Experimental observations on the histamine-provoked asthmatic attack in the guinea pig

Abstract

A series of experimental investigations are done on asthma in the guinea-pig, provoking attacks with histamine and acetylcholine.

Experiments in controlled respiration. — Controlled respiration is brought about with positive pressure, with constant insufflation pressure recording quantitatively the volumen of expired air. In the same graph the curve of expiratory flow and the tracheal pressure are recorded, measuring the velocity of air flow comparatively in different conditions: in control movements, during the effect of histamine, and during the narrowing provoked by histamine at the entrance of the respiratory tree.

The effect of intravenous injection of histamine on the recording of the volume of expired air is described (figs. 1 and 2), the immediate effect of the injection being called the acute phase. This effect is attributed to bronchial constriction, and is more prolonged in injections after repeated doses. The acute effect having passed, the graph does not return to the same amplitude as at first, but there remains a certain diminution of volume of expired air which is accentuated in the measure in which the injections of histamine or acetylcholine are repeated. This latter effect is attributed to the Progressive alteration of the parenchyma which diminishes lung elasticity.

The effects of histamine are compared with the effects of stenosis at the entrance of the respiratory tree, recording lung volume by means of a plethysmograph in which the animal is enclosed, its chest being opened (fig. 3). It is observed thar in the graph of stenosis, lung volume at the end of inspiration diminishes while at the end of expiration it returns to the same position of rest. In the effect of histamine on the contrary, it is noted that for reduction of volume equal to that of the former case, the lung retracts less at the end of expiration, remaining in an emphysema-like situation. This latter effect is due to diminution of lung elasticity.

On measurement of expiratory rate with tracheal pressure, comparing the stenosis of air entry to the respiratory tree and the histamine effect, the following results are obtained (figs. 4 and 5): with small doses of histamine the volume of expired air diminishes somewhat but the rate of air flow in expiration is slightly slower than in normal expiration or does not change. This is due to the fact that bronchial resistance increases little or is not modified, by weak doses of histamine. As bronchial resistance is not modified and the volume of air is diminished the logical conclusion is that lung elasticity is diminshed. In stenosis, for a diminution of volume of expired air equal to the former case, the rate of flow is markedly slower, which evidently corresponds to the increased resistance. To clarify the interpretation, other very significant data must be considered. In the first place, the recording spirometer has a certain resistance, slightly higher than atmospheric pressure. This resistance which is opposed to air leaving the lung, does not prevent the lung from emptying to its normal' position of rest when the parenchyma is found in normal conditions; but the lung is not emptied to the same position of rest when the force of elastic retraction is diminished. This being taken into account, the characteristics of the graphs in figure 4 are explained. In this figure, an interesting fact is that during the effect of histamine [fig. 4 (1)], above all in weak doses, an expiratory pause is noted, that is, there is an interval during which air does not pass from the lung to the spirometer, though the coresponding valve of entrance to the bellows is still open, which indicates that lung retraction clearly ends before the closure of the air exit. On the other hand in stenosis [fig. 4 (2)], where the volume of expired air is equal to that of the histamine case, it is noted that in the moment of closing the valve — which marks the end of expiration on the apparatus — the exit of air has not yet finished, and for that reason lung retraction could continue if this valve had remained open longer.

