Laboratory of Neurophysiology, Department of Physiology, University of Minnesota, Minneapolis, Minnesota

The Tuning of the Autonomic Nervous System through the Alteration of the Internal Environment (Asphyxia)* By E. GeBhorn With i9 Figures Previous investigations 5, 6 showed that the autonomic nervous system cab be "tuned" through drug-induced changes in the blood pressure. Since this tuning effect is absent after denervation of the sino-aortic area, it was inferred that the change in the reactivity of the autonomic nervous system was the result of baroreceptor reflexes 9. The present investigations are concerned with changes in central autonomic reactivity induced by an alteration in the internal environment of the organism. Earlier studies 3, 4, 11, 16, lz had shown that hypoglycemia leads to an increased responsiveness of the sympathetic system to direct stimulation of the vasomotor center and to reflex stimuli. In the experiments reported in this paper, asphyxia induced by the clamping of the trachea was chosen as the experimental condition because asphyxia alters profoundly but reversibly the reactivity of the sympathetic and parasympathetic divisions of the autonomic nervous system. The changes produced in the "tuning" of the autonomic nervous system under these conditions will be described, and related fundamental phenomena such as reciprocal innervation and homeostasis will be discussed. Methods The experiments were performed on more than 26 cats which were prepared under light barbiturate anesthesia (pentothal or nembutal) or chloralose and local anesthesia, later supplemented by intocostrin. Artificial respiration was used routinely. The blood pressure (from the femoral artery), the heart rate (through an ordinate writer) and the normal and acutely denervated nictitating membranes (n. m.) were recorded as in previous investigations from this laboratory 13, 21. The posterior hypothalamus was stimulated by means of a square wave generator (Grass) through Hess" elecThis work was carried out with the aid of a grant from the Louis W. and Maud ttill Family Foundation.

E. Gellhorn: Tuning of the Autonomic Nervous System

515

trodes. In some experiments the central end of the sciatic nerve was stimulated either with square wave currents or condenser discharges. The duration and spacing of the stimuli was regulated by a timer (see z). Aeetylcholine, mecholyl and histamine were injected intravenously. Results

I. T h e

Alteration

in

Sympathetic Asphyxia

Reactivity

during

Brief periods of asphyxia are characterized by sympathetic discharges indicated by the rise in the blood pressure, the acceleration of the heart rate, the contraction of the n. m., the dilatation of the pupil and other phenomena.

NNM

NNM

80 40 I30

c

t

Fig. 1. The reactivity of the hypothalamus during asphyxia and in the post-asphyxial state. A, asphyxia (horizontal line) for 60 seconds with stimulation of the right posterior hypothalamus (as in B) 15 and 55 seconds after the beginning of the asphyxia; B, stimulation of the right posterior hypothalamus at an interval of 40 seconds (1 v, 128/see., 0.4 ms fro" I second); C, 60 seconds of asphyxia with h y p o t h a l a m i c stimulation as in B, 55 seconds after readmission of air. Stimulation indieated by arrows. NNM, normal nictitating m e m b r a n e (n. m.); DNM, denervated n . m . ; last record, blood pressure (labeled PR by mistake).

If during this period the sympathetic division of the hypothalamus is stimulated, an increased sympathetie responsiveness occurs. Thus Fig. 1 shows that a stimulus which under control conditions (B) does not significantly alter the blood pressure and elicits a small contraction of the n. m., evokes when applied 15 seconds after the onset of the asphyxia a distinct pressor

516

E. Gellhorn:

effect which is greater than that produced by asphyxia by itself (C) and greatly increases the duration and height of the contraction of the n. m. (A). In the experiment of Fig. 1 this stimulus was applied a second time in "late'" asphyxia (55 seconds after the onset). During this phase the blood pressure and the heart rate decrease frequently. Nevertheless, the reactivity of the sympathetic system is still markedly increased, indicated by the augmented and greatly prolonged contraction of the n. m.

IGO 120 80

Fig. 2. Influence of asphyxia on hypothalamic sympathetic reactivity. A, stimulation of left posterior h y p o t h a l a m u s (1 v, 179/see., 1.6 ms for 5 seconds); B, 25 seconds of asphyxia with hypothalamie stimulation as in A; (3, 25 seconds of asphyxia. BP, blood pressure; PR, pulse rate. A n increase in the a m p l i t u d e of t h e pulse rate signifies a decrease in heart rate and vlce-versa.

~

B

C

NNM DNM

I

I

I

Fig. 8. H y p o t h a l a m i e stimulation during prolonged asphyxia. A, 90 seconds of asphyxia; B, h y p o t h a l a m i c stimulation indicated by a vertical line (I,5 v, 100/sec., 1.6 ms for 1.5 seconds) before asphyxia and 80 seconds after the onset of 90 seconds of asphyxia; C, h y p o t h a l a m i c stimulation as. in B. Note that the hypothalamie stimulus applied during the late phase of asphyxia elicits a contraction of the denervated n . m . (signifying adrenomedullary secretion) in B although neither asphyxia as such (A) nor the hypothalamic stimulus by itself (C) evokes this reaction.

Fig. 2 shows that the hypothalamically induced pressor response is increased and prolonged during asphyxia. Moreover, a shift in the autonomic balance occurs as disclosed b y the curve of the heart rate since the poststimulatory slowing of the heart rate is greatly diminished and delayed during asphyxia. Although this phenomenon will be discussed in a later section, attention is called to the fact that neither the increased pressor effect

Tuning of the Autonomic Nervous System

517

nor the diminished parasympathetic reactivity of the heart rate in B can be explained as the result of the algebraie summation of the effects seen in A and G. Whereas the fall of the blood pressure in "late'" asphyxia was small in the experiment of Fig. 1, it may reach shock levels if, as in Fig. 8, the asphyxia is prolonged. Nevertheless, the sympathetic reactivity remains increased. This is evident from the greatly enhanced responsiveness to hypothalamie stimulation of the normal n.m. and the occurrence, in the postasphyxial period, of an adrenomedullary secretion (contraction of the denervated n. m.~). As pointed out previously 5, 7a, increased sympathetic stimulation or increased excitability of the sympathetic system causes not only an increased neurogenie response b u t may also convert a sympathetic into a sympathetico-adrenal discharge. If a prolonged asphyxia is applied in a eat after extensive experimentation when the blood pressure is below 100 mm Hg, there is a tendency for the blood pressure to fall to shock levels and remain at such levels even after readmission of air. Restitution may be induced b y intravenous injection of adrenaline or b y hypothalamie stimulation. Hypothalamie stimuli given under these conditions elicit much greater sympathetie responses than in the pre-asphyxial control period. Although in the majority of our experiments the sympathetic reactivity was tested with hypothalamie stimuli, it was shown that similar results were obtained when the stimulus was applied to the sympathetic center in the medulla oblongata or to the central end of the sciatic nerve. In either case it was found that the sympathetic response was increased in asphyxia as indicated by an increase in the rise of the blood pressure, in the acceleration of the heart rate or in the height and duration of the eontraetion of the n . m . W h e t h e r one, two or all three indicators gave an increased response in asphyxia seems to depend on the site to which the test stimulus was applied, the parameters of stimulation, the excitability of the preparation, the duration of the asphyxia and similar factors. A final series of experiments was performed on the effect of asphyxia on the action of hypotensive drugs. It was shown in earlier work that hypotensive drugs elicit sympathetic discharges through reflexes involving the baroreeeptors of the sino-aortie area 9, is. In addition, conditions of increased sympathetic reactivity at the hypothalamie level caused a lessening of the hypotensive action due to an accelerated return of the blood pressure to, or even above, the control level and often also an increased acceleration of the heart rate and the appearanee of a contraction of the n. m. which was absent under control conditions 13. If asphyxia were associated with a sympathetic "tuning" of the autonomic nervous system one would expect similar changes to occur in the action of hypotensive drugs. Fig. 4 shows a typical experiment in which the great reduction of the hypotensive effect of aeetylcholine in asphyxia is illustrated. A similar effect is seen when meeholyl or histamine are injected. The chief alteration in the ~ Ligation of the adrenal veins abolishes the contraction of the denervated n. m. under these conditions ~4

