products2. Clearly, if similar results to those obtained by Ginezinsky

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1 THE EFFECT ON MUSCLE CONTRACTION O1NJ.j SYMPATHETIC STIMULATION AND OF VARIOUS MODIFICATIONS OF CONDITIONS. BY DR HELENE WASTL (VIENNA). (From the Physiological Laboratory, Cambridge.) THE question, whether the sympathetic system has any direct influence upon striated muscle, has been widely discussed within the past ten years. Most observers, who have supported the theory that such influence exists, have considered that it consists of an increase of some form of tonic contraction. One of the difficulties in the way of this conception is, that no one has been able to cause increase of muscle tone by stimulating the peripheral end of any sympathetic nerve. Recently a different view of the mode of action of the sympathetic on striated muscle has been put forward by Orbeli. Orbeli and his pupil Ginezinsky(l)1 have described in a preliminary paper experiments on survival frog's muscle, which they consider show, that if the muscle is fatigued, its activity is more or less restored by stimulating the sympathetic. On Orbeli's view the sympathetic has all the effects on striated muscle that it has on the heart: increasing the height, strength and rapidity of the contraction and the conductivity of the muscle. On this view the action of the sympathetic might be regarded as primarily trophic and by its trophic influence secondarily increasing muscle tone. The action corresponds fairly closely to that which a number of observers have found to be produced on fatigued muscle by adrenaline, and Grub er(3) has suggested that adrenaline has some kind of trophic action on the muscle either direct or by aiding in the removal of metabolic products2. Clearly, if similar results to those obtained by Ginezinsky in frog's muscle were obtained on mammalian muscle (and his results in frog's muscle were confirmed) the doubts as to the existence of any relation of sympathetic nerves to skeletal muscle would hardly be tenable. 1 In a letter to Prof. Langley, Prof. Orbeli mentions a number of confirmatory experiments made in different ways by others of his pupils. a According to L. Lapique the chronaxie of the fatigued muscle, which is very much increased, can be brought back to its normal value by treating the fatigued muscle with adrenaline. PH. Lx. 8

2 110 H. WASTL. From this point of view I have, at Prof. Langley's suggestion, investigated the question first in mammalian and then in frog's muscle. Sympathetic nerve stimulation during fatigue of the tibialis anticus muscle of the cat. Ginezinsky's experiments were made on the posterior part of a frog severed from the anterior part. The contraction of the gastrocnemius was recorded; the 8th and 9th spinal nerve roots stimulated to produce contraction of the muscle and the sympathetic trunk stimulated at the level of the 7th ganglion during fatigue of the muscle. The experiments were of several types (isotonic and isometric contractions, fatigue by single shocks and by a short series of tetani) but as the same conclusion was drawn from each of these, one type is sufficient to test the results. I have taken that first mentioned. In this, the roots were stimulated with simple induction shocks and when the muscle was strongly fatigued and in contracture, the sympathetic was stimulated. Ginezinsky found that after a long latent period the contractions gradually increased in height, reached their maximum a short time after the end of the sympathetic stimulation and very slowly lessened. My experiments were made in cats ancesthetised by subcutaneous injections of urethane and subsequently with chloroform-ether. A tracing was taken of the contractions of the tibialis anticus muscle, the proximal origin of the muscle being fixed by clamping a rod passed through the knee-joint. The anterior roots of the 6th and 7th lumbar nerves (or one of these nerves) were stimulated with single break shocks produced by an interrupter driven by an electric motor. The make shocks were short circuited and the number of breaks administered to the roots were varied by a resistance. Usually stimuli per minute were used, a 1-8 to 2 volt cell being in the primary circuit. The sympathetic chain of the same side was reached retro-peritoneally through a cut parallel with the vertebral column a little anterior to the edges of the processi transversi and cut just below the 5th lumbar ganglion, this being the last in the cat which (usually) receives a white ramus. The sympathetic was stimulated between the 5th and 6th ganglia with faradic currents from a second coil. Only those experiments are counted, in which sympathetic stimulation caused a prompt erection of the hairs of the tail, thus indicating a good e;xcitability of the nerve. In some cases the blood-pressure was registered from the carotid artery. The general course of these contraction curves, especially of the

