The location and excitation of pulmonary deflation receptors by chemical substances

1. Deflation fibres from the intact chest of the cat can be identified by observing that inflation of the lungs abolishes the discharge produced by phenyl diguanide and that this discharge reappears when the lungs collapse. 2. Some deflation receptors in the intact chest were stimulated by collapse of the lungs without chemical sensitization. This indicates that in some cats these receptors may be activated normally during rapid expiratory efforts. 3. The injection-discharge time shortened as the dose of phenyl diguanide injected into the right atrium was increased. However, increasing the dose did not influence the intensity of the discharge. 4. The stimulating effect of 5-hydroxytryptamine was not affected by a previous injection of dibenzyline; in this respect deflation receptors differ from smooth muscle. 5. Nicotine and urethane stimulated and sensitized the deflation receptors. The injection-discharge time was shorter than that following phenyl diguanide. Unexpectedly, however, the duration and intensity of the discharge produced by nicotine and urethane were also shorter than those produced by phenyl diguanide. 6. Acetylcholine stimulated and sensitized some deflation receptors. This response was abolished by atropine. The injection-discharge time following acetylcholine was greater than that following phenyl diguanide. In other respects the discharges produced by the two substances were similar. It was concluded that the activation time of acetylcholine for stimulating deflation receptors is the longest, and that of nicotine and urethane the shortest; phenyl diguanide and 5-hydroxytryptamine occupy an intermediate position. 7. Large doses of potassium chloride and veratrum alkaloids did not stimulate the receptors. 8. Discharges in deflation fibres were again shown to produce reflex slowing of the heart. 9. Insufflation of the lungs with ether, trichlorethylene and chloroform stimulated and sensitized the deflation receptors. This was followed by depression or total loss of excitability of the receptors. A varying degree of depressed excitability was also found after all the chemical substances which stimulated the deflation receptors. 10. The results have provided conclusive evidence that the deflation receptors are located in the respiratory bronchioles, atria or the alveoli

Re-evaluation of respiratory reflexes

In cats anæsthetized with chloralose it was found that below about 18° C. the rhythmic pattern of discharge in low-threshold pulmonary stretch fibres is reversed in relation to the respiratory cycle. This reversed pattern is apparently responsible for the reversal of the Hering Breuer inflation reflex (Head's paradoxical reflex). Evidence favouring this is that reflex inhibition of respiration, produced by high frequency electrical stimulation of pulmonary stretch fibres applied against a background of low frequency stimulation, is converted to excitation between 9 and 11° C. Head's paradoxical reflex appears when the total discharge in low- and higher threshold pulmonary fibres during inflation becomes less than the total discharge in the former before inflation. A nomogram showing the relation between temperature and the peak frequency of a train of impulses in fibres of different conduction velocities is presented. The likely mechanism responsible for the quantitative variation of the inflation reflex (and its reversal) with temperature is given

A method of locating the receptors of visceral afferent fibres

This article does not have an abstract

A comparison of the nerve impulses of mammalian non-medullated nerve fibres with those of the smallest diameter medullated fibres

1. Filaments were dissected from the aortic nerve of cats and impulses recorded monophasically in vivo. 2. The temporal characteristics of impulses of non-medullated fibres were compared with those of medullated fibres with conduction velocities between 4·5 and 12 m/sec. There were no obvious qualitative differences between the two types of fibres and they appeared to belong to a homogeneous sample. 3. In non-medullated fibres the rise time, fall time and absolute refractory period varied inversely with conduction velocity, the relation being similar to that in the medullated fibres. There was practically no difference between the temporal characteristics of the fastest non-medullated fibres and those of the slowest medullated fibres, a result which might throw light on the question why fibres below 1 μ in diameter are not medullated. 4. The mean blocking temperature of sixteen non-medullated fibres was 4·3°C, a value that was significantly different from the mean blocking temperature of sixteen medullated fibres (6·5°C)

Mechanism of stimulation of aortic chemoreceptors by natural stimuli and chemical substances