518

E. Gellhorn:

hypotensive action appears in the quicker return of the blood pressure to the control level. This is likewise evident in Fig. 5 and is particularly striking in Fig. 6. In addition, the experiment of Fig. 5 shows an increased acceleration of the heart rate and Fig. 6 a more rapid and increased contraction of the n.m. during the aeetyleholine test in asphyxia. Here again it is obvious that the described alterations in the action of acetylcholine (and other hypotensive drugs) in asphyxia are not the result of the additive effects of the action of asphyxia and aeetylcholine when each of these factors is

KX) 03 A

glO

tc

I00 03

Abb. 4. Influence of asphyxia on the hypotensive action of aeetylcholine. A, 85 seconds of asphyxia; B, 0.002 mg/kg acetylcholine i. v.; C, aeetylcholine (as in B), during 85 seconds of asphyxia.

studied by itself. This is well illustrated in Fig. 6 which shows that asphyxia (C) but not aeetylcholine by itself (A) elicits a contraction of the normal n.m. Nevertheless, aeetylcholine plus asphyxia elicit a greatly increased contraction of the n.m. In other experiments an adrenomedullary response (contraction of the denervated n.m.) appeared on administration of acetylcholine in asphyxia although this hormonal response was absent when acetylcholine and asphyxia were administered separately. II. T h e

Reactivity

of the Parasympathetic Asphyxia

System

in

The reactivity of the parasympathetic system in asphyxia was studied by means of direct stimulation of the hypothalamus or by reflex stimuli. When the hypothalamus or the sciatic nerve were stimulated at a frequency

Tuning of the Autonomic Nervous System

5i9

of 10/see. or less, a parasympathetic effect on blood pressure and heart rate resulted in most experiments, although occasionally such effects were obtained also with somewhat higher frequeneies (Fig. 9). The first group of experiments comprise tests of parasympathetic reactivity which were performed during the "early" phase of asphyxia. As was mentioned above, asphyxia causes at first more or less generalized sympa-

A .

.

.

.

-1140

140 I00 6O

"160 120 80 Fig. 5. Effect of asphyxia on the action of aeetylcholine on blood pressure and pulse rate. A, 0.008 mg/kg acetylcholine i. v.; B, 45 seconds of asphyxia with acetylcholine (as in A) injected at the arrow; C, 4,5 seconds of asphyxia.

thetic effeets (rise in blood pressure, increase in heart rate, pupillary dilatation and contraction of the n. m. ~) whereas at a later phase signs appear which point to a shift in the autonomic balance to the parasympathetie side (falI in blood pressure and heart rate). If during the sympathetic phase of asphyxia noradrenaiine is injected, the reflex slowing of the heart rate which accompanies the noradrenalineinduced rise of the blood pressure under control conditions 21 is greatly reduced or absent (compare Fig. 7 B with A). This occurs although there was no significant change in the heart rate when asphyxia was administered by itself (Fig. 7 C). How greatly the parasympathetic reactivity is reduced in asphyxia is apparent from the fact that as the result of the interaction of The latter regularly in unanesthetized preparations 1~

520

E. Gellhorn:

the effects of asphyxia and noradrenaline on the blood pressure the latter rises in B considerably more than when noradrenaline is applied by itself (A). Nevertheless, the pulse slowing is less in B than in A although the noradrenaline-indueed parasympathetic reflex increases with increasing blood pressure, other conditions being equal. In order to give an approximate idea of the degree to which the parasympathetic reactivity is reduced in B, noradrenaline was injected in a slightly higher dose (0.005 mg/kg) in D in order to match the blood pressure effect produced by 0.0088 mg/kg during asphyxia (B). The degree of pulse slowing shown in D is the theoretically expected effect for B if no sympathetic tuning had taken place; or, to express it differently, the difference in the degree of pulse slowing between D and B rather than between A and B indicates the reduction in parasympathetic reflex reactivity occurring in asphyxia. Whereas the reflexly induced pulse slowing was used as an indicator of the parasympathetic reactivity in the experimental group represented in Fig. 7, the fall in blood pressure resulting from stimulation of the central end of the sciatic nerve served for this purpose in Fig. 8. As this figure shows, the depressor effect seen in A and D under control conditions is almost completely obliterated during asphyxia (B). It was shown elsewhere 5, 8 that stimulation of the sympathetic division of the hypothalamus is followed by a brief and abrupt slowing of the heart rate. This parasympathetic "rebound"-phenomenon is greatly weakened o~ abolished in asphyxia. Fig. 2 A shows that this "parasympathetic induction" occurs after 1 or 2 seconds following the period of stimulation, but it fails to occur during asphyxia *. It is inferred from these three groups of experiments that during the state of sympathetic tuning induced by asphyxia the parasympathetic response elicited by direct or reflex activation of the autonomic system or resulting as a "'rebound" from a preceding stimulation of the sympathetic system, is greatly reduced. The following experiments are concerned with the parasympathetic phase of asphyxia. It was stated earlier that asphyxia induces at first a sympathetic and then a parasympathetic phase. This parasympathetic phase is most frequently characterized by a fall in blood pressure and heart rate. Since, however, these phenomena may also result from heart failure, most experiments utilized for this group were performed while the blood pressure was still adequate. If in the same preparation a series of periods of asphyxia is administered at suitable intervals, there is a tendency for a shift in the autonomic balance to the parasympathetic side to occur. At first the rise in blood pressure and heart rate are most marked, and signs of parasympathetic dominance (fall in blood pressure and/or heart rate) are absent or occur only at the end of a prolonged asphyxia. After the asphyxia test had been applied repeatedly, the sympathetic changes produced by asphyxia are lessened, and the slowing of the heart rate becomes dominant. In a single experiment it was observed that injection of pentothal in the posterior hypoSee also Fig. 32 in no. 5.

Tuning

of the Autonomic

521

Nervous System

NM I00

C

EbP

I00

-t-Fig. 6. Increased sympathetic reactivity in asphyxia indicated by the response of the n . m . to acetylcholine. A, 0.008 mg/kg acetylcholine i . v . (arrow); B and D, acetylcholine as in A injected during a 50 seconds period of asphyxia (horizontal line); C, 50 seconds of asphyxia. The large deflections in the PR-curve are artifacts.

A

B

lt8o

BP

t C

D

,~1/1~,.

ll80

BP PR

I

I

-

Fig. 7. The noradrenaline-iuduced pulse slowing during asphyxia. A, 0.0083 mg/kg i. v. noradrenaline (arrow); B, noradrenaline (as in A) injected 7 seconds after the onset of a 50 seconds period of asphyxia; C, 50 seconds of asphyxia; D, 0.005 mg/kg i. v. noradrenaline.

