milliamperes, and the frequency of interruption to be varied from 2 to action(1). reflex effects on the heart. It is advisable to do this previous to

Transcription

1 STUDIES OF REFLEX ACTIVITY IN THE INVOLUNTARY NERVOUS SYSTEM. I. Depressor Reflexes. BY SAMSON WRIGHT, (Physiological Laboratory, Middlesex Hospital.) THE vaso-motor effects of stimulating the central end of the vagus (cat) or the depressor nerve (rabbit) have been re-investigated in an attempt to elucidate some of the processes which take place in the nerve centres of the involuntary nervous system; many of the experiments were carried out.in the light of Sherrington's "humoral" theory of reflex action(1). METHODS. The animals employed were the cat and rabbit, anwsthetised with chloralose or ether, or decerebrated (under deep C.E. ansesthesia) through a trephine opening at various levels in the midbrain. In the case of the decerebrate animals about 1 hour was allowed to elapse after the operation to permit the initial aneesthetic to be blown off completely (cf. Vincent and Curtis2). Both vagi were divided in all cases to exclude reflex effects on the heart. It is advisable to do this previous to decerebration while the animal is deeply ansesthetised; section of both vagi subsequent to decerebration often gives rise to grave disturbances of respiration and of blood-pressure and may prove fatal. In my experience a separate depressor nerve in the cat is uncommon. Both vagi may be depressor (perhaps the left more so than the right) or they may give rise to a mixture of pressor and depressor effects(3); occasionally they may produce pressor effects only. The proportion of depressor to pressor fibres in the vagus of the cat seems to differ in different animals. For stimulation I have used, in addition to the ordinary coil, a special coil kindly made for me by Prof. Russ and Mr Watters. This enables the current in the primary circuit to be varied from 5 to about 400 milliamperes, and the frequency of interruption to be varied from 2 to 50 double shocks per second. Make and break shocks were equalised by the Helmholtz arrangement. The position of the secondary coil in relation to the primary was kept fixed and the strength of shock was raised by adjusting the current in the primary. PH. LXVI. 26

2 388 SAMSON WRIGHT. Irregular results tend to be obtained after the nerve has been stimulated a considerable number of times, if a slight over-dose of chloralose has been given, or if Traube waves have been set up. If strong afferent stimulation has been employed to produce marked lowering of the blood-pressure these irregular responses set in earlier in the course of the experiment. Little attention has consequently been paid to the results obtained under such conditions. The respiratory disturbances which may be set up by the vagus nerve in the cat tend to produce secondary blood-pressure changes. A considerable number of experiments were therefore carried out under artificial respiration. Mechanical and thermal stimulation. It has been pointed out by Sharpey-Schafer(4) that the depressor nerve in chloralose anaesthesia is very sensitive to mechanical stimulation (cf. Fig. 10); in my experience the same is frequently true of the depressor nerve in the decerebrate animal (Fig. 1). Care was therefore taken to avoid traction and the nerve Fig. 1. Cat. Decerebrate. Stimiul&te left central vagus 25 milliamp. in primary; stimuli are approximately of equal duration. lst, 8 double shocks per second. 2nd, 2 d.s.p.s. 3rd, 50 d.s.p.s. Time in 2 sew. The slight fall of blood-pressure which precedes; the second stimulus is due to sliht pulling on the nerve during the adjustment of the electrodes was stimulated by means of fixed electrodes. It is interesting to note, too, that a hot swab applied to the depressor nerve often produces a marked reflex fall of blood-pressure, the thermal stimulus apparently being a very effective one. "Splanchnic preparation. " It has been shown by BayIisss, 6),7) that the dilator fibres in the sacral autonomic and the antidromic vasodilator fibres in the posterior nerve roots are involved in the depressor