1. Impulses were recorded in single fibres of aortic chemoreceptors of cats anaesthetized with chloralose. There was no demonstrable difference between the responses of the endings of medullated and non-medullated fibres respectively to any of the natural stimuli, such as hypoxia, reduction in blood pressure, or reduction in O2 content. This indicates that the generator processes are qualitatively and quantitatively identical at the endings of both types of fibres. 2. Most of the endings were practically silent while ventilating the lungs with air. The maximum frequency of discharge averaged over 4-10 sec while ventilating the lungs with 4% O2 ranged from 1·5 to 24 impulses/sec; in most fibres (twenty-one out of twenty-six endings) it was less than 12 impulses/sec. 3. All the chemoreceptors tested were considerably stimulated following administration of 0·2 or 2% CO at a time when the O2 content was greater than 4 ml./100 ml. 4. All the chemoreceptors were markedly and rapidly stimulated following circulatory arrest while the cat was ventilated with air. This stimulation fell considerably within 3 min of circulatory arrest. Very little or no excitation followed circulatory arrest while ventilating the cat with pure N2. These results suggest that excitation following circulatory arrest is not produced by a metabolite. 5. There was a remarkable difference between the sensitivities of endings of medullated and non-medullated fibres to drugs. The former were either unaffected by relatively large doses of ACh (100-200 μg) or phenyl diguanide, or if they were stimulated, the excitation so produced was much less than that produced in endings of non-medullated fibres. This supports the hypothesis that drugs produce their effects by an action at the regenerative regions of the endings, i.e. regions where the nerve impulse is initiated (Paintal, 1964). It also indicates that ACh is not likely to be a transmitter in the normal processes of excitation of chemoreceptors. 6. A mechanism of stimulation of chemoreceptors not involving metabolites is presented

Impulses in vagal afferent fibres from specific pulmonary deflation receptors. The response of these receptors to phenyl diguanide, potato starch, 5-hydroxytryptamine and nicotine, and their rôle in respiratory and cardiovascular reflexes

1. The endings of certain vagal afferent fibres have been located in the lungs, using the method of locating visceral receptors described recently [Paintal, 1954 a). These receptors were sensitized specifically by pulmonary deflation. 2. The fibres were found to be normally inactive. With the cats' chest intact it was sometimes possible to evoke a rapidly adapting discharge of impulses by suction of air from the trachea or by collapse of the lungs with open chest. The receptors were unaffected by anoxia but they could be sensitized by congestion of the lungs. 3. The action potentials of these fibres were the smallest yet observed in vagal afferent fibres; in most deflation fibres the potentials barely exceeded the base-line noise level. It is estimated that the conduction velocities of the majority of the fibres are below 6 m./sec. 4. The receptors were stimulated by injection of phenyl diguanide, starch, nicotine and 5-hydroxytryptamine. Some of the receptors yielded considerably reduced responses following subsequent injections of phenyl diguanide, but the majority of them were little affected. 5. The injection-discharge time following rapid injections of phenyl diguanide into the right atrium of cats with intact chest ranged from 0·9 to 2·7 sec. With open chests the injection-discharge time could be varied by injecting the drug during different phases of artificial respiration; the values were increased when the drug was injected during inflation of the lungs. The drug sensitized the receptors from 7 to 21 sec. 6. Apart from the usual response of respiratory inhibition, phenyl diguanide on many occasions gave rise to respiratory acceleration without the initial period of apnœa. This response could be elicited more frequently by small doses of phenyl diguanide, but it could also be produced by large doses injected slowly. 7. Nicotine, starch and HT gave rise to early reflex respiratory and cardiac responses identical with those following phenyl diguanide. 8. It is suggested that the deflation receptors are primarily responsible for producing reflex respiratory acceleration (rapid shallow breathing) and that they cause respiratory inhibition when greatly stimulated by drugs. They may also take part in the reflex bradycardia following injections of the drugs used in this investigation. 9. The receptors are not connected with the bronchial circulation or with any part of the broncho-pulmonary shunt, but with the pulmonary circulation. They are probably situated near the alveoli. 10. In many cats the deflation fibres were encountered grouped in bundles. At present the only way of isolating them is by injecting drugs which stimulate them. 11. These deflation receptors are quite different from the so-called deflation receptors described previously [Adrian, 1933; Paintal, 1953 b]