522

E. Gellhom:

thalamus distinctly aggravated the intensity of pulse slowing in asphyxia. This effeet was reversible. In agreement with this observation is the fact that eats with a low sympathetic hypothalamie threshold seemed to show predominantly sympathetic discharges whereas in animals with higher sympathetic threshold (deeper anesthesia) the parasympathetic effects of asphyxia became more distinct.

A

E3

IOO i

.......L _ _ .

2

'

"~,

D

C

IOO

ESP

Fig. 8. The diminution of parasympathetic reactivity during the early phase of asphyxia. A and D, stimulation of the central end of the sciatic nerve (4 v, I0/sec., 8 ms for 12 seconds); B, sciatic stimulation (as in A) during an asphyxia of 85 seconds. Stimulation begins 15 seconds after its onset; C, .35 seconds of asphyxia.

] `o 'i' 'l

L

~1

ap

~

aSO

ii

B

~:

,J!lh . ~1 . J,_till,_ _ , ,

C

Jso

D

Fig. 9. Increased parasympathetic reactivity during the parasympathetic phase of asphyxia. A and D, 45 seconds of asphyxia with stimulation of the left posterior h y p o t h a l a m n s (4.4 v, g0/see., 8 ms for I0 seconds); B, 45 seconds of asphyxia; C, hypothalamic stimulation (as in A) by itself.

Fig. g B shows that in this preparation the blood pressure rises slightly during asphyxia but the heart rate does not increase. After about 15 seconds of asphyxia the heart rate decreases slightly to a steady level, whereas in the last third of the period of asphyxia rhythmical variations in blood pressure and heart rate occur. As the record shows, a fall in the blood pressure is associated with a decrease in heart rate. During this phase a hypothalamic stimulus is applied which by itself (C) displays first a minimal sympathetic effect on the blood pressure (questionable acceleration of the heart rate) and then a moderate parasympathetic action (slight fall in blood pressure

Tuning of the Autonomic Nervous System

523

and heart rate). This effect disappears in a few seconds after the stimulation. If, however, this stimulus is applied during the parasympathetic phase of asphyxia no sympathetie effects appear on the blood pressure during the stimulation, and the pulse slowing is slightly greater than in the eontrol test C. The main effect occurs in the post-stimulatory period. The blood pressure falls rapidly while the heart rate is greatly decreased. This phenomenon occurs once in A and twice in D, but is absent in the control test C. Another example of increased parasympathetic reactivity is shown in Fig. 10. A hypothalamic stimulus of a low frequency (8/see.) was chosen whieh elicits in the control test (C) a slight fall in the blood pressure and a minimal slowing of the heart rate. If this stimulus is applied during asphyxia which by itself (B) slows the heart rate to only a minimal extent, its

1120

,, ..............

BP

J PR

II

I ~ --

A

,.

13

C

Fig. 10. Increased parasympathetic reactivity during asphyxia. A, 40 seconds of asphyxia with stimulation of left posterior hypothalamns (8 v, 8/see., 0.8 ms for 10 seconds); B, 40 seconds of asphyxia; C, hypothalamie stimulation (as in A) by itself.

parasympathetic aetion on the heart rate is greatly enhanced (A). In another experiment it was seen that the parasympathetic reflex action eaused by stimulation of the central end of the sciatic nerve applied during the last 10 seconds of a 60 seconds period of asphyxia, produced a greatly increased parasympathetic effeet on blood pressure and heart rate, not only during the stimulation but also in the post-stimulatory period after air had been readmitted. From these and similar experiments it is concluded that during the parasympathetic phase of asphyxia the reactivity of the parasympathetic system to hypothalamic and reflex stimulation is increased. III. A u t o n o m i c

Discharges in Period

the

Post-asphyxial

The post-asphyxial period is eharaeterized by the occurrence of "spontaneous" discharges of the autonomic nervous system on readmission of air and also by changes in autonomic reactivity. Since these discharges seem to account for the alterations in reaetivity they will be described first. When in lightly anesthetized cats asphyxia is administered for a brief period of time (80 to 50 seconds) it elicits in general a rise in blood pressure, an acceleration of the heart rate and a contraction of the normal n. m. (but not of the denervated n. m.). On readmission of air these ehanges become reversible. It may be said that the sympathetic discharges are con-

524

E. Gellhom:

fined to the period of asphyxia under these conditions (Stage I of Fig. 11). If; however, this experiment is repeated after more barbiturate has been administered or after the preparation has somewhat deteriorated by prolonged experimentation, the sympathetic discharges which occur during asphyxia are lessened, and the contraction of the normal n.m. is absent. If

llll/m~ DI/M

.L

-

r

r

X/t/,/

Dill,4

I

.....

.

,

////H DNW

I ~

I

Fig. 11, Diagram illustrating sympathetic and sympathetico-adrenal discharges during and after asphyxia of increased duration. T h e normal n. m. is an indicator of sympathetic, the denervated n . m . an indicator of sympathetlco-adrenal discharges. Further explanation in the text,

in this state the influence of a more prolonged asphyxia is studied it is found that a sympathetico-adrenal discharge occurs on x'eadmission of air. This is characterized by the fact that several seconds after readrnission of air (or oxygen) the heart rate and the blood pressure rise abruptly, and the normal n. m. contracts. Then the denervated n. m. contracts gradually while

Tuning of the Autonomic Nervous System

5"25

the normal n. m. relaxes (Stage If). Not infrequently an intermediary stage is observed in which the neurogenic sympathetic discharge causes the contraction of the normal n.m. to appear in the later part of the asphyxia, whereas the adrenomedullary discharge (contraction of the denervated n. m.) occurs after the readmission of air. Finally, with further depression of the excitability of the central nervous system, or under the influence of a longer period of asphyxia, the shift in the autonomic balance to the parasympathetic side becomes more pronounced and, on readmission of air, only the denervated n.m. and not the normal n.m. contract (Stage III). If under these conditions large adrenomedullary discharges occur they may lead to Table 1. Effect of asphyxia of different durations and sympathetic discharges and

adrenomedullary secretion Blood Pressure

NNM**

Asphyxia

J

DNM

1"

2*

3*

4*

60"

128

160

160

172

24 (2o)

0

95 j~

106

156

90

176

13 (30)

5 (108)

120"

120

170

96

188

12 (25.)

45 (126)

1, initial blood pressure; 2, maximal blood pressure during asphyxia; 3, blood pressure at the end of the asphyxia; 4, post-asphyxial rise. 3, Height of contraction of NM in arbitrary units. The number in ( ) indicates the onset of the contraction in seconds after the beginning of the asphyxia. NNM z normal n.m.; DNM ~ denervated n.m. a contraction of the normal and of the denervated n. m.; but the characteristic difference in the latent period is absent: both membranes contract at the same time. This occurs often many seconds after readmission of air. The following figures and Table 1 illustrate these characteristic stages in the action of asphyxia through typical examples. The three tests involving periods Of asphyxia of 60, 95 and 120 seconds respectively (Table 1) show the following changes to occur with increasing duration of asphyxiai 1. The fall in the blood pressure following the initial sympathetic phase is considerable in the 95 and 120 seconds asphyxia tests * but is not present. in the 60 seconds asphyxia experiment, suggesting an increasing parasympathetic dominance with increasing duration of asphyxia. 2. The rise of the blood pressure following readmission of air increases with the increase in the duration of the preceding asphyxia. 3. The contraction of the normal n. m. decreases and that of the denervated n.m. increases from tests 1 to 8. The neurogenie response (normal n.m.) occurs during asphyxia, but the adrenomedullary response (denervated n. m.) occurs in the post-asphyxial period. 9 Note that the blood pressure does not fall to shock levels! Aeta Neurovegetativa, Bd. XX, Heft 4.