3 DEPRESSOR REFLEXES. 389 reflex. The recent work of Lewis and his co-workers(8) suggests that these latter dilator fibres cause the liberation of a "histamine-like" substance in the skin which accumulates under prolonged peripheral stimulation and is but slowly dissipated when stimulation is discontinued: Many experiments have therefore been carried out on animals in which the circulation was restricted to the thorax and abdomen ("splanchnic animal ") by means of the following procedure. The femoral, subelavian and carotid arteries on both sides are tied and the skin is completely removed from the trunk, neck and the proximal parts of the limbs. A well-marked depressor reflex can still be obtained; further, the fall of blood-pressure noted in the splanchnic preparation may not be appre- 'ciably less than that previously obtained with similar stimulation in the intact animal. This observation shows that the depressor reflex affects the splanchnic area to an important extent. The splanchnic blood vessels are supplied by many vaso-constrictor fibres; though vaso-dilators are present, their number is small and they can only be demonstrated with difficulty(9,1o, U). In the splanchnic animal, therefore, the fall of blood-pressure which results from depressor stimulation may be attributed largely to central inhibition of vasomotor tone. RESULTS. Frequency of stimulation, A. Intact animal. The results obtained on varying the frequency of stimulation depend to a considerable extent on the strength of current which is employed. 1. (a) With weak currents, increasing the frequency of stimulation may increase both the extent and the rate of the fall of blood-pressure (Fig. 1). In this figure the duration of the recovery of the blood-pressure to normal is proportional to the extent of the fall; the slope of the recovery curve in this case is least after stimulation with 2 d.s.p.s. (b) Under certain circumstances the blood-pressure does not remain down under prolonged stimulation of low intensity. In Fig. 2 stimulation was carried out on each occasion for a period of about 50 sec. With a frequency of 8 d.s.p.s. the pressure fell slowly and to a small extent but soon returned to its original level and then exceeded it in spite of continued stimulation. With 20 d.s.p.s. the pressure returned more gradually to normal during the latter part of the stimulation; with 50 d.s.p.s. there was a sharp and marked fall of blood-pressure and the pressure was maintained almost at the lowest level throughout the period of 26-2

4 390 SAMSON WRIGHT. stimulation; the return to normal was complete about half t minute after stimulation was discontinued. Fig. 2. Cat Chloralose. Stimulate left central vagus. 25 milliamp. in primary. Stimuli: 8 d.s.p.s.; 20 da.p.s.; 50 d.s.p.s. Time in sec. 2. When strong currents are employed in the primary circuit there is usually little difference in the extent and rate of the fall of bloodpressure during the period of stimulation. But in Fig. 3 there is a marked Fig. 3. Cat. Decerebrate. 0 3 amp. in primary. Stimulate left central vagus. Stimuli: 2 d.s.p.s.; 30 d.sp.s. Time in 2 sec. Initial blood-pressure 110 mm. Hg. difference in the blood-pressure curve when stimulation is discontinued. With 2 d.s.p.s. after 2 sec. the blood-pressure begins to rise and is back to normal in about 40 sec.; with 30 d.s.p.s. the pressure continues to fall for 12 sec. and the return to normal occupies about 70 sec. The response of the vagus nerve to variation in frequency of stimulation is thus seen to differ from that of mixed nerves like the great sciatic, in which, as shown by Gruber(12), a fall of blood-pressure is

5 DEPRESSOR REFLEXES. 391 obtained with slowly interrupted stimuli, and with rapidly interrupted stimuli a rise results. B. Splanchnic animal. 1. In this preparation too, with weak currents, increasing the frequency of stimulation may increase the extent and rate of the fall of blood-pressure. The same result is obtained after section of the right splanchnic nerve, to exclude the vaso-dilator fibres which are present in this nerve (Fig. 4) and also after section of the left splanchnic nerve. Fig. 4. Cat. Chloralose. Splanchnic preparation. Right splanchnic nerve divided. Stimulate left central vagus. 10 milliamp. in primary circuit; secondary coil fixed throughout. Stimuli: 2 d.s.p.s.; 50 d.s.p.s. Time in 2 sec. 2. When strong currents are employed in the primary circuit it is found in the splanchnic animal (as in the intact animal) that there is little difference in the extent and rate of fall of blood when the frequency is varied. The recovery process may be prolonged, however, following the more frequent stimulation. Thus in Fig. 5 the falls of blood-pressure Fig. 5. Cat. Chloralose. Splanchnic preparation. Artificialrespiration. (Natural breathing also present.) Stimulate left central vagus. 0 3 amp. in primary. 1st stim. 20 d.s.p.s. 2nd stim. 50 d.s.p.s. 3rd stim. 10 d.s.p.s. Time in 2 sec.

