stimulated, although the atropine prevents any apparent action upon the

Transcription

1 THE DIFFERENTIAL PARALYSIS OF CARDIAC NERVE ENDINGS AND MUSCLE. BY W. R. WITANOWSKI (Fellow of the Rockefeller Foundation). (From the Pharmacological Department, University College, London.) 0. L 0 EWI (1) has shown that the inhibitory action of the vagus on the heart is associated with the liberation of a cardiac depressor substance, which has a pharmacological action on the heart similar to that of choline. Loewi and Navratih(2) also have shown that in the atropinised heart this inhibitor substance is still liberated when the vagus is stimulated, although the atropine prevents any apparent action upon the heart. The site of action of atropine therefore is the heart muscle and not the vagal nerve endings. Navratil(3) found that camphor had a double action in that it diminished the liberation of depressor substance from the vagal nerve endings, and also diminished the action of such substances upon the heart muscle. Lo ewi(1) has also shown that stimulation of the sympathetic nerves is associated with the liberation of an augmentor substance which resembles adrenaline in its action. The experiments described below were undertaken to try and find means of paralysing the vagus and sympathetic nerve endings in the heart without diminishing the response of the heart to choline compounds or to adrenaline. Method. The experiments were performed on the isolated heartvagus preparation of Rana temporaria. A Straub cannula holding about 1 c.c. was used. The Ringer's fluid had the following percentage composition: NaCl 065; KCIl002; CaCl2 002; NaHCO (ph - 8). In order to eliminate effects due to changes in frequency the ventricle in most experiments was driven at about 35 per minute by break induction shocks. The vagus was stimulated by induction shocks at a rate of 10 to 20 per second. The weakest effective stimulus was always employed. The Effect on the Vagus of Reduced Sodium Concentration. To study the effects of reduction in sodium chloride concentration a perfusion fluid was used containing NaCl 0*325 p.c., cane sugar 3-4 p.c., or glucose 1X7 p.c., together with the other constituents of Ringer in normal con-

2 CARDIAC NERVE ENDINGS. centration. This fluid is referred to as "half sodium Ringer." Acetyl choline was employed as a convenient vago-mimetic drug. Fig. 1 shows the effect of changing from normal Ringer to half 89 _ ~ ~ ~~~~~~~~~~ _. - Fig. 1. Effect of reduction of sodium chloride content of Ringer's fluid on the response of the heart to vagal stimulation and to acetyl choline. Artificial rhythm, 34 per min. The tracings show from above downwards. (1) Contraction of the heart. (2) Signal for vagal stimulation. (3) Time 5 secs. The arrows mark the introduction of acetyl choline 109 molar. I. Normal Ringer (NaCl 065 p.c.). II. Ringer containing NaCl p.c. and glucose 1-7 p.c. sodium Ringer upon the response of the heart to vagal stimulation and to acetyl choline. With normal Ringer it was found that addition of 10-9 molar acetyl choline produced the same reduction in amplitude of contraction as stimulation of the vagus with a weak current of known intensity and frequency. The figure shows that the immediate effect of changing to half sodium Ringer was to reduce very greatly the response to vagal stimulation (the current strength used being unchanged), while the response to acetyl choline was unaltered. Prolonged perfusion with half sodium Ringer gradually reduced the response to acetyl choline as well as the response to vagal stimulation. When the perfusion fluid was changed back to normal Ringer the activity both of the vagus and of acetyl choline were completely and rapidly restored. This experiment was repeated fourteen times and on ten occasions results similar to those shown in Fig. 1 were obtained, but on four occasions the two actions were affected equally. Reduction in sodium chloride concentration reduces therefore both the activity of the vagus and the intensity of action of acetyl choline, but since it affects the former much more rapidly than the latter the two actions are partly separable.