Natural stimulation of type B atrial receptors

This article does not have an abstract

Study of respiratory and cardiovascular reflex mechanisms involving the lungs

In the present study of Respiratory and cardio- vascular reflexes of the lungs attention has been particularly directed to the afferent mechanisms involved. This was considered necessary since there is little definite information about the nature of these fibres although much is now known about the jpossible reflexes in which they may participate. with this object a first attack on the problem was made as described in the first part of this thesis by the determination of the conduction velocities of the known vagal thoracic afferents. It is hoped that information so gained will be of value in the interpretation of results of previous investigators. The second part of the thesis presents the results of investigation into the afferent fibre composition of the vagal rootlets as studied by the electrical recording of nerve impulses. This was undertaken because it was hoped that a functional differentiation of the vagal afferents might occur at this level as suggested by the work Beer & Kreidl (1895) and Cadman (I9OO), and thereby provide a means of selective stimulation. This was found not to be the case and further investigation in that field was therefore discontinued. From the work of Dawes, Matt, and Widdicombe (I951) it appeared that certain araidines such as phenyl diguanide are capable of producing a reflex respiratory inhibition which is blocked by cooling the vagi to 31°C. Because of the low blocking temperature it seems possible that this drug affords the means of selective stimulation of small afferents of trie vagus and as will be shown in the 3rd section, this is certainly true. Further in order to test the hypothesis of Dawes et al that the pulmonary vascular afferents described by Whitteridge (1948) were probably concerned in the above reflex, the action of phenyl diguanide on these and other afferents has been studied. Evidence will be presented to indicate that none of the known vagal afferents including the pulmonary vascular ones are sensitized or stimulated by phenyl diguanide

The influence of the sympathetic outflow on aortic chemoreceptors of the cat during hypoxia and hypercapnia

1. An attempt has been made to reconcile differing observations, made by different groups of investigators, on the responses of aortic chemoreceptors of cats during normoxia, hypoxia and hypercapnia. 2. In cats anaesthetized with sodium pentobarbitone it was observed that during hypoxic stimulation of twelve chemoreceptors, an intravenous injection of about 20 mg sodium pentobarbitone produced hypotension which was accompanied by an initial fall in chemoreceptor activity instead of the expected increase that invariably occurred in all the receptors when hypotension was produced mechanically by distending a balloon in the right atrium (twenty-six during normoxia, eleven during hypoxia and eight during hypercapnia). 3. In twelve receptors a reflex fall in blood pressure produced by injecting 8-25 μg veratridine (Bezold-Jarisch reflex) yielded results qualitatively similar to those following injection of sodium pentobarbitone. 4. In sixteen out of twenty-five chemoreceptors it was observed that ventilating the cat with 5.6-6.7 % CO2 produced either no or little increase in activity; in nine receptors there was a clear increase in activity, which fell initially or was abolished after injecting a single dose of 20 mg sodium pentobarbitone. 5. In all seven chemoreceptors tested in seven deeply anaesthetized cats it was found that a larger dose (about 50-60 mg) of sodium pentobarbitone had no direct depressant effect on aortic chemoreceptor activity. It followed that the initial depressant effect of the much smaller doses of sodium pentobarbitone observed during hypoxic and hypercapnic stimulation (see above) must be due to reduction in the sympathetic outflow to the aortic bodies. This conclusion was supported by the results following injections of veratridine. 6. By comparing the present results with those reported previously it was concluded that the variations in the responses of aortic chemoreceptors during hypoxia and hypercapnia reported by different investigators could be partly due to variations in the level of sympathetic activity prevailing under different experimental conditions

Factors affecting movement of excitatory substances from pulmonary capillaries to type J receptors of anaesthetized cats

1. Using phenyl diguanide (PDG) as an excitatory substance, the role of certain factors that could influence the movement of such substances across the pulmonary capillaries to the J receptors was studied in cats anaesthetized with sodium pentobarbitone. This was aided by using a new method for estimating continuously in vivo the concentration (C) of PDG in the blood of the pulmonary artery. 2. Reduction of pulmonary blood flow by partial occlusion of the inferior vena cava enhanced the responses of the J receptors to PDG significantly in twelve out of thirteen trials. These effects, which occurred at a time when pulmonary capillary pressure (PCP) had fallen, could be related to the increase in the estimated mean C of PDG over the first 3 s or to the C t (concentration × time) area to 50% of peak C. The responses bore no relation to peak C or rate of rise of C. 3. The responses of the receptors to PDG increased significantly after three out of eight injections of PDG while the PCP was raised by partial occlusion of the mitral orifice; reduced responses were recorded after two injections. These results, showing relatively much weaker stimulation by PDG in spite of the enhanced level of J receptor excitability produced by the raised PCP itself, suggest that movement of PDG out of the capillaries to the J receptors must be influenced primarily by forces governing diffusion, not filtration. 4. In addition to C of PDG there appear to be other factors that influence the responses of the receptors to PDG