6 392 SAMSON WRIGHT. which occurred as a result of stimulation with 10, 20 and 50 d.s.p.s. were 64, 64 and 70 mm. Hg respectively. The respective durations of the recovery of the blood-pressure to normal were 23, 48 and 60 sec. There was in this case an after-rise following stimulation with 10 d.s.p.s. Pressor complications. Exceptionally it has been found that increasing the frequency of stimulation may diminish the fall of blood-pressure which occurs during stimulation and increase the extent of the afterrise. Intensity of stimulation. A. Intact animal. Increase in the strength of the stimulus applied to the depressor nerve (the frequency being kept constant) shortens the latency of the reflex, usually increases the rate and extent of the fall of blood-pressure and may prolong the duration of the recovery process. The shortening of the latency with stronger stimulation is difficult to demonstrate conclusively in the decerebrate animal, but quite clear cut results have been obtained under chloralose (Fig. 6). Fig. 6. Rabbit. Chloralose. Stimulate left depressor nerve. Distance of secondary coil from primary in cm. 0, 10, 15 in successive stimulations. Time in 2 sec. Initial blood-pressure 110 mm. The other features are well shown in Fig. 7 in which all respiratory disturbances were excluded. There is an appreciable difference in the rate of the initial part of the fall when the results with secondary coil at 5 and at 2l5 are compared; the difference is very evident in the latter part of the curves. With secondary coil at 2l5 the pressure fell as much during 12 sec. stimulation as it did during 36 sec. stimulation with it at 5. With the stronger stimulus there was a marked after-fall following the cessation of stimulation. In respect of strength of stimulation the vagus nerve also differs from the somatic nerves in the case of which the general rule is that weak

7 DEPRESSOR REFLEXES. 393 stimuli produce a reflex fall and strong stimuli a reflex rise of bloodpressure (13). B. Splanchnic animal. 1. In this preparation also, increasing the strength of stimulation may increase the rate and extent of the fall of blood-pressure. Thus in a Fig. 7. Cat. Chloralose. Artificial respiration. (Natural breathing also taking place.) Stimulate left central vagus. 1st signal: coil at 5 and coil at 2-5 for 12 sec. (superimposed tracings). The beginning and end with coil at 5 slightly precede that with coil at 2 5. Compare rate and extent of fall and the recovery process. 2nd signal: coil at 5 (36 sec.). Note in this case the more rapid return of the blood-pressure to normal after longer stimulation. Time in 2 sec. typical experiment stimulation with coil at 22X5, 20, 15 and 12-5 cm. resulted in falls of blood-pressure of 20, 28, 50 and 54 mm. Hgrespectively. 2. In some experiments there is little difference in the extent and rate of the fall of blood-pressure during the period of stimulation with different coil strengths, but a definite after-fall occurs on cesqation of the stronger stimulus. In Fig. 8 the extent of the fall of blood-pressure during the period of stim,ulation with coil at 17, 12-5 and 7*5 was 45, 48 and 56 mm. Hg respectively. Following stimulation with coil at 17

8 394 SAMSON WRIGHT. and 12-5 recovery set in almost immediately and was complete in 30 and 37 sec. respectively; following stimulation with coil at 7-5 there was Fig. 8. Cat. Splanchnic preparation decerebrate. Natural breathing and artificial respiration. Stimulate left central vagus for 10 sec. with coil at 12'5 and 7-5 (lst signal) with coil at 17 (2nd signal). (The stimulus with coil at 7-5 was applied first and was followed after an interval by weaker stimuli) Blood-pressure was lowered as a result of traction of nerve prior to stim. coil at Note after fall and slow recovery process following stim. coil at 7-5. Time in 2 sec. an after-fall of 34 mm. during the next 24 sec., then recovery set in and was not quite complete after another 100 sec. 3. Further points are brought out in the experiment illustrated in Fig. 9. A smaller initial rise of blood-pressure is there obtained on Fig. 9. Cat. Chloralose. Splanchnic preparation. Artificial respiration. 1st signal: stimulate left central vagus coil at 5. 2nd signal: stim. coi4 at 2-5. Drum stopped for periods of 30 sec. during recovery of blood-pressure. Time in 2 sec.