3 SYMPATHETIC NERVES AND MUSCLE. ill tibialis anticus of the cat (which has always been a favourite in studies on fatigue) with their returning features of the staircase phenomenon, of the initial more or less great decrease of the height of contractions, of the subsequent continuation of the contractions for a long time on a level height ("fatigue level" or "steady state"), and, finally, of the more or less steep decline in height till exhaustion, are too well known to render it necessary to describe and picture them anew. The sympathetic nerve was stimulated with various strengths offaradic currents (coil distance about 30 to 5 cm.) during various periods (about 30" to 2 mins.) at the different points of these contraction curves: during the initial decline, or when the muscle was working on the fatigue level, or when the muscle was already more or less fatigued, or when it responded with feeble contractions only. In the greater number (six cats) of successful sympathetic experiments (ten' cats) no effect upon the muscle curve was -obtained by sympathetic stimulation. Fig. 1. Uppermost tracing: contractions of anterior tibial muscle of cat at fatigue level; (1) the anterior roots of 6th and 7th lumbar nerves stimulated 220 times a minute; 2nd record: time (as in the other figures), in 10 second intervals; 3rd record: stimulation of sympathetic (coil distance 15 cm.). Lowest tracing: signal of the anterior root stimulation (omitted in the other figures). Fig. 1 is an example of the complete absence of effect of stimulating the sympathetic during contractions of the musc. tibialis anticus of the cat at the fatigue level. The contractions continued at the height shown for nearly one hour, during which the sympathetic was stimulated a number of times with different strengths of current, all strong enough to cause good erection of the hairs of the tail. In three animals, sympathetic stimulation caused a marked decrease in the height of the contractions; the decrease was gradual and only gradually passed off after cessation of the sympathetic stimulation. The extent of the decrease in any one experiment depended within certain limits upon the strength of stimulation of the sympathetic. In 8-2

4 112 H. WASTL. Fig. 2 (a) and (b) are taken from another. one experiment and (c) from 710",q_4.. Fig. 2. (a) Moderate (22 cm.); (b) stronger (20 cm.) stimulation of sympathetic during fatigue level of anterior tibial muscle (stimulation of anterior root of 7th lumbar nerve 180 times per min.); (c) strong (16 cm.) stimulation of sympathetic from another experiment (anterior root of 6th lumbar nerve stimulated 160 times per min.). In one experiment only there was a slight increase in height twice coincident with sympathetic stimulation, but in this experiment there were also some slight rises of the muscle curve independent of sympathetic stimulation, and the other sympathetic stimulations tried had no effect. I conclude from these experiments that sympathetic stimulation has no direct effect on striated muscles undergoing marked fatigue in mammals (cats). It may have an indirect effect by decreasing the blood supply, but this causes a decrease and not an increase in the contractions of the fatigued muscle. A decrease in muscular efficiency was not found in all cases. But in a working muscle the vessels are kept strongly dilated by local chemical influences, so that vaso-constrictor impulses passing down the sympathetic may be unable to produce such a considerable contraction of vessels in the muscle as to influence its working power. That is -probably the case when the blood-pressure is high and the

5 SYMPATHETIC NERVES AND MUSCLE. 113 blood supply of the muscle abundant. Further, it is a common experience that the degree of vascular contraction in sympathetic stimulation varies with the conditions of the animal and the degree of anaesthesia. As regards the action of adrenaline in fatigue, I have made a few experiments only. Observations on the tibialis anticus muscle of the cat have been made by Cannon and Nice(2), and by Gruber(3). Cannon and Nice obtained an increase in the working power of the muscle on stimulating the peripheral end of the splanchnic nerve. Part of this increase they considered was due to the action of adrenaline on the muscle. Gruber injected adrenaline and found that it increased the height of contraction and lowered the threshold of stimulation and shortened the duration of the latent and contraction period both in fatigued and in unfatigued muscle. The conditions are complex, for a small dose of adrenaline causes some vascular dilatation in muscle (Hartmann and Fraser(4), Gruber and others) and whilst a large dose reduces the muscle circulation, there may be an intermediate stage in which the vaso-constriction produced in the visceral area and the consequent high blood-pressure may overcome the feebler vaso-constrictor action in the muscles. My experiments were made in the manner given above, adrenaline-chloride (Parke, Davis and Co.) being injected into the jugular vein instead of the sympathetic being stimulated. The blood-pressure of the carotid artery was recorded. Fig. 3. Top tracing=carotid blood-pressure: (a) injection of *5 c.c. adrenaline *001 p.c. into jugular vein; (b) of *75 cm. *001 p.c. Lowest tracing: anterior tibial muscle, 7th lumbar anterior root (stimulated).