34:

526

E. Gellhorn:

A similar shift from the dominance of the neurogenic sympathetic reaction to that of the adrenomedullary reaction was observed in our earlier studies 22, 32 under the influence of increasing concentrations of barbiturates. Three different types of sympathetieo-adrenal discharges elicited by asphyxia are shown in the following figures. Fig. 1 C illustrates an experiment

biNM

BP A Fig. t2. Sympathetieo-adrenal discharges in a rise in the blood pressure; B, 85 seconds asphyxia (contraction of the normal n . m . ) the denervated

B asphyxia. A, 60 seconds of asphyxia causes only of asphyxia causes a sympathetic discharge during and an adrenomedullary discharge (contraction of n. m.) a#er asphyxia.

DNM

Fig. 13. Adrenomedullary discharges after prolonged asphyxia. The figure illustrates the end of the period of asphyxia (125 seconds, indicated by the horizontal line) and the post-asphyxial period. During the latter the n. m.'s contract simultaneously. Vagotomized cat. Small horizontal line z 10 seconds.

in which the sympathetico-adrenal discharge occurs after the readmission of air, the neurogenic discharge distinctly preceding the hormonal discharge. An experiment in which the contraction of the normal n. m. occurs during but that of the denervated n. rn. after the period of asphyxia is illustrated in Fig. 12 B. Under these conditions the interval between the onset of the contraction of the normal and the denervated n.m. may be considerable, in some experiments longer than one minute. When both membranes con-

Tuning of the Autonomic Nervous System

527

tract in the post-asphyxial period as in the experiment of Fig. 1 A, the interval is only about 8 to 10 seconds, but the rapidity and short duration of the contraction of the normal n. m. differentiate the neurogenic from the more slowly developing and more prolonged hormonal response. Finally, Fig. 18 shows that after prolonged asphyxia contractions of both membranes develop in a parallel fashion long after the readmission of air. They are interpreted as being due to the secretion of the adrenal medulla ~ The autonomic discharge of the post-asphyxial period can be modified by stimulation of the sympathetic system during the asphyxia. If, for instance asphyxia produces a slight contraction of the denervated n. m. on readmission of air, this effect can be greatly increased by the application of a weak stimulus to the posterior hypothalamus toward the end of the period of asphyxia ~ . In other experiments it was seen that when asphyxia of a certain duration failed to produce a contraction of the denervated n.m. on readmission of air, the application of a hypothalamic sympathetic stinmlat/on in the latter part of the asphyxia produced not only signs of increased sympathetic reactivity (as described earlier) but induced a hormonal response (contraction of the denervated n. m.) after cessation of asphyxia. These and similar experiments have the fact in eommon that hypothalamie sympathetic stimulation when applied in asphyxia increases adrenomedullary discharges in the post-asphyxial period. Sympathetieo-adrenal discharges have been observed on readmission of air after asphyxia induced by clamping of the trachea and also after rebreathing. Since this discharge is most marked after a prolonged asphyxia, which tends to lower the blood pressure, one might think that the baroreceptor reflexes may be essential for this phenomenon. It was seen, however, that the sympathetico-adrenal discharge in the post-asphyxial period occurs in eats with denervation of the sino-aortie area and also in normal cats in which the asphyxia did not produce a fall in the blood pressure. These findings do not exclude the possibility that a signifieant fall of the blood pressure at the end of the asphyxia may contribute, on readmission of air, to the greater reactivity of the sympathetic centers and thereby to a sympathetico-adrenal or an adrenomedullary discharge. In the report given in this section, the behavior of nictitating membranes as indicators of neurogenic and adrenomedullary discharges was emphasized. These data must be supplemented by observations on the blood pressure and heart rate in the post-asphyxial period. Our experiments show two phases in the post-asphyxial period: 1. Several seconds after the readmission of air the blood pressure rises more or less abruptly, and [his rise is assoeiated with a brief but marked acceleration in the heart rate (Fig. 14). This rise in blood pressure is greatest in experiments in which the blood pressure had fallen below the control The slightly greater contraction of the denervated n. m. is due to its greater sensitivity to noradrenaline and adrenaline. ~ See the greater post-asphyxial eontraetion of the denervated n.m. in Fig. 1 A (involving hypothalamie stimulation) than in the corresponding control test in C. 34"

528

E. Gellhorn:

level at the end of the asphyxia. In such experiments the post-asphyxial pressor phase leads often to higher pressure than was observed during asphyxia. However even in those tests in which the blood pressure was still above the control level at the end of the asphyxia period, the readmission of air may initiate a distinct rise in blood pressure as in Fig. 15 B.

Fig, I4. Sympathetie and parasympathetic discharges in the post-asphyxial state. Asphyxia for 85 seconds. Note the acceleration of the heart rate associated with the sharp pressor effect followed by a period of sustained increased blood pressure with marked reflex slowing of the heart rate.

2. The last phase is followed by one in which the blood pressure continues to rise, but at a lesser gradient. It then levels off. During this second phase the heart rate is greatly reduced (Fig. 14). Then blood pressure and heart rate return gradually to the control level. These experiments seem to show that during asphyxia as well as in the post-asphyxial period a sympathetic phase precedes a phase in which the parasympathetic system is dominant.

60

r

~X3 60

Fig. 15. Alteration in the autonomic response to asphyxia with prolonged experimentation, A and C, 0.0014 mg/kg noradrenaline i . v . ; B and D, 70 seconds of asphyxia. T h e tests G and D were performed after an interval of 21 and 77 minutes respectively.

The degree and duration of these changes in autonomic discharges depend on the duration of the asphyxia as mentioned earlier, and also on the state of the autonomic nervous system before the administration of the asphyxia. Previous studies ~2 had shown that the type of sympathetic discharge elicited by asphyxia and other conditions is altered when the cerebral reactivity in general and the hypothalamic responsiveness in particular are decreased,-regardless o f whether this change is brought about by an increasing, depth of anesthesia, prolonged experimentation or other factors. It was found that under these conditions the neurogenic discharge (indicated

Tuning of the Autonomic Nervous System

529

by the normal n.m.) is lessened and the adrenomedullary discharge (indicated by the denervated n.m.) is augmented. But, in addition, even more profound changes in autonomic balance may occur. Fig. 15 B shows that asphyxia produces a strong sympathetic effect: the blood pressure rises considerably and remains even at the end of the asphyxia period about

~ D ~ ~

120 80 40

Illl I zx

I B

i

120 80 40 I

C

I

D

Fig. 16. Comparison between the hypothalamic responsiveness during and after asphyxia, (For further e:~planation see the text.) A and C, stimulation of the left hypothalamus (1.5 v, ]00]sec., 1.6 ms for 1.5 seconds); B, 80 seconds of asphyxia with hypothalamic stimulation (as in A) at 40 seconds of asphyxia and I0 seconds after asphyxia; D~ 90 seconds of asphyxia with hypothalamic stimulation 19 seconds after readmission of air.

