(Received 30 April 1947)

Transcription

1 107 J. Physiol. (I948) I07, I07-II I3I-3I:6i2.288 THE ACTION OF PHOSGENE ON THE STRETCH RECEPTORS OF THE LUNG BY D. WHITTERIDGE From the University Laboratory of Physiology, Oxford (Received 30 April 1947) Since the classical paper of Laquer & Magnus (1921), no attempt seems to have been made to account for the respiratory effects produced during exposure to phosgene. This work of Laquer & Magnus has been used to support one of the current hypotheses on the nature of dyspnoea, that it is due to sensitization of the stretch endings in the lung (Christie, 1938). This hypothesis seems to be contrary to a number of experimental observations (Biilbring & Whitteridge, 1945; Whitteridge & Biilbring, 1944; Walsh & Whitteridge, 1945). On the other hand, the view put forward by Schmidt (1941) that dyspnoea is due to excitation of excito-inspiratory fibres throughout the respiratory cycle, though satisfying, is based on very tenuous evidence of the nature of these fibres. It was therefore thought desirable to observe directly the effect of exposure to phosgene on the activity of pulmonary stretch endings. METHODS Single-fibre preparations of pulmonary stretch fibres have been obtained by dissection of the vagal trunk in the neck in cats. In decerebrate animals, the fibres were dissected from a slip of the trunk, the larger part of which was preserved. The nerve impulses were made audible by a-conventional amplifier and loud speaker and recorded with a cathode-ray tube and camera. The volume changes in the chest in the spinal animals were produced by ventilation with an all-metal respiratory pump of known stroke volume. Decerebrate cats were enclosed in a metal plethysmograph with the tracheal tube opening externally, and the volume changes in the plethysmograph were recorded by a Krogh spirometer. Its excursions were checked by introducing known quantities of air into a closed circuit made by the spirometer, the plethysmograph and the respiration pump. Owing to the inertia of the moving parts of the spirometer and to wave formation in the water in the tank, amplitudes recorded at rates above 90 per min. are unreliable. Approximately known concentrations of phosgene vapour were prepared by introducing measured quantities of pure phosgene into partially evacuated dry bottles of about 151. capacity, and then allowing-air to enter. The animals were made to rebreathe from these bottles. As the exposure was limited to few minutes no attempt was made to absorb carbon dioxide. Control observations were made on the effect of rebreathing from the bottles in the absence of phosgene. All animals were given 2 mg. atropine subcutaneously. After decapitation or decerebration under ether, time was allowed for the anaesthetic to blow off before beginning observations. When

2 108 D. WHITTERIDGE it was necessary to prevent spontaneous movement in decerebrate animals; small doses of nembutal, or preferably chloralose, 10 mg./kg. were given. In some experiments, pleural pressure below the sternum was recorded by a wide-bore needle with air transmission to a sensitive membrane manometer. Activity in the diaphragm was sampled by- a hypodermic needle electrode pushed into the xiphisternal head and tied into position. RESULTS The effect of phosgene on pulmonary stretch endings was first followed in spinal cats ventilated artificially with constant volumes of air. In different experiments, the phosgene concentration varied from 1/50,000 to 1/2000, with an exposure of 5 min. Preparations which gave the simple response to stretch attributable to a single unit were made from the vagus and on these the effect of phosgene was compared with that of various volatile anaesthetics administered immediately before or after. Although the usual increases in the response of the stretch endings to inflation were seen with the anaesthetics (Whitteridge & Biilbring, 1944), there was no consistent change during exposure to phosgene. The fluctuations in the rate of discharge during exposure were considerably greater than they were in the control period beforehand (Fig. 1). Two of the animals developed pulmonary oedema, and one died within 2 hr. It therefore seemed that the dosage was adequate. These negative results could perhaps be attributed to the unphysiological condition of the respiratory mechanisms in spinal cats, and it was felt that the observations should be extended to cats which were breathing spontaneously. Decerebrate animals were used with both vagi preserved as far as possible, with a small slip cut from the side of one vagus for recording purposes. When a single-fibre preparation was- on the electrodes, the cat was enclosed in the plethysmograph, which was made airtight, with the tracheal tube connected to the external air. The tracheal tube could also be connected through valves to wide-bore tubes ending at opposite ends of the reservoir bottle. A side tube connected to a small balloon minimized respiratory pressure fluctuations. Control observations on the effect of rebreathing from the bottle when it contained room air, showed that there was a decrease or an increase in the respiratory rate of not more than 8 breaths per min. after 5 min., with an increase in the volume of air in the chest at expiration, namely the functional residual air, of 5-10 ml. Of fourteen such experiments, phosgene had no effect on the rate or depth of respiration in six. In the remaining experiments there was always an increase in the rate of respiration and in the functional residual air, but the depth sometimes increased and sometimes decreased. There was always an increase in the minute volume of air breathed. On occasion, the increase in the functional residual air amounted to as much as 70 ml. After removal of the phosgene, the rate and depth returned to their initial values, but the functional residual air remained at a higher level for some time.

