/8. possible to distinguish between active and passive P.A.p. changes.

Transcription

1 /8 BRONCHOMOTOR AND PULMONARY ARTERIAL PRESSURE RESPONSES TO NERVE STIMULATION. By I. DE BURGH DALY and CATHERINE 0. HEBB.1 From the Department of Physiology, University of Edinburgh. (Received for publication 22nd October 1941.) IN isolated perfused lungs of the dog, stimulation of the stellate ganglion or thoracic vagosympathetic nerves (T.V.S.) has been shown to produce a rise of pulmonary arterial pressure (P.A.p.) in the absence of bronchomotor changes as measured by tidal air excursions [Daly and Euler, 1932]. These results support the view that these nerves contain vasomotor fibres to the lungs. They do not, however, militate against bronchomotor effects having some influence on the pulmonary vascular resistance; they only show that the resistance changes due to nerve excitation can occur independently of bronchial constriction. Recently we have had the opportunity of observing the effects of pulmonary nerve stimulation in the perfused whole animal under negative pressure ventilation. In many experiments strong stimuli caused complete bronchoconstriction which, among other effects, undoubtedly caused passive resistance changes in the pulmonary vascular bed reflected as alterations of P.A.p. In such experiments the activity of the pulmonary nerves progressively diminishes, and therefore the earlier in the experiment the tests are made the better will be the responses to nerve stimulation. This applies both to bronchomotor and vasomotor effects, so it is to be expected that the most marked P.A.p. responses due to true vasomotor activity will always be associated with passive alterations of P.A.p. of bronchomotor origin. It is therefore of paramount importance to determine whether it is possible to distinguish between active and passive P.A.p. changes. The method adopted in the present investigation for perfusion of the whole animal is described in the succeeding paper [Daly, Elsden, Hebb, Ludany, and Petrovskaia, 1942]. In some of the perfused animals one lung had been removed at a previous operation. We have also performed experiments on isolated lungs perfused by way of the pulmonary artery with heparinised blood. In our experiments the lungs, placed in an air-tight chamber, are perfused at a constant blood inflow and ventilated by rhythmic changes Beit Memorial Fellow. 211

2 21-2 Daly and Hebb in extrapulmonary pressure. This is done by connecting a vacuum cleaner to the chamber, the resulting pressure fall in the chamber being nearly abolished sixteen times per minute by means of a valve which admits air to the clhamnber. The duration of the forces causing expansion of the lungs produced by the fall of extrapulmonary pressure is approximately equal to the duration of the elastic recoil of the lungs which causes almost complete collapse when air is suddenly admitted (a) (b) FiG. 1. (a) Expt. 38'W.L.8. Dog, Y,.5 7 kg. Left lung reoiioecd at precious operation. Isolated perfuised lunirgs. Negative pressuire venitilatiorn (N.P.V.). At 1 an(l 5, graduial occlusion of trachea; at 2, 3, andl 4, suidden oceltusion of trachea. The release of the occlusion is gradual in all except 2. P.A.p. --pulmonary arterial pressuire: T.A. =tidal air. (b) Expt. 39 9). Dog, $., 6-6 kg. Perftusion of whole animiial (P.W.A.). N.P.V. At 6, 7, 8, and 9, sudden aind complete occlusion of trachea followsed by sudden release. The dluratioii of occlusion in every case is shown by the horizontal lwhite lines. Inspiration is downwards and expiration uipwards in this and all T.A. tracings. to the chamber through a wtide-bore tube. This is shown by the fact that when the tracheal outlet is progressively obstructed by mneans of a screw-clip so as gradually to increase the resistance to air flow, the resultant static air volume of the lungs shows little or I10 clhange from the dynamic mean air volume (fig. 1, obs. 1). The static volume is defined as the quantity of air in the lungs after tracheal occlusion. Owing to there being differences in the visco-elastic properties of the lungs of the preparations used, gradual occlusion of the trachea did not always fix the lungs in the mid-respiratory position: in general 55-65