80 mm Hg above the control value. When this test was repeated 77 minutes later (D) after the animal had been subjected to some further tests, the sympathetic phase occurring during asphyxia is lessened in duration and intensity as the record of the blood pressure and heart rate indicate, and the parasympathetic phase becomes dominant; the blood pressure falls slightly and the heart rate is decreased greatly. It is of interest to point out that a noradrenaline test applied at an earlier (A) and later time (C) of the experiment shows likewise an increase in parasympathetic reflex excitability. The noradrenaline-indueed slowing of the heart rate is more marked in C than in A although the rise of the blood pressure was less in C.

530 IV. T h e

E. Gellhorn: Autonomic

Reactivity Period

in t h e

Post-asphyxial

If the sympathetic division of the hypothalamus is stimulated within the first 10 to 12 seconds after readmission of air i. e. during the time when in most experiments the blood pressure rises and the heart rate increases, the responsiveness of the sympathetic system is greatly augmented. This is clearly seen by the nearly maximal response of the n. m. in Fig. 16 B to a stimulus which under control conditions (A) elicited only a small contraction. Fig. 16 D shows in the same cat the effect of hypothalamic stimulation after several additional asphyxia tests had been performed in an experiment in which the period of A was extended to 90 seconds. In this experiment the blood pressure fell briefly to shock levels but recuperated rapidly on readmission of air. The sympathetic responsiveness was again greatly increased in the post-asphyxial period. The experiment shows that the increased sympathetic responsiveness occurs in the post-asphyxial period regardless of whether the blood pressure at the end of the asphyxia is above or greatly below the control level. The increased responsiveness of the sympathetic system during the post-asphyxial period is further illustrated by the fact that a hypothalamic stimulus which elicits under control conditions a contraction of the normal but not of the denervated n.m., may call forth after asphyxia a contraction of both membranes (with a greater latent period on the denervated membrane). Moreover, the pressor effect of the hypothalamie stimulus is often magnified and prolonged. In a typical example it was found that after 85 seconds asphyxia the blood pressure rose to 120, 145 and 145 mm Hg after 20, 40 and 60 seconds respectively. If, however, a hypothalamic stimulus which by itself raised the blood pressure 8 mm (and this effect was confined to the 10 seconds period of stimulation) was applied 4 seconds after the 85 seconds asphyxia, the pressure was more than 200 mm Hg at 20, 40 and 60 seconds. It was shown in section III that the post-asphyxial period may be divided into a short sympathetic phase and a more prolonged phase in which the blood pressure remains elevated but the heart rate is decreased. If during the latter phase the hypothalamus is stimulated the pressor response is greatly decreased or abolished (Fig. 17). Moreover, the contraction of the n.m. to hypothalamic stimulation is likewise diminished (see ~, p. 60). It may, therefore, be said that during this phase of parasympathetic dominance the sympathetic reactivity is decreased. In a final group of experiments the parasympathetic reactivity was tested during this phase. Fig. 18 shows an experiment in which a hypothalamic stimulus of low frequency applied under control conditions elicits a gradual fall in blood pressure and a slight slowing of the heart rate (A). This stimulus applied during the parasympathetic phase of the post-asphyxial period when the blood pressure is elevated and the pulse rate is diminished, evokes a more abrupt fall in the blood pressure and a much greater deceleration of the heart rate (B) than in the control test. Such increased responsiveness ef the parasympathetic system in the post-asphyxial period may even appear when the late post-asphyxial phase fails to show signs of slowing of the

Tuning of the Autonomic Nervous System

531

heart rate. Fig. 19 A shows that following asphyxia the blood pressure rises moderately while the slight deceleration of the heart rate whiche occurs at the end of the asphyxia disappears. Then follows a phase during which the blood pressure remains elevated but no slowing of the heart rate occurs. If

1(30 6O

A

t

CB

Fig. 17. Lessened sympathetic reactivity in the post-asphyxial state. A, 40 seconds of asphyxia followed in the post-asphyxial state by a hypothalamic stimulation (arrow') with 3 v, 207/see., 0.2 ms for 5 seconds; B, same stimulation by itself.

~dlll~~..

1120

rr'~m

A

B

Fig. 18. Increased parasympathetic reactivity to hypothalamie stimulation in the post-asphyxial state. A, stimulation of the left posterior hypothalamus (8 v, 8/see., 0.8 ms for 10 seconds); B, 65 seconds of asphyxia (long horizontal line) followed by hypothalamic stinmlation as in A (short horizontal line)9

BP PR-

'PR

s-~

I

Fig. 19. Increased parasympathetic reactivity to sciatic nerve stimulation in the post-asphyxial state. A, 70 seconds of asphyxia; B, 70 seconds of asphyxia followed, 9 seeonds after readmissimt of air, by stimulation of the central end of the sciatic nerve with 4 v, 10/see., 8 ms for 9 seconds; C, sciatic stimulation (as in B) by itseIf; D, 70 seconds of asphyxia followed by sciatic stimulation 12 seconds after readmission of air.

532

E. Gellhorn:

during this period the parasympathetic system is stimulated reflexly, a greater response occurs than under control conditions, Fig. 19 C shows that stimulation of the sciatic nerve at a low frequency produces a slight fall in the blood pressure and a trace of slowing of the heart rate. If this stimulus is applied 9 seconds (B) or 12 seconds (D) after readmission of air it evokes a marked deceleration of the heart rate and an abrupt fall of the blood pressure to the control level. This experiment shows that following the sympathetic discharge of the post-asphyxial period a phase of increased parasympathetic reactivity occurs even in those experiments in which the heart rate does not fall below the control level. Discussion Two groups of data were obtained from the experiments described in this paper; one pertains to the autonomi c discharges occurring during and after asphyxia, the other to the alterations in autof~omic reactivity in these conditions. The increased blood pressure and heart rate and the contraction of the normal n. m. indicate the prevalence of sympathetic discharges in early asphyxia. The frequent absence of the contraction of the n.m. in our anesthetized animals is in agreement with the previously investigated assumption 1~, 22 that this reaction depends on diencephalic-cortical structures and, therefore, is easiIy depressed by a/aesthetics. Although in normal animals the blood pressure and heart rate decrease in the later phases of asphyxia, experiments on vagotomized cats showed that the increased pulse rate persists throughout the asphyxia. It may be said, therefore, that although the dominance shifts from the sympathetic to the parasympathetic Side with increasing duration of asphyxia, increased sympathetic discharges continue throughout this period * On readmission of air the sympathetic discharges become again dominant and intensified. The blood pressure and heart rate rise considerably while sympathetic or sympathetieo-adrenal discharges lead to contractions of the normal n. m. or of the normal and denervated n. m.'s. This phase is followed by one in which the blood pressure reaches a plateau while the heart rate declines. The high blood pressure indicates the persistence of sympathetic discharges while the decline in the heart rate shows the effect of parasympathetic reflex activity. These observations seem to indicate that a similar pattern in autonomic activity prevails during asphyxia and in the post-asphyxial state: the sympathetic discharges are increased throughout but the parasympathetic reactions become manifest only in the later stages of asphyxia and of the post-asphyxial period. If in these different periods the autonomic reactivity is tested by direct stimulation of the hypothalamus or the medulla oblongata or by reflex stimuli (through stimulation of the sciatic nerve or administration of hypotensire drugs) it is found that the sympathetic reactivity is increased during asphyxia and also during the sympathetic discharge which occurs on reConcerning the older literature see E, Gellhorn 4