3 PHOSGENE AND PULMONARY STRETCH RECEPTORS 109 Some attempt was made to discover the nature of this insensitivity to phosgene shown by six of these decerebrate cats. It did not seem to be related to the level of the transection, and its appearance was unpredictable. Insensitive animals tested were also found to be insensitive to trichlorethylene and to carbon dioxide, neither of which modified the rate or depth of respiration i 160 e Time in minutes Fig. 1. Spinal cats ventilated with constant volumes of air. Changes in peak frequency of discharge of stretch fibres as percentage of normal, plotted during exposure to phosgene (0), and to cyclopropane, chloroform and ether (0). Phosgene and the anaesthetics were administered for 5 min., except in those cases in which the return of the fibre activity to the base line is not shown. The decerebrate cats were exposed to concentrations of phosgene of 1/10,000 to 1/5000. Two of those which showed an immediate respiratory acceleration were allowed to survive for 4-6 hr. The resting respiratory rate rose steadily during this time to per min. Bilateral vagotomy reduced the resting respiratory rate to 20 per min., a rate which is perhaps within normal limits. After bilateral vagotomy, further exposure to phosgene had no more effect on

4 110 D. WHITTERIDGE respiration than had rebreathing from the bottle containing room air. Cooling of both vagi to 00 C. during the administration of phosgene reversibly abolished the respiratory changes, and section of the vagi and the injection of nembutal Fig. 2a. A 1 IV Fig. 2 b. Figs. 2 a, 2 b. Decerebrate cat, phosgene 1: 7500 administered for 4 min. from t to 4,. A, B and C in Fig. 2a correspond to A, B and C in Fig. 2b. In Fig. 2a, B and C, from above down, are records of the E.c.G. (inverted), a vagal stretch fibre, the intra-pleural pressure (a fall =more negative pressure), and time in 1/100th and 1/10th sec. The pleural pressure record is omitted in A, Fig. 2 a. Fig. 2 b is a record of the respiration from the body plethysmograph. Time in sec. (10 mg./kg.) abolished them irreversibly. It was therefore evident that an intact vagus nerve was essential for the appearance of these phenomena, and an attempt was made to find signs of increased centripetal activity in its fibres.

5 PHOSGENE AND PULMONARY STRETCH RECEPTORS 111 As the amount of air in the chest was likely to increase considerably during these experiments, it was first necessary to determine the effect on the ending of an increased lung volume without phosgene. This was done by blowing measurable volumes of air into the chest, or by making the animal breathe more deeply by administering mixtures containing increased amounts of C02. By itself, C02 has no effect on the sensitivity of endings (Adrian, 1933). The peak frequencies of discharge were then plotted against the change in lung volume. An increase in the slope of this curve would then indicate an increase in the sensitivity of the ending, while the vertical displacement of the curve, without change in slope, would indicate a change in the initial level of excitation of the ending. Lung volume (ml.) Fig. 3. Decerebrate cat, exposed to 10% 02 and 10% CO2 (@), to phosgene 1: 10,000 (0) and to 1: 5000 (0). Peak frequency of discharge of a stretch fibre plotted against changes in lung volume. In calculation of the regression line for CO the points from the four largest breaths have been omitted. In general, small increases and small decreases in sensitivity have been seen during and after exposure to phosgene, but there have been no changes comparable with those seen with the volatile anaesthetics (Whitteridge & Biilbring, 1944). In the experiment shown in Fig. 3, for example, with the lower conce5tration of phosgene, there was no change at all in the activity of the ending