3 Bronchomotor and Pulmonary Arterial Pressure Responses 213 per cent. of the tidal air was entrapped in the lungs. It should be mentioned that the method of lung ventilation used automatically I FiG. 2. Dog, 0, 10-3 kg. Isolated perfused lungs. Blood-flow c.c./min. N.P.V. Shlowing similar effects to those in fig. 1, but intrapulmonary pressure and lung bloodl voluiimei (L.B.V.) changes included. Extraptulmonary pressure variations, -1-5 to cmn. H20. L.B.V. increasing downwards. a= gradual occlusion of trachea; b occlusion at full inspiration; c =occlusion at full expiration. results in the extrapulmonary pressure fa,lling slightly more when the trachea, is occluded than when air is allowed normally to enter the lungs [cf. Berry and Daly, 1931].

4 214 Daly and Hebb Mechanical Factors.-In order to throw light upon the mechanisms which determine the P.A.p. change during complete bronchoconstriction, we have attempted to simulate the intrapulmonary pressure changes which occur during vagal bronchoconstriction by suddenly occluding the tracheal outlet at different phases of the respiratory cycle. Sudden tracheal occlusion at the height of lung expansion leads, during the succeeding rise of extrapulmonary pressure, to a rise of mean intrapulmonary pressure due to the elastic forces of the lungs, which act to compress the air they are no longer able to expel. An intrapulmonary pressure rise causes, as is well known, a rise of P.A.p. due to compression of the capillaries. If, however, the trachea is occluded when the lungs are collapsed, no air can enter the lungs during the succeeding extrapulmonary pressure fall, with the result that the intrapulmonary pressure also falls causing a corresponding drop in the P.A.p. due to capillary dilatation (see fig. 1, obs. 4, 8, and 9; fig. 2). In all probability the intrapulmonary pressure changes described above are the main cause of the observed P.A.p. alterations during sudden tracheal occlusion. That other mechanisms also play some part we have no doubt. There are three main mechanisms which govern the respiratory P.A.p. variations as well as the mean P.A.p. of lungs perfused at a constant blood inflow under "negative" pressure ventilation: (1) lung expansion per se which, owing to the internal architecture of the lungs, increases the calibre of the pulmonary capillaries. The resulting increase in blood capacity of the capillaries lowers the P.A.p. only whilst the lungs are expanding, and if this was the only factor, the P.A.p. would return to its initial value when the lungs had reached full expansion. The associated diminished capillary resistance, however, also lowers the P.A.p. during expansion and remains effective in keeping the P.A.p. down just as long as the lungs remain expanded. The P.A.p. is therefore partly determined by the degree of lung expansion (fig. 3). (2) The falling extrapulmonary pressure which increases the capacity of the relatively large blood-vessels lying on the surface of the lungs without producing a significant change in their resistance: this gives rise to a transient drop of P.A.p. only during the period, of falling extrapulmonary pressure. (3) Changes in intrapulmonary pressure which are determined by the resistance to air entering or leaving the lungs. Normally a slight capillary dilatation producing a fall of P.A.p. occurs during normal lung expansion by virtue of the intrapulmonary pressure being reduced slightly below atmospheric pressure. Opposite effects take place during expiration. The greater the resistance to air flow and the greater the speed of ventilation, the more marked will these effects become. These considerations are based upon the work of de Jager [1879], Dixon and Brodie [1903], Spee [1909], Romanoff [1911], and Daly [1930, 1938], as well as upon unpublished work. It should be noted