3 90 W. R. WITANOWSKI. The effect on the sympathetic of reduced sodium concentration. The fact that reduction in sodium concentration reduces the effect of vagus stimulation more than the effect of acetyl choline might possibly be due to the change in sodium concentration making the sympathetic fibres more easily excitable. The effect produced on the sympathetic by reduction in sodium concentration therefore was tested. The hearts were atropinised and the vago-sympathetic trunk stimulated. The heart was allowed to beat with its normal rhythm but otherwise the experimental conditions were unaltered. Fig. 2 shows a typical result. In this case stimulation of the vago-sympathetic trunk produced a 20 p.c. acceleration while adrenaline 10-5 molar produced a similar effect. The following percentage accelerations were observed with varying molar concentrations of adrenaline: 10-4 molar - 62; 10-5 molar - 27; 10-6 molar - nil. Fig. 2 shows that introduction of half sodium Ringer practically 1 V Fig. 2. Effect of reduction of sodium chloride content of Ringer's fluid on the response of atropinised heart to sympathetic stimulation and to adrenaline. Tracings as in Fig. 1. Natural rhythm. Arrows mark the introduction of adrenaline 10-5 molar. I and II normal Ringer; III Ringer containing NaCl p.c. and cane sugar 3-4 p.c. IV Normal Ringer. The acceleration in frequency produced was as follows. Sympathetic Adrenaline stimulation 10- molar I and II III 3 34 IV abolished the response to vago-sympathetic stimulation but did not affect the response to adrenaline. A return to normal Ringer completely restored the response to vago-sympathetic stimulation. A reduction in sodium chloride concentration therefoxe depresses the activity of the

4 CARDIAC NERVE ENDINGS. sympathetic nerve endings in the same manner as it depresses the vagal endings. The adion of ether. Ruttgers(4) found that vagal stimulation produced no effect on the heart in the presence of 025 p.c. ether. I tested the effect of ether on the response of th'e heart to vagal stimulation and to acetyl choline. The experimental method was the same as that previously described except that the volatility of ether necessitated frequent changes of the fluid in the Straub cannula. The effect of 0*25 p.c. 'ether by voluime is shown in Fig. 3. This concentration of ether produced no measurable reduction in the amplitude of contraction of the heart. The heart in Fig. 3 had been perfused for 24 hours and was in a hypodynamic condition and the amplitude actually increased after the addition of ether. This did not happen with' the fresh heart but even in this case no certain and permanent reduction in the force of contraction occurred with 025 p.c. ether. In Fig. 3 acetyl choline 2-53 x 10- molar,.=~~~~~~~~~~~~~~~~~~~~~~~~~w produced the same depression as vagal stimulation in normal Ringer, but the addition of 91 Fig. 3. The influence of ethyl ether on the response of the heart to vagal stimulation and to acetyl choline. Tracings as in Fig. 1. Artificial rhythm, 29 per min. The arrows mark the introduction of acetyl choline 2-5 x 108 molar. I. Normal Ringer. II. Ethyl ether 0*034 molar introduced just previously. III. 5 mins. later. IV. 10 mins. after III. Ether present in II, III and IV p.c. ether at once abolished the effect of vagal stimulation whereas the action of acetyl choline was at first unaffected but it also was abolished after about ten minutes' exposure to ether. The action of ether therefore resembles that of reduction in sodium chloride in that in both cases the vagus is paralysed rapidly but the action of acetyl choline is reduced much more slowly. A similar effect was produced by 1 p.c. ether; I found however that, as Ruttgers(4) stated, ethyl and methyl alcohol in moderate concentrations did not paralyse the vagus. Discussion. These experiments show that it is possible to produce

5 92 W. R. WITANOWSKI. a condition in the heart in which the vagus and sympathetic'nerves are paralysed although the response to acetyl choline and adrenaline are unaffected. In the experiments described the condition was a transitory one for the response to the drugs mentioned was slowly diminished. I was not able to find a drug which would paralyse the vagus or sympathetic and would leave the response to acetyl choline and adrenaline permanently unaffected. The results are in accordance with L o ewi's view that the action of the vagus or sympathetic' on the heart consists of two separable stages, namely, (1) the liberation of some active substance by the nerve endings, and (2) the action of these substances upon the muscle cells. CONCLUSIONS. (1) Either a reduction of the sodium chloride content of Ringer's fluid to one half, or the presence of 025 p.c. ether, paralyses the vagi more rapidly than it abolishes the effects produced by acetyl choline. (2) A reduction of the sodium chloride content of Ringer's fluid to one half paralyses the sympathetic more rapidly than it affects the response of the heart to adrenaline. REFERENCES. 1. Loewi, 0. Pfluiger's Arch p Loewi, 0. and Navratil, E. Ibid p Navratil, E. Ibid p Ruttgers, P. Zeit. f. Biol. 67. p