9 DEPRESSOR REFLEXES. 395 increasing the strength of stimulus. With stimulation coil at 5 when stimulation was discontinued rapid recovery occurred; with stimulation coil at 2-5 not only was there a greater fall of pressure during the period of stimulation and an after-fall, but in addition the blood-pressure remained at its minimal value for several minutes and then recovery occurred extremely slowly, though it was finally complete. The longer duration of the recovery process following stronger stimulation may be noted whether the stronger precedes the weaker stimulus or vice versa (Figs. 8 and 9). Prolongation of stimulation. A. Intact animal. 1. (a) Prolongation of the period of stimulation may increase the extent of the fall of blood-pressure in animals under chloralose and in the decerebrate condition (Fig. 10, see also Fig. 7). These effects may be Fig. 10 Rabbit. Chloralose. Stimulate left depressor nerve coil at 10. TiLme in 2 sec. Effect of prolongation of stimulus on extent of fall of blood-pressure and on subsequent recovery process. The slight fall which precede the stimuli are due to puffing on the nerve when adjusting the electrodes. Initial blood-pressure 105 mm. Hg. observed with stimuli which are well below maximal, and by increasing the strength or frequency of afferent stimulation the vascular relaxation can be made to proceed much faster. The blood-pressure does not usually fall with uniform speed; there may be a rapid initial fall and the rest of the fall proceed more gradually. (b)' Certain variations from this rule have been encountered-: (i) increasing the duration of stimulation may not increase the extent of the fall which is obtained, though submaximal stimuli are employed, (ii) the blood-pressure may tend to return to normial if weak stimulation is prolonged (Fig. 2), (iii) under continued stimulation an initial rise may pass into a fall.

10 396 96SAMSON WRIGHTO 2. As a rule the duration of the recovery period increases, within limits, with the length of the previous stimulation (Fig. 10). (a) The recovery process may be uniformly slowed down following the longer period of stimulation. This is most often noted when little further fall of pressure occurred during the latter part of the longer stimulation. Thus in the animal from which Fig. 10 is a sample it was found at a later stage of the experiment that stimulation for 25 or 52 sec. produced falls of blood-pressure of almost equal extent; but the durations of the recovery processes were 40 and 120 sec. respectively. These results may be obtained whether the longer stimulus succeeds the shorter or vice versa. (b) In other experiments, though the total duration of the recovery process is greater after more prolonged stimulation, the folowing feature is noted. After -a short stimulus the blood-pressure returns rapidly to normal, while after* l6nger stimulation a rapid partial recovery takes place followed by a gradual completion of the return of blood-pressure to normal. (c) Exceptionally the recovery period may be shorter after the stimulus of longer duration (Fig. 7). B. Splanchnic animal. In this preparation too, prolongation of the period of stimulation may increase the extent of the fall of blood-pressure and the duration of the recovery process. Thus in Fig. 11 stimulation for 8 sec. lowered the Fig. 11. Cat. Chloralose. Splanchnic preparation. Stimulate left central vagus 25 mrilliamp. in primary circuit. 54) d.s.p.s., secondary coil fixed. Time in 2 sec. Effects of prolongation of stimulus. pressure by 34 mm. Hg, and recovery was complete.in another 20 sec. Stimulation for 24 sec. lowered the pressure by 60 mm. Hg, and the

11 DEPRESSOR REFLEXES. 397 recovery process occupied 1 min. Later in this experiment stimulation for 50 sec. lowered the blood-pressure by 80 mm. Hg, and recovery occurred in 2 mi.; 10 sec. stimulation lowered the pressure by 35 mm. Hg, and recovery took place in 24 sec. DIscussIoN. 1. The results described show that there is a general resemblance between the effects of increasing the frequency and increasing the strength of stimulation. Both these procedures lead as a rule to an increase in the rate and extent of the fall of blood-pressure, and under certain circumstances to a prolongation of the duration of the recovery process. Increasing the duration of stimulation may also increase the extent of the fall of blood-pressure and the duration of the recovery process. Certain exceptions to these generalisations have been described, but these may possibly be attributed to some extent to a variable admixture of pressor fibres in the nerves stimulated. Very similar results have been obtained in the decerebrate animal and in chloralose anaesthesia, and most of the observations which were made in the intact animal have also been repeated in the splanchnic preparation. The results obtained resemble in a general way those described by Liddell and Slherrington (14, 15) in their studies of the skeletal muscle reflexes. In their researches, however, the reacting tissue is very rapid in its responses and a highly sensitive optical myograph was employed. The arteriolar wall on the other hand is a much more slowly reacting tissue, and the method employed for recording the changes which take place in it is relatively clumsy and possessed of considerable inertia. Further, the vasodilatation produced may set up secondary changes in the circulation such as reducing the venous return and interfering with the nutrition of the heart. It might be thought that these difficulties would exclude the possibility of any light being thrown by a study of these vascular reflexes on the intricate changes which take place in the nerve centres. Sharpey- Schaf er(4), however, has shown that the venous return is not diminished as a result of depressor stimulation, but may be inferred to increase. It is probable too that unless the mean blood-pressure is reduced very considerably and for a long time that the nutrition of the heart is not seriously impaired. The fact that these resemblances between skeletal and vascular reflexes can be shown suggests that the processes which take place in the sympathetic centres, controlling as they do slowly reacting peripheral structures, are much slower than those in the centres con, trolling skeletal muscle.