5 Bronchomotor and Pulmonary Arterial Pressure Responses 215 that the change of P.A.p. which occurs when the trachea is suddenly occluded at full lung expansion will be determined not only by the subsequent intrapulmonary pressure rise, but by the absence of subsequent collapse of the lungs which normally increases the capillary FIG. 3.-Expt. M.S.16. Dog, 3', 10-3 kg. Isolated perfused lungs. N.P.V. Effect of alterations in extrapulmonary pressure on the P.A.p., lung blood volume and air volume. The extrapulmonary pressure was reduced in steps to - 2, - 4, - 6, - 10, -14 cm. H20 and then raised to - 6 and finally to 0 cm. H20. L.B.V. =lung blood volume, increasing downwards. The observations were made at the beginning of the experiment before ventilation, hence the small changes and the response lag of the intrapulmonary volume. resistance and causes a P.A.p. rise. These two influences tend to balance one another, but it appears that the intrapulmonary pressure effect predominates so that the resultant effect is a P.A.p. rise. Reasoning on the same lines, the fall of P.A.p. due to the reduced mean intrapulmonary pressure caused by tracheal occlusion with the lungs in the

6 216 Daly and Hebb collapsed condition is greater than the fall of P.A.p. which would have occurred if the lungs had been allowed to expand. No mention has been made of the effects on the P.A.p. of blood redistribution in the lungs which may be produced by tracheal obstruction during "negative" pressure ventilation. They are too complex to evaluate, but redistribution might cause changes in the volume 0 0 /0 t to0 Pexcentia8c amowunt of ticdal a;r in WunSs w&tan track6al oul2was~ uci.cu&a.c FIG. 4.-From same experiment (39/9) as fig. 1. Effect on the pulmonary arterial pressure of sudden and complete occlusion of the trachea at different phases of the respiratory cycle. AB =extrapulmonary pressure - 0*5 to cm. H120, tidal air before occlusion, 50 c.c. CD==extrapulmonary pressure - 0*5 to cm. 1120, tidal air before occlusion, 120 c.c. elasticity coefficients of the blood-vessels and so modify to some extent the relative effects on the P.A.p. of the factors enumerated above. For a similar reason the effect on the larger intrapulmonary bloodvessels of restricting lung expansion is not discussed. We believe, however, that since the capillaries form the greater part of the pulmonary resistance and contain at least twice as much blood as the rest of the lung vessels [Daly, 1938], they play the major part in determining P.A.p. changes brought about by mechanical influences. The graph of fig. 4 shows the effect on the mean P.A.p. of sudden and complete tracheal occlusion at different phases of the respiratory

7 Bronchomotor and Pulmonary Arterial Pressure Responses 217 cycle. The slope of the curve CD, denoting the change of P.A.p. due to tracheal occlusion with extrapulmonary pressure variations of 0 to - 12 mm. Hg is, as would be expected, steeper than that of AB taken with extrapulmonary pressure variations of 0 to - 8 mm. Hg. The T.A. values before tracheal obstruction were 50 c.c. for curve AB and 100 c.c. for curve CD. The fact that the curve CD does not cross AB at the point corresponding to occlusion with 50 per cent. of the tidal air present in the lungs is probably due to the visco-elastic forces of the lung having changed as the result of altering the extrapulmonary pressure values. These results suggest that when sudden and complete obstruction of the trachea occurs during ventilation of the lungs, the main mechanical factor which determines alterations of P.A.p. is the amount of air entrapped in the lungs. When the obstruction entraps more air than that contained in the lungs at the mid-respiratory position, the intrapulmonary pressure and P.A.p. rise, whereas when less air is entrapped than that held by the lungs in the mid-respiratory position the intrapulmonary pressure and P.A.p. fall. If no other factors are involved, it follows that the mean P.A.p. should not alter when complete and sudden obstruction takes place midway between expansion and collapse, provided also that in their duration the forces causing ex-pansion and collapse are equal. The effect of the degree of lung expansion on the capillary resistance in the absence of capacity effects can best be demonstrated by the application in steps of a steady extrapulmonary pressure to produce varying degrees of expansion (fig. 3). The Relation between Bronchomotor Effects of Nervous Origin and the Pulmonary Arterial Pressure Response.-If we are so far correct in our interpretations, then complete and sudden bronchoconstriction produced by pulmonary nerve stimulation should cause similar qualitative changes in the P.A.p. as does tracheal occlusion, provided no direct effect on the pulmonary vessels is produced by the stimulation, and provided also that the elastic recoil of the lungs undergoes no change. We have examined the effects on the mean P.A.p. of some 70 stimulations of the caudal ends of the cervical vagosympathetic (C.V.S.), cervical vagus (C.V.), and cervical sympathetic (C.S.) nerves, all of which produced a concomitant bronchoconstriction, either complete or partial. When complete or partial bronchoconstriction has taken place, the percentage amount of tidal air retained in the lungs has never been greater than 55 per cent. and usually less than 50 per cent. (figs. 5 and 6). That is to say, the lungs have tended to collapse as bronchoconstriction supervened. Even when a sudden and complete bronchoconstriction has appeared likely to fix the lungs in the expanded position a final expulsion of air has apparently taken place (fig. 5, a, d). Since in these experiments the duration of the forces causing expansion