6 112 D. WHITTERIDGE at a time when the respiratory acceleration was well marked. With higher concentrations of phosgene, and resulting large increases in the functional residual air, the endings undergo a considerable amount of adaptation. In Fig. 2 the discharge ceases at expiration even at the height of the effect of phosgene, although the lungs then contain as much air as at the peak of inspiration before the administration of phosgene. Adaptation of endings during the maintained increase in functional residual air due to phosgene is also seen in Fig. 4. Here the ending continued to discharge throughout expiration, and its activity decreased, although the lung volume at the end of expiration had increased by 20 ml Lung volume (ml.) Fig. 4. Decerebrate cat, before (0), during (O), and after (c3), exposure to phosgene, 1: Peak frequency of discharge of a single stretch ending plotted against change in lung volume. This fibre continued to discharge throughout expiration. Some evidence of the mode of production of this conspicuous increase in functional residual air was obtained by recording the intrapleural pressure and the activity of motor units in the diaphragm. The intrapleural pressure usually becomes more negative both at inspiration and at expiration, and the diaphragm goes into continuous activity (Fig. 5). After exposure, the changes in intrapleural pressure and diaphragmatic activity both persist to some extent, as does the increase in the functional residual air. During asphyxia, similar increases in functional residual air have been reported by Verzar (1946) and by Harris (1945). DISCUSSION The effects of phosgene on the lung tissue are seldom evenly distributed and, in these experiments, patchy collapse and compensatory overdistension of alveoli was frequently seen in sections of the lungs, even when there was no visible oedema. Some increase in the fluctuations in the rate of discharge of

7 PHOSGENE AND PULMONARY STRETCH RECEPTORS 113 stretch fibres is therefore to be expected, and it is necessary to observe activity in as large a number of fibres as possible. In the spinal cats, there was no Fig. 5a. Decerebrate cat, exposed to phosgene, 1: 8000 from t to 4,. A, B, C and D in Fig. 5a correspond to A, B, C and D in Fig. 5b. Fig. 5a shows records of diaphragmatic activity beginning with an inspiration. Time in 1/10 sec. ):II1. '- LJ I, Fig. 5b. Records of respiration from the body plethysmograph. evidence of sensitization of stretch endings, and, in the decerebrate animals, respiratory acceleration occurred when there was no change in the activity of the stretch fibre observed. In the other decerebrate cats it is only possible to PH. CVII. 8

8 114 D. WHITTERIDGE say that if there was any sensitization it occurred at a rate slower than the adaptation of the endings. There is, therefore, no experimental support for the theory of the nature of dyspnoea advanced by Christie (1938). Although a number of other fibres of pulmonary origin exist in the cervical vagus (Partridge, 1939; Hammouda, Samaan & Wilson, 1943), some of whose electrical activity has been recorded (Whitteridge, unpublished observations), unfortunately none of these fibres were present in the vagal slips used in these experiments. SUMMARY 1. The effect of phosgene on the pulmonary stretch endings has been investigated in spinal and decerebrate cats. 2. No sensitization of these fibres has been seen. 3. No alternative explanation of the part played by the vagus in these respiratory changes is at present available. The author wishes to thank Prof. C. G. Douglas, F.R.S., for his constant help and advice, and the Chief Scientist, Ministry of Supply, for permission to publish. REFERENCES Adrian, E. D. (1933). J. Physiol. 79, 332. Bailbring, E. & Whitteridge, D. (1945). J. Physiol. 103, 477. Christie, R. V. (1938). Quart. J. Med. 31, 421. Hammouda, M., Samaan, A. & Wilson, W. H. (1943). J. Physiol. 101, 446. Harris, A. S. (1945). Amer. J. Physiol. 143, 140. Laquer, E. & Magnus, R. (1921). Z. ges. exp. Med. 13, 31. Partridge, R. C. (1939). J. Physiol. 96, 233. Schmidt, C. F. (1941). MacLeod's Phy8iology in Modern Medicine. London. Verzar, F. (1946). H6hen Klima Forechungen. Basle. Walsh, E. G. & Whitteridge, D. (1945). J. Physiol. 103, 370. Whitteridge, D. & Builbring, E. (1944). J. Pharmacol. 81, 340.