Tuning of the Autonomic Nervous System

533

admission of air*. This increased reactivity may appear as an increased responsiveness of all the indicators used (blood pressure, heart rate, n. m.) or it may be restricted to one or two structures, illustrating the important fact that experimentally induced alterations in autonomic reactivity may involve only a part of the sympathetic system. Another observation is worthy of emphasis. The sympathetic discharge on readmission of air is in general ** much stronger and more abrupt than that seen during asphyxia. This phenomenon is paralleled by the greater sympathetic reactivity to stimulation following readmission of air than was seen during asphyxia. If we consider now the changes in the parasympathetic reactivity during and after asphyxia, it may be said (see Figs. 9 and 10) that during the late stages of asphyxia in which the parasympathetic discharge manifests itself in a slowing of the heart rate (and also in a fall of the blood pressure) the reactivity of the parasympathetic system to direct and reflex stimulation is distinctly increased. In the early stage of asphyxia, however, these stimuli elicit a lesser parasympathetic response than under control conditions (Figs. 2, 7 and 8)***. The early phase of asphyxia, is therefore, characterized by reciprocal relations between the responsiveness of the two divisions of the autonomic system, whereas during late asphyxia the parasympathetic and sympathetic reactivity are augmented. During the late stages of the post-asphyxial period in which the blood pressure is elevated and a reflex slovCing of the heart rate occurs, the autonomic reactivity shows reciprocal relations: parasympathetic effects (elicited directly or reflexly) are increased (Figs. 18 and 19) while the responsiveness of the sympathetic system is lessened (Fig. 17). When we correlate the alterations in autonomic reactivity ("tuning") with the autonomic discharges prevailing at the various phases of asphyxia (including the post-asphyxial period) it may be said that a state of sympathetic tuning occurs when the sympathetic discharges are increased, and a state of parasympathetic tuning predominates when the parasympathetic discharges are augmented. These data suggest that the alteration in the reactivity of the autonomic system results from the interaction of the test stimulus with the autonomic discharges induced by the "tuning". Previous experiments z have shown that two sympathetic or two parasympathetic stimuli applied simultaneously produce much greater effects than corresponds to the algebraic summation of the individual effects. Therefore, if we increase sympathetic discharges through asphyxia, the sympathetic test stimulus produces an effect which is greater than in control conditions. This simple explanation seems to hold also for the state of parasympathetic tuning in the late stages of asphyxia and of the post-asphyxial period and apConcerning the inhibition of sympathetic reactivity during strong adrenomedullary discharges see ~a and ~s ~ Except in experiments with very brief periods of asphyxia in which the post-asphyxial sympathetic discharge is absent. ~ See also the disappearance of the pulse slowing in asphyxia when the sympathetic discharges are increased reflexly through aeetylcholine (Fig. 6 D),

534

E. Gellhom:

pears to be applicabIe to the tuning of the autonomic nervous system induced by baroreeeptor reflexes as described in a preceding investigation 6. Since the interaction of t~vo stimuli exciting the sympathetic (or the parasympathetic) division of the autonomic nervous system leads to potentiating effects 7 it is understandable that during asphyxia a stimulus may be effective at an intensity which is below the threshold under control conditions. Similarly, a brief period of asphyxia may in a certain case fail to raise the blood pressure and yet increase the pressor effect of a hypothalamie stimulus. Although our experiments on the reactivity of the autonomic system in early asphyxia and during the late stage of the post-asphyxial period give evidence for the validity of the law of reciprocity under the conditions of tuning through asphyxia, it should be stressed that certain exceptions occur. In late asphyxia there is an increased reactivity to sympathetic and parasympathetic stimuli. The reason for this behavior seems to lie in the fact that sympathetic and parasympathetic discharges are increased as evidenced by the increased heart rate of the vagotomized animal and the slowing of the pulse rate of the normal eat in late asphyxia. That reflex stimuli and excitation of central autonomic structures may lead to simultaneous discharges in both branches of the autonomic system was shown in previous investigations in which the blood sugar served as an indicator: numerous conditions were shown to cause vago-insulin and sympathetieo-adrenal discharges 4. Although the "tuning" action of asphyxia elicits with great regularity the changes in autonomic reactivity described in this paper, certain important variations occur spontaneously or may be induced experimentally. Thus it was shown that prolonged experimentation lessens sympathetic and augments parasympathetic discharges in asphyxia (see Fig. 15). Since the quality and the degree of "tuning" depends on the nature and intensity of the autonomic discharges present when the test stimulus is applied, it is easily understandable that a fresh preparation may differ, at least quantitatively, in its autonomic reactivity from a somewhat deteriorated one. It is obviously the balance between the sympathetic and the parasympathetic discharges which determines the reactivity. This principle may be illustrated by a few examples. It was emphasized that during early asphyxia the sympathetic reactivity is greatly increased (see Figs. 1 and 2). On the other hand, it was shown previously 6 that a rise in blood pressure leads via the baroreeeptor reflexes to a "parasympathetic tuning" as illustrated by the increased responsiveness of the parasympathetic system and by the diminished reactivity of the sympathetic system during the noradrenaline-indueed pressor phase. This baroreceptor reflex is, of course, elicited when the blood pressure rises during asphyxia, but, in general, it is offset by the prevailing sympathetic discharges. Occasionally, however, the balance is shifted in the opposite direction; then it is seen that a hypothalamie sympathetic stimulus is less effective during the asphyxia-induced pressor phase than under control conditions (see Fig. 16 B). The contraction of the n. m. is less than in the preceding control test A.

Tuning of the Autonomic Nervous System

535

Another example concerns the late post-asphyxial period. In one eat it was seen repeatedly that the post-asphyxial rise in blood pressure was excessive (the blood pressure rose to more than 210 m m after a 95 seconds period of asphyxia) and was maintained at this level for more than 2 minutes. During this time the heart rate was greatly accelerated, whereas, in general, a reflex slowing prevails in the late post-asphyxial phase. W h e n a hypothalamie stimulus was applied during this phase it evoked a greater contraction of the n. m. than under control conditions. Apparently the sympathetic discharge was so strong that it wiped out the parasympathetic reTable 2. The occurrence of parasympathetic discharges during asphyxia at an increased level of the blood pressure Sympathetic I Parasympathetic Control

1. B1. Pr. H.R.

2. B1. Pr. H.R. 3. B1. Pr. H.R.

149 * q- ** 106 *

+ + ** tO0 *

Phase of Asphyxia

1w

Duration of Asphyxia in seconds

160

75

140

95

210

16~

95

+q-q-

-4-++

+§ 168

+§

* In mm Hg. ** Indicating relative changes in heart rate. The heart rate was much greater under control conditions in experiment 2 than in experiment 1 and slowest in experiment 8.

flexes which are ordinarily dominant in this phase and lead to an increased parasympathetic (Figs. 18 and 19) and a decreased sympathetic reaction (Fig. 17). Although it is known that the fall in the blood pressure and heart rate which occurs late in asphyxia may be related to the failure of the heart 2 our experiments demonstrate a slowing of the heart rate in late asphyxia when the blood pressure is still high. In several experiments this slowing was shown to disappear after vagotomy. Whereas in the typical experiments described above a sympathetic discharge (rise in blood pressure and heart rate) followed by a parasympathetic discharge (fall in blood pressure and heart rate) is observed in asphyxia, in some instances the parasympathetic phase appeared in late asphyxia while the blood pressure was considerably above the pre-asphyxial level (Table 2). W h e n the preparation was in a state showing a considerable sympathetic discharge indicated b y a high heart rate in the control period (as in no. 2 of Table 2) no further acceleration of the heart rate occurred in asphyxia. In such eases the parasympathetieally induced slowing of the heart rate takes place, as usual, in late asphyxia. Conversely, it was seen that when asphyxia produced a particularly great sympathetic response a parasympathetic discharge did not ap-