8 218 Daly and Hebb and collapse of the lung is approximately the same before nerve stimulation, we interpret these results as indicating that pulmonary nerve stimulation causes an increase in the viscance and/or elastance of the lungs, as Bayliss and Robertson [1939] found for vagal stimulation in the cat. Whether active contraction of the interstitial musculature of a d FIG. 5. Expt. 31/2A. Dog, i, 4-7 kg. Left lung removed at previous operation. P.W.A., N.P.V. Both cervical vasosympathetic (C.V.S.) nerves cut. Eserine 2.0 mg. Caudal end of nerves stimulated in each case. a two stimulations of R.C.V.S., coil distance (c.d.) 7 cm.; b =stimulation of L.C.V.S., c.d. 0 cm., and tracheal occlusion followed by release; c =two stimulations of R.C.V.S., c.d. 7 cm.; d =stimulation of R.C.V.S., c.d. 0 cm.; e =three occlusions of trachea at different points in the respiratory cycle. The T.A. lever had reached its lowest possible level in last portion of tracing. The rise of the T.A. tracing during complete bronchoconstriction in a, c, and d is due to the flow of oxygen into the closed circuit respiratory system. If this flow is perfectly balanced with the oxygen consumption of the animal, the T.A. tracing remains horizontal as at the beginning of a. the lungs plays a part in the production of this phenomenon we are unable to state. If the lung "hindrance," a term suggested by Bayliss and Robertson to denote the total force developed in response to a unit deformation at unit rate, is increased during the development of complete bronchoconstriction, the effect upon the P.A.p. will be complex depending upon the rate of development of lung "hindrance" leading to complete bronchoconstriction. If the complete bronchoconstriction of vagal origin takes place slowly enough to allow the mean intrapulmonary pressure to become equal to atmospheric pressure, then the position in which the lungs are finally immobilised will be the main mechanical factor determining the P.A.p. change. If, however, the

9 Bronchomotor and Pulmonary Arterial Pressure Responses 219 bronchoconstriction is sudden and complete, the intrapulmonary pressure change as well as the final position in which the lungs are fixed will govern the P.A.p. It follows that since under the conditions of our a b c d e f FIG. 6. From-i same experilmreit (38, V.L.8) as fig. 1. Botth C.V.S. nerv-es cut; eserine 2 0 Ilog. L(ft loqgyre/oovcd at previo1t..s op(ratioo. a, c, and c stinltilation of cail(lal en(l of L.C.X.S., c.d. 0 cm.; b an(lf =stimiiulation of aud(lal enid of R.C.X.S., c.d. 0 ci. The systemic circtl]ation ptimp xnas stoppedl shortly b)efore (1, wvhen adreinaline 20 jig. was injected into the pilmnonary arterial tubing. The T.A. tiaciing ]ever sttock at the top, an(l whein movedl donrivwar(ls complete bronchoconstriction was found to hax-e been prodtuced by IR.C.V.S. stiiitilation. experiments the lungs always become immobilised towards the expiratory position durinig bronchoconstriction of vagal origin, the P.A.p. will rise if the bronchoconstriction is partial or, when complete, if its onset is slow enougli to allow the intrapulmonary pressure to beconle equal to the atmospheric pressure. If, on the other hand, the bronchoconstriction is sudden and complete the P.A.p. will fall. The volume of air entrapped in the lungs as a result of vagal bronchoconstriction will be, for any given extrapulmonary pressure variations, less than that entrapped by tracheal occlusion, owing to the former taking place