6 114 H. WAST7L. With small doses, which caused a fall of blood-pressure or with somewhat larger doses, which caused a brief moderate rise of blood-pressure, there was sometimes a slight gradual rise in the height of the contractions of the tibialis anticus muscle, but I did not obtain this constantly (cp. Fig. 3). On the other band, in a number of experiments made, a somewhat larger dose of adrenaline sufficient to cause a large though not protracted rise of blood-pressure caused a decrease in the height of the contractions (Fig. 4), and this was not followed by an increase in height, i.e. any lessening in fatigue which the adrenaline may have caused was more than antagonised by the reduced blood supply. ~Fig. 4. Injection 1-25 c.c p.c. adrenaline (at 3). Effect of stimulation of the posterior roots. Since decreased blood supply of the muscle whether brought about by sympathetic stimulation or by injecting adrenaline causes decreased height of contraction in the fatigue curve, increased blood flow might be expected to increase the height of contraction. An attempt was made to increase the blood supply of the muscle by stimulating the posterior roots of the 6th and 7th lumbar nerves. Few direct experiments have been made on antidromic vaso-dilation in muscle, but B ayiiss (.5) found that after removal of the skin of the hind limb a stimulation of posterior roots caused a slight increase in the volume of the limb. In the course of taking contraction curves of the

7 SYMPATHETIC NERVES AND MUSCLE. 115 musculus tibialis anticus of cats, as described above, the posterior roots of the 6th and 7th lumbar nerves were stimulated either with slow stimuli (single induction shocks between per minute) or with suitable faradic currents. No trace of effect upon the muscle curve was found either on non-fatigued strongly contracting muscles or in muscles in various states of fatigue. In order to meet the possible objection, that the sympathetic vaso-constrictor fibres were in high tone and so prevented vaso-dilator action the experiment was repeated after section of the abdominal sympathetic below the 5th lumbar ganglion, without any alteration however in the negative result. It seemed possible that an effect might be obtained if an interval of inactivity were given to the muscle, during which period a stimulation of the posterior root might provide better conditions for the recovery of the muscle through antidromic vaso-dilation. This was not found to be so (cp. Fig. 5). Fig. 5. Contractions; of anterior tibial muscle produced by stimuaigthe anterior root of 7th lumbar nerve (120 times per min.). Interval 60"~. During the second interval, the posterior roots of the 6th and 7th lumbar nerves were stimulated (100 times per min., make and break shocks). The lower curve follows on the upper. The negative results of these experiments might be due either to the absence of antidromic vaso-dilation in the muscle or-as seems more probable-to the dilatation consequent on contraction of the muscle being already practically maximal, for it has been shown by Gask ell (6) and others that stimulation of a motor nerve to a voluntary muscle produces a very great vaso-dilation therein.

8 116 H. WASTL. Sympathetic nerve stimulation duringfatigue of the gastrocnemius of frogs. Since the mammalian experiment had given negative results it was obviously desirable-notwithstanding the apparent decisiveness of Ginezinsky's results-to try the effect of stimulating the sympathetic in the gastrocnemius muscle of the frog. The manner in which Ginezinsky's experiments were conducted, I have mentioned above. The method I employed was practically the same as that used by him in his isotonic series. The experiments were carried out on large, mostly male frogs (Rana temp.); most of them were freshly caught (one experiment was done with a male American bull-frog, of 635 grm. weight, where the nerves are of course much longer). The frog was pithed, the left sympathetic chain was reached through a cut in the side of the animal without removing any viscera; the sympathetic was tied at the 5th ganglion and the sympathetic chain very carefully isolated to a little below the 7th ganglion, the intervening rami communicantes being cut, so that it was possible to stimulate the nerve at the region of the 7th ganglion. Then the spinal cord was exposed, the left 8th and 9th anterior roots (in some cases also the 7th root) were tied, usually separately, and the spinal cord with the rest of the roots were removed. In nearly all experiments the aorta was cut and there was no circulation in the hind limbs. In a few, however, the vessels were left intact and a very feeble circulation existed. This apparently made no difference to the results. The tendon of the left gastrocnemius was attached to an isotonic lever and the muscle allowed to pull against a load of grm. according to its strength. The roots were stimulated with a pair of small platinum electrodes partly with single induction shocks applied with various frequency (between shocks per minute), partly with short faradic currents each of a duration of ca. 3-1 second, at a frequency between per minute. The sympathetic was stimulated for various lengths of time (j-3 minutes) and with various strengths of current. Care was taken to keep the nerves in good condition and not to touch the electrodes during each experiment. The roots were stimulated in the various experiments either each alone (in some cases also the 7th anterior root was found to be effective), or together. The sympathetic was stimulated with a suitable strength at almost every possible point of the fatigue curve of