536

E. Gellhorn:

pear in the heart rate during a 95 seconds period of asphyxia (see no. 8 of Table 2). These observations are of interest because they demonstrate the importance of the state of the autonomic systSm for its quantitative and often even qualitative response to asphyxia. If, in the late post-asphyxial period the sympathetic discharges are excessive, the parasympathetic reflexes are suppressed and the sympathetic reactivity remains greatly increased in contradistinction to the reduced sympathetic responsiveness seen in most animals in this phase. It is suggested that the increased baroreceptor reflexes which result from the excessive pressor effect are unable to become effective in a phase of unusually large central sympathetic discharges which were initiated by the readmission of air. On the contrary, when the sympathetic discharges elicited during asphyxia are relatively weak, the rise of the blood pressure in asphyxia may increase the baroreceptor reflexes to such a degree that these parasympathetic reflexes become dominant. Under such conditions as in Fig. 16 B, the sympathetic reactivity is reciprocally diminished. In spite of these important deviations from the normal, the regular as well as the unusual responses seem to be explainable on the basis of the summation processes outlined above. The tendency for the sequence sympathetic d o m i n a n c e - parasympathetic dominance to occur during asphyxia and also in the post-asphyxial period seems to serve homeostasis. The excessive sympathetic discharges seen occasionally in the post-asphyxial period are obviously examples of an overshooting reaction which follows marked parasympathetic discharges occurring at the end of a prolonged asphyxia. Finally, the phenomena occurring a few seconds after readmission of air should be discussed. It was known from earlier studies that severe anoxia or asphyxia which causes disappearance of normal and convulsive cortical potentials is followed, after air or oxygen had been administered, by a striking "rebound" phase during which the potentials reveal an intensive excitation of the cortex 10, 19. Even generalized convulsions may occur 23. At the same time the threshold of various sense organs is lowered 1~, 28. The circulatory changes such as the sudden rise in blood pressure and heart rate described in this paper for the cat were observed by Noell and Schneider 20 in rebreathing experiments in the dog. The simultaneous recording of the n. m.'s in our work shows that asphyxia leads to a sympathetico-adrenal discharge on readmission of air and suggests that the marked alterations in the cerebral functions which occur at this phase are closely related to these strong autonomic discharges *. Summary In experiments on lightly anesthetized, curarized cats the autonomic discharges occurring during asphyxia and in the post-asphyxial period were investigated. Moreover, the changes in the reactivity~ 0 f t h e autonomic system were studied by Concerning the influence of sympathetico-adrenal discharges and adrenomedullary secretion on cerebral activity see 1 and is

Tuning of the Autonomic Nervous System

537

testing it under these conditions by means of direct stimulation of the autonomic centers in the hypothalamus and medulla oblongata as well as by reflex stimuli (stimulation of the central end of the sciatic nerve and baroreceptor reflexes elicited by hypo- and hypertensive drugs). It was found: 1. that during asphyxia sympathetic discharges lead to a contraction of the normal nictitating membrane (n. m.), a rise in blood pressure and an acceleration of the heart rate. In more prolonged periods of asphyxia the blood pressure tends to fall and the heart rate is slowed considerably. The increased heart rate, however, persists in the vagotomized cat, indicating that the sympathetic discharges persist throughout the whole period of asphyxia although the parasympathetic discharges become dominant for the heart rate in the late phase of asphyxia; 2. that strong sympathetic discharges are observed immediately following the readmission of air or oxygen which lead to an abrupt increase in blood pressure and heart rate and a contraction of the normal and denervated n. m.'s; 8. that after this phase the blood pressure remains elevated for a considerable period of time during which the heart rate is slowed reflexly and the n.m.'s are relaxed (late post-asphyxial phase). The testing of the autonomic reactivity during asphyxia disclosed: 1. that the reactivity of the sympathetic system to direct and reflex stimuli is increased throughout the period of asphyxia, even in its latter part when the blood pressure and the heart rate tend to fall below the pre-asphyxial level; 2. that the reactivity of the parasympathetic system is diminished during the early phase of A in which the sympathetic system dominates, but increased in the late phase of asphyxia when the dominance of the parasympathetic discharges causes a distinct vagal induced slowing of the heart rate. The testing of the autonomic reactivity during the post-asphyxial period

shows: 1. that a few seconds following the readmission of air or oxygen the sympathetic reactivity is greatly increased. This effect occurs after an adequate period of asphyxia (usually 60 seconds or longer) regardless of whether the preceding period of asphyxia led to a fall of the blood pressure or not; 2. that during the "late" post-asphyxial period (while the blood pressure is elevated but the heart rate is slowed) the sympathetic reactivity is decreased and the parasympathetic reactivity is increased. The theoretical interpretation of the altered reactivity ("tuning") of the autonomic system in asphyxia and as the result of changes induced via the baroreceptor reflexes (see the preceding paper) is based on the fact that the effect of the test stimulus summates " with the prevailing autonomic discharges. If, as in early asphyxia, the sympathetic discharges are increased, a sympathetically acting stimulus will have a much greater sympathetic effect than under control conditions. The principle of reciprocal innervation is commonly valid in experimentally induced states of "'tuning" of the autonomic nervous system as indicated by the fact that states of "sympathetic tuning" are associated with a lessened parasympathetic reactivity. Apparently, the parasympathetic discharges are diminished under these conditions. If, however, in special conditions, as in "late" asphyxia, sympathetic and parasympathetic discharges are increased, the reactivity of both branches of the autonomic system is augmented at the same time. That a potentiation and not an algebraic summation is involved was shown in a preceding investigation L