10 220 Daly and Hebb nearer to the terminal air tubes than the latter. Thus sudden and complete bronchoconstriction of vagal origin will have a greater effect on the intrapulmonary pressure and P.A.p. than tracheal occlusion in whatever phase of the respiratory cycle the obstruction to air entering and leaving the lungs takes place. We attribute the fall of P.A.p. in fig. 5, c, d, to the fall of intrapulmonary pressure which accompanies the complete bronchoconstriction. These tracings should be compared with those obtained by tracheal obstruction (fig. 5, e). On the other hand, the rise of P.A.p. accompanying partial bronchoconstriction shown in fig. 7 cannot have been due to changes in the mean intrapulmonary pressure for the airway is only very slightly obstructed. The dynamic mean air volume has shifted towards the expiratory position, and this in itself may be sufficient to account for the rise of P.A.p. It would be expected that on occasion the rates of onset of complete bronchoconstriction giving rise to a new mean air volume and of the tendency for equalisation of the intrapulmonary pressure with the atmospheric pressure might be such that the effects on the P.A.p. nearly tend to balance one another, Slight differences in the temporal relations of these effects might therefore produce a diphasic P.A.p. response. We believe that fig. 5, a, illustrates such a mechanism. In this tracing the initial effect during one respiratory cycle of a reduction in T.A. towards the expiratory position would tend to produce a temporary rise of intrapulmonary pressure and of P.A.p. During the next cycle, at the end of which complete bronchoconstriction occurred at the mid-respiratory position, the intrapulmonary pressure would tend to equalise with the atmospheric pressure, thus causing a reduction of P.A.p. to its initial value. Thus the final P.A.p. value would be determined only by the position in which the lungs became fixed during complete bronchoconstriction. The fact that the P.A.p. changes lag considerably behind the bronchomotor effects is due to the large inertia of the mechanisms involved. Changing Response of Pulmonary Arterial Pressure to Nerve Stimulation.-If we now assume that intrapulmonary pressure changes and the position in the respiratory phase at which the lung is immobilised are the only two mechanical factors responsible for passive P.A.p. alterations, then some of the P.A.p. responses to nerve stimulation we have obtained are apparently due to vasomotor effects. It has often been found that the relation between the P.A.p. and the accompanying bronchomotor response does not remain constant throughout an experiment. A description of one of these experiments will suffice to illustrate this point. Fig. 6 is a record of the effects of three strong stimulations each lasting 30 sec. of the L.C.V.S. nerve which successively gave a fall, no change, and a rise of P.A.p. (a, c, e). The fall of P.A.p. to the first stimulation appears to be of a permanent nature, a type of response we describe in a later paper as not unusual. It is accompanied by a

11 Bronchomotor and Pulmonary Arterial Pressure Responses 221 slight bronchoconstriction during which the dynamic mean air volume alters little, therefore no passive effects on the P.A.p. would be expected FIG. 7.-Expt. M.S.13. Dog, (D kg. Isolate(d perfuise(d lulngs. N.P.V. Two stimutlationis of the thoracic vagosympathetic (T.S.) nerx e, c.d. 0 cin., are shiowni at the beginning aaicl enl (Iof the recor(l. 1 =gradual tracheal occtiasion follo-,ved by release. 2 =sudclclen an(d coroplete occltusion of t,rachea at height of expiration, an(a 3, at lheight of inispiration. to take place. The second L.C.V.S. nerve stimulation, which is accompanied by a slight release of the complete bronchoconstriction produced by a previous stimulation of the R.C.V.S. nerve, has no effect on the