9 SYMPATHETIC NERVES AND MUSCLE. 117 the muscle in the different experiments, at the beginning when the muscle contracted strongly and regularly, at the first signs of developing fatigue, during the various degrees of fatigue and especially at -the end of the fatigue curve, when the muscle was already nearly exhausted. Particular stress was laid upon the effects of the first stimulation of the sympathetic in each experiment, since in the absence of circulation there is probably a more or less rapid decrease in the effects of successive stimulations. In no case, provided escape of current from the sympathetic electrodes to the adjoining plexus iliolumbalis was carefully avoided, was there any effect of the sympathetic stimulation (long or short) upon the muscle contractions whether they were a series of single contractions or of short tetani or whether the muscle was in good condition, fatigued or exhausted Xmore than two dozen experiments were made). But if the strength of the current applied to the sympathetic was fslowly increased, a point could be found in a few cases when, probably in consequence of spread of current, the muscle suddenly began to produce higher contractions in the rhythm of the root-stimulation. At this point apparently an escaped current was added to the rhythmic stimulations of the roots and strengthened their effects, though it was still too weak to excite the roots of itself. Beyond that point the escaped current produced a simple tetanus,of the muscle with its rhythmic contractions superposed on the tetanus. That these stronger contractions could not have been due to a sympathetic effect was proved by the fact that pinching the nerve below the electrodes did not alter the phenomenon and that the change came suddenly and not gradually. Action of adrenaline in the excisedfrog's sartorius muscle. The absence of effect of the sympathetic on the gastrocnemius described above, led me to make some observations to determine whether adrenaline has any obvious effect on survival frog's muscle a point on which different observers have arrived at contradictory results. For this purpose, I took the sartorius muscle of the frog (R. temp.) immersed in Ringer's fluid in a Lucas chamber. The muscle was stimulated by means of electrodes placed at the opposite ends of the muscle. Induction currents were thus sent through the length of the muscle times a minute. Whilst a series of contractions (fatigue curve) were being obtained, adrenaline was added to the Ringer's fluid to bring the adrenaline content in it to a degree varying from 1:500,000 to

10 118 H. WASTL. 1: 10,000 (adrenaline chloride of Parke, Davis and Co. or epinephrin of Merck). The strength of the muscle stimulation and the load (isotonic contractions) was also varied. In a dozen or more experiments there was no change in the height of the contractions at whatever stage of theseries of contractions the adrenaline was added. As a control of the diffusion of the adrenaline into the muscle, veratrine was added to the bath to make a solution of 1: 50,000-1:20,000. This soon caused an increase in the height of the contractions. SUMMARY. The experiments were made to determine whether sympathetie nerve stimulation increased the fatigue contractions of striated muscle. In the anwesthetised cat with intact circulation, the anterior roots of the 6th or 7th lumbar nerves (or the roots combined) were stimulated with break shocks at a rate varying from a minute and at various periods during the resulting fatigue of the anterior tibial muscle the lumbar sympathetic was stimulated with varying strengths of faradic current. Only those experiments were counted in which the sympathetic caused good erection of the hairs of the tail. In six experiments, the sympathetic stimulation had no effect. In three experiments, the height of the contraction was decreased by the stimulation and only slowly recovered the previous height after the stimulation had ceased. In one experiment in which there were a number of sympathetic stimulations there was twice a slight increase in the height of the contractions coincident with the stimulation; but in this experiment there were similar increases when there was no stimulation. Stimulation of the sympathetic therefore does not increase the height of contraction of mammalian muscle fatigued by rapid single contractions and it decreases the height if it causes marked vaso-- constriction. Observations were made in another series of experiments on the effect of vascular change by injecting adrenaline intravenously during the progress of fatigue. Small amounts of adrenaline, causing a decrease or but a brief moderate rise of blood-pressure, had little effect on the fatigue contractions-sometimes a slight increase in height. A larger amount, causing greater and more prolonged rise of blood-pressure, caused sometimes a decrease in the height of contractions like that produced at times by sympathetic stimulation. Attempts were also made to increase the circulation by antidromic action. The posterior roots of the 6th and 7th lumbar nerves were

11 SYMPATHETIC NERVES AND MUSCLE. stimulated during the fatigue curve of the anterior tibial muscle. The result, however, was a negative one. Similar experiments were made on the frog's gastrocnemius muscle, when the circulation had ceased or nearly ceased. Stimulation of the sympathetic in this case was not found to have any effect. Finally, the fatigue contractions of the excised sartorius muscle of the frog (direct stimulation) was not found to be modified by adrenaline. Thus, by the method employed, no evidence was found that the sympathetic affects striated muscle except by modifying the circulation. I should like to thank the Council of Girton College, Cambridge, for the opportunity of studying in Cambridge, offered to me by their kind invitation. My thanks are further due to Prof. Langley for all his kind advice and interest. REFERENCES. 119 (1) Orbeli. Journ. Petrograd Med. Instit. 6. p Also abstract in Med. Science Abstr. and Reviews, 10. p (2) Cannon and Nice. Amer. Journ. of Physiol. 32. p (3) Gruber. Journ. Pharmak. a. exper. Therapeut. 23. p Quotations of most of his papers on the subject ( ) may be found therein. (4) Hartmann and Fraser. Ibid. 44. p (5) Bayliss. This Journ. 26. p '6) Gaskell. Ibid. 1. p