538

E. Gellhorn:

Zusammenfassung Die autonomen Entladungen, die an kurarisierten, leicht narkotisierten Katzen w~hrend der Asphyxie (Ahklemmung der Trachea) und im post-asphyktischen Zustand auftreten, wurden untersucht. AuBerdem wurden die Ver~inderungen der autonomen Erregbarkeit mittels direkter Reizung der autonomen Zentren im Hypothalamus und in der Medulla oblongata wie auch durch Reflexreizung (Reizung des afferenten N. isehiadicus und Ausliisung yon Blutdruekziiglerreflexen dureh hypo- und hypertonisch wirkende Pharmaka) studiert. Folgende Ergebnisse wurden erhalten: 1. Asphyxie tuft eine Kontraktion der normalen Membrana nietitans (M. n.) und eine ErhShung des Blutdruekes und der Pulszahl hervor. Mit zunehmender Dauer tritt eine neue Phase auf, in der Blutdruek- und Pulszahl herabgesetzt sind. An vagotomierten Katzen treten die letztgenannten parasympatisehen Erseheinungen nieht auf, sondern die PulserhShung bleibt w~hrend der Gesamtdauer der Asphyxie bestehen. Es folgt hieraus, dab die sympathisehe Erregung wahrend der Gesamtdauer der Asphyxie erhSht ist, obwohl in der Sp/itphase die parasympathisehen Erseheinungen dominieren. 2. Wenige Sekunden naeh Zulassung von L u f t oder Sauerstoff treten starke. sympathische Entladungen auf, die zu einer pl6tzliehen erheblichen Blutdrueksteigerung, Pulszunahme und zu einer Kontraktion der normalen und denervierten M.n. ffihren. 8. Hiernaeh bleibt der Blutdruck fiir l~ingere Zeit erh6ht, wiihrend die Pulszahl reflektoriseh abnimmt (Sp~tphase des post-asphyktisehen Zustandes). Die Anwendung geeigneter, zentral oder reflektoriseh wirkender Reize wShrend und naeh der Asphyxie zeigte: 1. dab die Erregbarkeit des sympathisehen Systems wShrend der Asphyxie erhSht ist, aueh w/ihrenct der Spiitphase, in der der Blutdruek und die Pulszahl unter den Kontrollwert fallen; 2. dab die Erregbarkeit des parasympathischen Systems w~ihrend der Friihphase der Asphyxie, in der das sympathisehe System dominiert, vennindert ist; in der Sp~itphase dagegen, in der das parasympathisehe System dominiert (erhebliehe Verlangsamung des Pulses), ist die parasympathisehe Erregbarkeit gesteigert. Die Anwendung yon Testreizen w~ihrend des post-asphyktisehen Zustandes zeigt: 1. dab die sympathisehe Erregbarkeit wenige Sekunden naeh Zulassung yon Luft oder Sauerstoff erheblieh gesteigert ist. Diese Wirkung tritt regelm~iBig naeh einer adiiquaten Asphyxie (60 Sekunden oder liinger) ein, gleiehgiiltig ob der Blutclruek in der Sp~itphase der Asphyxie gefallen war oder nieht; 2. dab wahrend der post-asphyktisehen Sp~tphase, in der der Blutdruek erh6ht und die Pulszahl erniedrigt ist, die sympathisehe Erregbarkeit vermindert und die parasympathisehe Erregbarkeit vermehrt ist. Die theoretisehe Erkliirung der ver~inderten Erregbarkeit (Umstimmung des autonomen Systems, die dureh Asphyxie und aueh dureh Barorezeptorreflexe, wie in der vorangehenden Arbeit gezeigt wurde, herbeigefiihrt werden kann) beruht auf der Tatsaehe, dab die Wirkung des Testreizes sieh mit den jeweils bestehenden autonomen Entladungen summiertC Wenn in einer bestimmten Phase der Asphyxie die sympathisehen Entladungen erhSht sind, so wird ein, das sympathisehe System erregender Testreiz, eine grSf3ere sympathisehe Wirkung als im entEs wurde in einer frtiheren Arbeit gezeigt, dab unter diesen Umst~inder, nieht eine algebraisehe Summierung, sondern eine Potenzierung erfolgt.

Tuning of the Autonomic Nervous System

539

sprechenden Kontrollversuch hervorrufen. Diese Theorie erkl~irt auch die Tatsache, dab im allgemeinen das Prinzip der reziproken Innervation w~hrend einer experimentell herbeigefiihrten Umstimmung giiltig bleibt; dab aber in besonderen F~llen wie in der Sp~itphase der Asphyxie, in der sympathische und parasympathische Entladungen vermehrt sind, die Erregbarkeit beider Anteile des autonomen Systems erh6ht ist. R6sum4

Les d6charges autonomes lesquelles furent ex6cut6es sur des chats curaris6s sous narcose superfieielle et qui surviennent pendant l'asphyxie (par compression de la trach6e) et sous conditions post-asphyetiques furent examin6es. Ainsi que ]es changements d'irritation autonomes ~ l'aide d'influenee directe des centres autonomes de 1'hypothalamus et de la moelle oblong6e comme l'irritation r6flexe (irritation du neff sciatique aff6rent et d61ib6ration de r6flets des inhibiteurs de la pression art6rielle par des drogues hypo- et hypertones) furent 6tudi6s. Les r6sultats sont les suivants: 1. L'asphyxie donne lieu /tune contraction de la membrane clignotante (m. c.), ~t une augmentation de la pression art6rielle et ~ la fr6quence du pouls. Avec augmentation de la dur6e une nouvelle phase se manifeste, dans laquelle la pression art6rielle et la fr6quenee du pouls sont diminu6es. Des chats vagotonis6s ne montrent pas ees symptSmes parasympathiques. Au contraire l'augmentation du pouls se maintient pendant toute la dur6e de l'asphyxie. 2. Apr6s quelques secondes d'administration d'air ou d'oxyg6ne des d6charges marqu6es sympathiques surviennent qui provoquent une augmentation grave subite de la pression art6rielle, une augmentation du pouls et une contraction de la m.c. normale et d6nerv6e. 8. Ensuite la pression art6rielle est augment6e pour quelque temps, tandis que la fr6quence du pouls diminue d'une mani6re r6flexe (phase tarde de l'6tat post-asphyetique). L'application de stimulation par moyen centrale ou r6flexe pendant ou apr6s l'asphyxie montre: 1. que 1'irritation du syst6me sympathique pendant l'asphyxie est augment6e aussi dans la phase tarde dans laquelle la pression art6rielle et la fr6quence du pouls diminuent sous des valeurs contr61es; 2. que l'irritation du syst6me parasympathique dans la phase initiale de l'asphyxie, dans laquelle le syst6me sympathique pr6vale, est diminu6e. Par contre dans la phase tarde, dans laquelle le syst6me parasympathique pr6vale (ralentissement marqu6 du pouls), l'irritation parasympathique est augment6e. L'applieation des stimulation-teste pendant l'6tat post-asphyctique montre: 1. que l'irritation sympathique quelques seeondes aprbs administration d'air ou d'oxyg~ne est augment6e remarquablement. Ca survient r6guli6rement apr6s une asphyxie ad6quate (60 secondes ou plus) sans 6gard $ la chute ou $ la hausse de la pression art6rielle dans la phase tarde de l'asphyxie; 2. que dans la phase tarde post-asphyctique, dans laquelle la pression art6rielle est augment6e et la fr6quenee du pouls est diminu6e, l'irritation sympathique est attenu6e et l'irritation parasympathique est augment6e. L'explication th6orique de l'irritabilit6 alt6r6e (conversion du syst6me autonome, laquelle peut 6tre provoqu6e par asphyxie et aussi par reflets barorecepteurs, ce qui est d6montr6 dans la publication pr6e6dente) ~ est bas6e sur le facte que l'effet du teste d'irritation se multiplie avee les d6charges autonomes actuelleDans cette publication rut d6montr6, que sous ces conditions r6sulte une potenee mais pas une addition alg6brique.

540

E. Gellhorn: Tuning of the Autonomic Nervous System

ment pr6sentes. Si dans une certaine phase de l'asphyxie les d6charges sympathiques sont augment6es un teste d'irritation pour le syst6me sympathique aura un plus grand effet sympathique que dans uns exp6rience contr61e. Cette th6orie explique aussi le fait que le principe de l'innervation r6ciproque reste g6n6ralement valide pendant une conversion exp6rimentale, mais dans des cas exceptionels, comme dans la phase tarde de l'asphyxie, dans laquelle les d6charges sympathiques et parasympathiques s0nt influenc6es, l'irritation des deux portions du syst6me autonome est 61ev6e. Re~erenees

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