12 222 Daly and Hebb P.A.p. The rise of P.A.p. following the third L.C.V.S. stimulation is definite and occurs in the absence of bronchomotor effects, and we have no alternative but to interpret this response as being due to stimulation of vasomotor fibres. The fact that the third L.C.V.S. stimulation caused a rise of P.A.p. may have been due to the administration of adrenaline sensitising the peripheral nerve apparatus [see Burn, 1932]; this point requires further investigation. There is one other difference in the conditions between the first and third L.C.V.S. stimulations which requires mention. The systemic circulation blood-pump supplies blood to the bronchial vascular system, and if the communicating channels between the bronchial and pulmonary vascular systems are open, the transfer of blood from the former to the latter is responsible for a proportion of the pressure in the pulmonary artery [Berry and Daly, 1931]. The fall of P.A.p. due to the first L.C.V.S. stimulation may therefore have been due to constriction of the bronchial arteries. We do not think so, however, because the reduction in systemic arterial pressure when the pump was stopped should have caused a fall of P.A.p. if the communicating channels had been open. The P.A.p. rise due to the third L.C.V.S. stimulation could not have been due to dilatation of the bronchial arteries leading to an increase of the blood transferred to the pulmonary vascular bed for the reason that the systemic bloodpump had been stopped. Thus the P.A.p. rise in this case appears to have been due to a true pulmonary vasoconstriction. The Nature of the Bronchomotor Response to C. V.S. Nerve Stimulation.-Stimulation of the caudal end of the C.V.S. nerves almost invariably produces bronchoconstriction. On a few occasions, however, a weak stimulus has caused slight bronchodilatation. Further, it has been found that when complete bronchoconstriction follows C.V.S. stimulation, a second stimulus of the same strength and duration temporarily releases the bronchoconstriction (fig. 5, c). Fig. 6 shows a somewhat similar phenomenon. In this experiment the left lung had been removed and strong stimulation of the contralateral L.C.V.S. caused only a weak bronchoconstriction (a), but when the stimulus was repeated (c) subsequent to a complete bronchoconstriction which had been produced by stimulation of the ipselateral R.C.V.S. nerve (b) it gave rise to a bronchodilatation. Several interpretations can be placed on these results. The C.V.S. nerves may contain bronchodilator fibres running in the cervical sympathetic portion as found by Dixon and Ransom [1912] and Saloz [1914] in the eserinised cat. Against this view are the results of Braeucker [1926] and of Daly, Elsden, Hebb, Ludainy, and Petrovskaia [1942], who invariably obtained bronchoconstriction on stimulating the caudal ends of the separated cervical sympathetic nerves in the dog, an effect which was potentiated by eserine. Alternatively, such results as we have obtained, which are similar to those of Braeucker [1926] on the dog, may be due, as he has suggested, to the