12 398 SAMSON WRIGHT. 2. It has been shown that increasing the frequency of stimulation often multiplies the size of the immediate effect produced (Figs. 1, 2). If it be accepted that in the splanchnic animal thoe vaso-dilatation observed on depressor stimulation is mainly due to inhibition of vaso-constrictor tone, then the fact that the results have been repeated in this preparation suggests that increasing the frequency of stimulation may result in the more rapid and more extensive formation of an inhibitory agent in the nerve centres; support is given to this contention by the fact that similar results are also obtained after section of the right splanchnic nerve (Fig. 4). 3. 'As the greater degree of dilatation which mayresult from increasing the duration of stimulation has been observed in the splanchnic animal it cannot be attributed wholly to peripheral accumulation of vaso-dilator substances, nor is it due to the properties of the slowly reacting peripheral mechanism. It is suggested that the process which is taking place is identical with the "inhibitory recruitment" described by Liddell and Sherrington, i.e. that prolongation of stimulation results in an increasing number of neurones being brought under the influence of the inhibitory process. 4. The results illustrated in Figs. 3, 7 and 10 seem to show that the duration of the return of the blood-pressure to normal does not depend entirely on the special properties of the blood vessels, for with approximately equal amounts of vascular dilatation the duration and character of the recovery process vary with the frequency, intensity or duration of the stimulation which has been previously employed. This suggests that the agencyresponsible forthe vaso.dilatation is capable of cumulation and that it may outlast the period of stimulation. In the intact animal the site of cumulation and persistence of the dilator agent might be central or peripheral or both; as some of these observations have been repeated in the splanchnic animal (Figs. 5, 8, 9) it is suggested that the inhibitory agent may persist in the nerve centres for a length of time which depends on the amount which has been accumulated during the stimulatory period, and that it may thus retard the return of the blood vessels to their normal posture, i.e. a process analogous to the " inhibitory after-discharge" of Liddell and Sherrington. SUMMARY. (1) The fall of blood-pressure which results from stimulation of the central end of the vagus (cat) or of the depressor (rabbit) has been studied from the standpoint of the physiology of reflex action, and particularly in the light of Sherrington's "humoral" theory.

13 DEPRESSOR REFLEXES. (2) The general features of the depressor reflex are the same in the intact animal as in the animal with the circulation restricted to thorax and abdomen ("splanchnic preparation"); in the latter the fall of blood-pressure which is obtained is probably chiefly the result of inhibition of vaso-motor tone. (3) The depressor reflex is often readily elicited by mechanical or thermal stimulation both under chloralose and in the decerebrate animal. (4) Increase in the frequency of afferent stimulation usually intensifies the inhibitory effect produced; there is an increase in the rate and extent of the fall of blood-pressure and sometimes in the duration of the recovery of the blood-pressure to normal. Similar results have been obtained in the "splanchnic animal." The first two results have also been observed after section of both splanchnic nerves in the splanchnic preparation. (5) Increase in the intensity of afferent stimulation in the intact and splanchnic animal increases the rate and extent of the fall of bloodpressure and may prolong the duration of the recovery period. In the intact animal it may shorten the latent period. (6) The effect of prolongation of the period of stimulation on the extent of the fall of blood-pressure and on the duration of the recovery period in both intact and splanchnic animal is described. (7) The results described resemble in many respects those obtained with skeletal reflexes. It is suggested they offer evidence that the processes of "recruitment" and "after-discharge" may take place in the vaso-motor "centre." REFERENCES Sherrington. Proc. Roy. Soc. B, 97. p Vincent and Curtis. This Journ. 63. p Langley, Ibid. 45. p Sharpey-Schafer. Quart. Journ. Exp. Physiol. 12. p Bayliss. This Journ. 14. p Bayliss. Proc. Roy. Soc. B, 80. p Bayliss. This Journ. 37. p Lewis and Marvin. Heart, 14. p ; This Journ ; Proc. Physiol. Soc. Nov Bradford. This Journ. 10, p Dale. Ibid. 46. p Thompson. Ibid. 65. p Gruber. Amer. Journ. Physiol. 42. p Ogata and Vincent. Journ. Comp. Neurol. 30. p Liddell and Sherrington. Proc. Roy. Soc. B, 95. p Liddell and Sherrington. Ibid. 97. p