The graphs of tracheal pressure in this type of experiment (fig. 5), record variations during stenosis and under the effect of histamine, which suggest an interpretation of the bronchial and pulmonary modifications which confirm the conclusions which we have reached in the study of previous graphs. To explain what the graph in figure 5 signifies, it is necessary to take into account the relations between tracheal pressure and bronchial resistance and elastic resistance of the parenchyma. The pressure at the tracheal entrance maintains a relation in the first place with the insufflation pressure of the apparatus which is determined by the height of the water colunm. The height of this column is graduated, at the begining of the experiment to get the desired volume of expired air, but afterwards it is not changed throughout the whole experiment. The pressure at the entrance to the trachea should be lower than the pressure at the exit of the apparatus, as is logical, as between the outlet of the bomb cylinder and the point at which the pressure is measured, there is a resistance to the flow which determines a fall in pressure. But as such resistance is constant, the height of tracheal pressure must also be constant, while the resistance between the point of measurement at the entrance to the trachea and the alveolar cavity does not vary. This resistance to flow, is the sum of bronchial resistance plus elastic. lung resistance. While this resistance — the total and the sum of the twn —, is maintained constant the pressure gradient will not vary throughout the system, and so neither will the pressure vary at the entrance of the trachea. But each increase in bronchopulmonary resistance will be shown in a rise in tracheal pressure, and then the volume of air entering the lungn will be inversely proportional to this elevation of pressure. In this way relating the tracheal pressure to the volume of air expired, the increase in tracheal pressure with diminution in volume of air expired means that less air is expelled in expiration because less enters in inspiration, and less enters because resistance has increased as is indicated by the rise in tracheal pressure. This is what happens in stenosis. On the other hand, if the tracheal pressure does not increase in relation to the control value, and at the same time the volume of expired air diminishes, this means that the resistance to air entry has not changed, and thus the same volume enters the lung but less is expelled at expiration because the force of elastic retraction has diminished and emphysema is being formed. During the effect of histamine [fig. 5 (2)] there is an increase in tracheal pressure in relation to the normal graph. which is so slight that to simplify matters one can suppose that there is no variation in tracheal pressure. If this is so, it can mean that the sum of resistances, bronchial, and elastic has not varied either. But if the sum of these forces has not varied, one may have increased and another decreased, that is to say, there may have been a diminution in elastic resistance with an increase in bronchial resistance, in which case pulmonary insufflation would be of the same magnitude but in expiration the logical consequence would be a diminution of volume of expelled air as the diminished force of elastic retraction encounters an increased bronchial resistance. Thus the graph would suggest that histamine diminishes the elastic pressure of the lung at least when weak doses are employed. With weak doses [fig. 5 (2)], it may even be supposed that the bronchial resistance has not' changed, and then the diminution in volume of expired air depends only on the fact that the diminished elastic pressure is insufficient to overcome the slight resistance of the recording spirometer, and this leads to the conclusion that in this case histamine possibly acts only by changing the elacticity of the parenchyma without appreciable modification of bronchial resistance.

Experiments with spontaneous respiration. — The course of the asthmatic attack is followed, recording the respiratory movements of the guinea pig by the plethysmographic method (figs. 6 and 7). A characteristic initial acceleration of respiratory rate is observed in unanesthetised animals almost as an exception even in the grave attack which passes rapidly to a bradypneic phase. In contrast to this effect, the rate is always slowed when stenosis is produced at the entrance to the respiratory tree by a purely mechanical effect. It is suggested that dyspnoeic breathing in the initial phase is due to a reflex provoked by pulmonary vasodilation. Once the effect of the histamine injection has passed, the final expiratory position tends to remain slightly higher than at the beginning. And this may be appreciated still more after repeated doses, as if there were a stenotic factor the influence of which is accentuated in the measure in which the histamine injections are repeated, or otherwise a loss of elastic retraction force. Thus the acute phase could be fundamentally attributed to bronchial constriction, and the more persistent effect either to a slower stenosing action through phenomena of cellular alteration in the mucous membrane and hypersecretion, or more likely to insufficient expiratory retraction caused by parenchymal change.

Anatomopatholigical obscrvations. — The lesions demonstrated by histological study in the various types of experiments are very similar in their fundamental characteristics. However differences are found from case to case which are interesting because they contribute to the interpretation. In some cases vascular spasm is evident (fig. 8) and capillary vasodilatation is very manifest. In athers spasm appears to be absent and an edematous aspect of the mucous membrane predominates with folds adherent one to the other, and also with evident pulmonary vasodilatation especially in atelectatic zones. On relating the lesions to the experimental conditions it is proved that in histamine tests, vasodilation and vascular lesions predominate and the conclusion is reached that the most important factor in the acute phase is bronchial constriction.

Comparison of the lesions observed with positive pressure and spontaneous respiration, in relating edema production to the intraalveolar pressure, does not facilitate data which would allow us to recognise a clear influence of negative alveolar pressure in transudation phenomena, as alveolar changes appear very similar in both type of cases, and their intensity shows more relation to the duration of the experiment than to the type of respiration.