13 Bronchomotor and Pulmonary Arterial Pressure Responses 223 changing response of the pulmonary ganglia which relay the stimulated fibres to the periphery. A further interpretation is that the changing response of the bronchial muscle itself determines the final effect of nerve stimulation. We consider one of the two last mechanisms to be the most likely explanation. In the experiments from which figs. 5 and 6 have been taken, the left lung had been removed prior to the acute experiment. The fact that L.C.V.S. stimulation causes a moderate bronchoconstrictor effect in one (fig. 5, b) and a weak bronchoconstrictor effect in the other experiment (fig. 6, a) indicates that the bronchomotor fibres are to some extent crossed. This confirms the results of previous workers [Dixon and Ransom, 1912; Braeucker, 1926]. That slight bronchodilatation can be produced by a second stimulation of the ipselateral C.V.S. nerve, the first stimulation having caused full bronchoconstriction (fig. 5, c), or by stimulation of the contralateral nerve after complete bronchoconstriction had been produced by stimulation of the ipselateral nerve, is of interest from one other point of view. Since only one lung is present, it rules out the possibility that the bronchodilatation is due to passive distension by bronchoconstriction of the opposite lung, this being a potential source of error in the interpretation of bronchomotor effects measured by lung plethysmography in the entire animal under positive pressure ventilation [see Dixon and Brodie, 1903; Weber, 1914]. DisCUSSION AND CONCLUSIONS. Experimental evidence is produced supporting the view that in lungs under "negative " pressure ventilation the passive changes of P.A.p. accompanying bronchoconstriction of nervous origin are mainly due to changes in intrapulmonary pressure and in the degree of lung expansion. Intrapulmonary pressure changes are chiefly responsible for the P.A.p. alterations when the bronchoconstriction is sudden and complete, their direction being determined by the point in the respiratory cycle at which bronchoconstriction occurs. P.A.p. alterations due to partial or slowly produced complete bronchoconstriction are mainly due to changes in the degree of expansion of the lungs, which in turn determines the resistance of the pulmonary capillaries. In this interpretation of the effects of pulmonary nerve stimulation we have tentatively ascribed the diminution or cessation of tidal air excursions to bronchoconstriction. It may be, however, that the tidal air changes are due in part to a stiffening of the whole lung structure caused by an increase in the viscance and elastance of the lung tissues, for this was the effect of vagal stimulation on the lungs of the cat found by Bayliss and Robertson [1939]. If it is eventually found that canine lungs exhibit a somewhat similar vagal response, then our interpretations will require some revision in that the position in the respiratory

14 224 Daly and Hebb cycle in which the lungs are immobilised by vagal stimulation rather than changes in intrapulmonary pressure will be the important mechanical factor in determining the P.A.p. Some of the observed changes of P.A.p. due to pulmonary nerve stimulation cannot be accounted for by passive effects; others take place in the absence of any bronchomotor response. We attribute the P.A.p. responses in these cases to stimulation of vasomotor fibres to the lungs. It is suggested that the vasomotor response which alters the P.A.p. may be a direct one on some portion of the pulmonary vascular bed, or an indirect one on some part of the bronchial vascular system. Daly and Euler [1932] have already shown that the bronchial vascular system is supplied with functionally active vasoconstrictor fibres. The P.A.p. is in part determined by the amount of blood transferred from the systemic circulation to the lesser circulation by way of the bronchial vascular system. Theoretically, therefore, constriction of the bronchial arteries should lead to a fall, and dilatation to a rise, of P.A.p. All our observations save one may be attributed to vasomotor effects on the bronchial or on the pulmonary vascular system. This exceptional observation, of a P.A.p. rise following C.V.S. stimulation, caused no bronchomotor effects and was made at a time when no blood flowed through the bronchial arteries. This suggests that vasoconstrictor fibres to the pulmonary vascular bed proper run in the C.V.S. nerves, and supports the earlier work of Cavazzani [1891] on isolated lungs perfused through the pulmonary artery without bronchial artery perfusion. The results of Daly and Euler [1932], however, which demonstrated vasoconstrictor effects of nerve stimulation in the absence of bronchomotor responses in lungs perfused through both the pulmonary and bronchial arteries, could be explained on the basis of true pulmonary vasoconstriction or of dilatation of the bronchial vascular system. We have considered the possibility that vagal stimulation may produce contraction of the interstitial musculature of the lungs [Baltisberger, 1921] and so compress the lungs as a whole, an effect which when accompanied by complete bronchoconstriction might well raise the intra-alveolar pressure and compress the alveolar capillaries. Contraction of the interstitial musculature would undoubtedly alter the "hindrance " of the lungs and thereby cause a change in the inspiratory and expiratory levels of the tidal tracing. Since P.A.p. responses to nerve stimulation have been observed without any effect on the tidal air, we do not think that in these cases such a mechanism plays any part Ȧlthough we feel that the results of this investigation clarify to some extent our knowledge concerning bronchomotor effects on the pulmonary arterial pressure, we are of the opinion that the complexity of the mechanisms does not allow of the unequivocal demonstration

