 1973; D’Angelo and Agostoni, 1975). PDG, on the contrary, was proved not to influence pulmonary stretch receptors discharge (Dawes and Comroe, 1954). Thus, our findings with histamine and PDG may be explained by irritants and/or J receptor stimulation. Vagal cooling and vagotomy
Block of afferent myelinated fibers of the vagus resulted in a consistent lengthening of T? in cats but in a very slight one in rabbits. Conversely, it caused a much more marked shortening of Tg in rabbits than in cats. These results are consistent with the general view that in anaesthetized animals the effect of stretch receptors is that of shortening T! but lengthening T$. Vagotomy, as compared to vagal block, caused a further lengthening of T?, greater in cats than in rabbits, but a lengthening of Tg much more marked in rabbits than in cats. These results show that some effect of unmyelinated afferents was present in our animals under control conditions. This effeci was a shortening one on the duration of the respiratory phases and confirms data by Fishman et al. (1973) and by Phillipson (1974) in awake dogs and by D’Angelo et al. (1976) in anesthetized dogs, cats and rabbits. Data from figures 3 and 4 indicate that a basic difference exists between cats and rabbits in that vagal afferents affect the central respiratory rhythm mainly through a modulation of the inspiratory time in cats and of the expiratory time in rabbits. Our results show that in both cats and rabbits the response to histamine and PDG was significantly diminished following vagal cooling to 6 ‘C. As far as histamine is concerned this is in line with other findings in rabbits (Karczewski and Widdicombe, 1969; Glogowska and Widdicombe, 1973). Moreover, vagal single-fiber recording showed that histamine acts mainly on irritant receptors (Mills et a/., 1969; Sellick and Widdicombe, 1971; Armstrong and Luck, 1974) although some stimulating effect on J receptors was also found (Paintal, 1973). As for phenyldiguanide, there are conflicting results in the literature. Dawes et al. (195 1) mentioned that in cats after cooling the vagi to 2-3 “C the response to PDG was little affected. In rabbits Karczewski and Widdicombe (1969) found that the response to PDG, in terms of tidal volume and frequency, was more markedly reduced with vagal cooling to 8-10°C than it was in Dawes’ cats. Guz and Trenchard (1971) found that in rabbits the response to PDG was enhanced when myelinated fibers were blocked through a direct current applied to the vagus. We found that in cats vagal
RAPID SHALLOW BREATHING IN CATS AND RABBITS
151
cooling to 6 “C abolished the tidal volume and frequency response to PDG, whereas, in rabbits the response was greatly reduced but still statistically significant. The former results are at variance with those of Dawes et al. (195 I), whereas, the latter are qualitatively in agreement with those of Karczewski and Widdicombe (1969). Quantitatively, the smaller reduction found by these authors in the response to PDG after vagal block, as compared to us, could be explained by the fact that they used a higher blocking tem~rature. After vagotomy the reflex response to histamine was abolished in both cats and rabbits. This is in agreement with lmdings in rabbits by Karczewski and Widdicombe (1969) and Glogowska and Widdicombe (1973). The postvagotomy response to PDG was abolished in cats confirming data from Dawes et al. (195 1). In rabbits we found that PDG after vagotomy still caused a significant shortening of the expiratory time. In these animals after vagotomy, Guz and Trenchard (1971) found no response to PDG, whereas Karczewski and Widdicombe (1969) found that a small response was still present. Our results agree with the latter finding. In this connection it should be noted that in our rabbits the postvagotomy effect of PDG was essentially due to a reduction of expiratory time and the latter was not different from that caused by PDG during vagal cooling to 6 “C. The fact that the frequency response to PDG was greater with vagi blocked than after vagotomy may be explained considering that the basic frequency of breathing was higher during vagal block than after vagotomy and that there is a hyperbolic relationship between frequency and total duration of the respiratory cycle. In conclusion, also in rabbits we failed to observe a response to PDG as being due to J receptor stimulation when myelinated fibers were blocked. This might suggest that the reflex effect of a change in J receptor discharge is dependent on intact myelinated fibers, although some reduction of this reflex effect should be expected because of the limitation of the maximum transmissible frequency of unmyelinated fibers from stimulated J receptors due to the cold block (Paintal, 1973). Conversely, one could also think that in our animals most of the response to PDG was mediated via irritant receptor stimulation. The results in rabbits are of interest since the tachypnea due to PDG occurs at an increased FRC, i.e. in a condition where the lengthening effect of pulmonary stretch receptors discharge on the expiratory time should be markedly increased. This might suggest that on the one hand J receptor stimulation results in an inhibition of the lengthening effect on TE due to pulmonary stretch receptor discharge and that the latter, on the other hand, is essential for the shortening effect of J receptor stimulation to be seen. This phenomenon is, at present, rather obscure. Deflation rejlex
In our rabbits a comparison could also be done between the pattern of breathing elicited by the deflation reflex and that caused by histamine aerosol. The main difference between the two was that, while histamine greatly affected both the VT US TI and TE USTr relationship; the deflation reflex essentially affected the second.
152
G. MISEROCCHI
et uf.
This might suggest different groups of myelinated fibers involved in response to histamine and deflation. Recently D’Angelo et al. (1976) reported that the classic rapidly adapting irritant receptors cannot be responsible for the deflation reflex. On the contrary, these authors reported that other receptors having myelinated Fibers showed a definite increase of firing during expiration, phenomenologically related to the shortening of expiratory time occurring during the reflex (D’Angelo et al., 1976). These receptors were similar to those described by Luck (1970) in rabbits, by Knowlton and Larrabee (1946) in cats, by Keller and Ferrer (1970) in guinea pigs, and to those defined as ‘intermediate receptors’ by Widdicombe (1954) in cats. Receptors involved in the response to histamine, on the contrary, might be the classic rapidly adapting ones which proved to greatly increase their activity when exposed to this drug (Sellick and Widdicombe, 1971; Mills el ai., 1969). In s~~~ar~~~,the rapid shallow breathing occurring after administration~f histamine aerosol or phenyldiguanide iv. seems to be due, both in cats and rabbits, to a marked decrease of the volume threshold for the inhibition of inspiratory activity (seen as a leftward displacement of the VT vs TI relationship) without a consistent increase in the output of the respiratory centers. The decrease in the volume threshold for inhibition of inspiratory activity is likely to be due to a stimulation of irritant and J receptor endings in the lung.
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