15 Bronchomotor and Pulmonary Arterial Pressure Responses 225 of pulmonary vasomotor responses to nerve stimulation when bronchomotor changes also occur. It is true, however, that when nerve stimulation causes a P.A.p. change, the direction of which is opposite to that which may be expected to be produced by a concomitant bronchomotor change, it is suggestive of a pulmonary vasomotor response. SUMMARY. Experiments on isolated perfused lungs and on the perfused whole animal preparation under "negative " pressure respiration are described. Attempts have been made to evaluate the bronchomotor mechanisms responsible for the changes of pulmonary arterial pressure (P.A.p.) which occur as a result of stimulation of the caudal end of the cervical vagosympathetic nerves (C.V.S.). When complete bronchoconstriction occurs, its rate of onset, which determines the intrapulmonary pressure change, and the final position in the respiratory cycle in which the lungs are immobilised, are the main factors in determining the degree and direction of P.A.p. change. When partial bronchoconstriction takes place the P.A.p. change is chiefly governed by the direction of change of the mean air volume of the lungs. Evidence is presented in support of the view that the C.V.S. nerves contain true pulmonary vasomotor fibres, but their functional activity cannot be unequivocally demonstrated by electrical stimulation if concomitant bronchomotor effects occur. Experiments are described showing that C.V.S. stimulation may produce broncho-constriction or -dilatation. The conditions governing the type of response have not been evaluated. We wish to express our thanks to the Government Grants Committee of the Royal Society for defraying the cost of the investigation by a grant to one of us (I. de B. D.). REFERENCES. BALTISBERGER, W. (1921). Z. Anat. Entwickl. 61, 249. BAYLISS, L. E., and ROBERTSON, G. W. (1939). Quart. J. exp. Physiol. 29, 27. BERRY, J. L., and DALY, I. DE BURGH (1931). Proc. Roy. Soc., B, 109, 319. BRAEUCKER, W. (1926). Arch. klin. Chir. 139, 1. BRAEUCKER, W., and KUMMEL, H. (1927). Pfluigers Arch. 218, 301. BRUNS, 0. (1912). Deutsch. Arch. klin. Med. 108, 472. BURN, J. H. (1932). J. Physiol. 75, 144. CAVAZZANI, E. (1891). Arch. ital. Biol. 16, 32. DALY, I. DE BURGH (1930). J. Physiol. 69, 238. VOL. XXXI., NO

16 226 Bronchomotor and Pulmonary Arterial Pressure Responses DALY, I. DE BuRGH (1938). Quart. J. exp. Phy8iol. 28, 357. DALY, I. DE BuRGHH, and EULER, U. VON (1932). Proc. Roy. Soc., B, 110, 92. DALY, I. DE BURGH, ELSDEN, S. R., HEBB, C. O., LUDANY, G. VON, and PETROVSKAIA, B. (1942). Quart. J. exp. Phy8iol. 31, 227. DIXON, W. E., and BRODIE, T. G. (1903). J. Physiol. 29, 97. DIXON, W. E., and RANSOM, F. (1912). Ibid. 45, 413. JAGER, S. DE (1879). Pflf1gers Arch. 20, 426. ROMANOFF, M. (1911). Arch. exjp. Path. Pharm. 64, 183. SALOZ, J. (1914). Contribution a l'etude de muwsces bronchiques. These, Universite de Geneve. SPEE, G. (1909). Quoted by SAUERBRUCH, Ergeb. Chir. Orthop., 1910, 1, 356. WEBER, E. (1914). Arch. Anat. Physiol. p. 63.