6I2.74I.63:6I2.8I7. averaging in one table only 65 p.c. and being rather variable. The

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1 6I2.74I.63:6I2.8I7 THE IDENTITY OF THE RESPONSE OF MUSCLE TO DIRECT AND INDIRECT STIMULATION. BY W. HARTREE. (From the Physiological Laboratory, Cambridge.) IT is commonly objected to myothermic observations that these have usually involved direct stimulation of the muscle, and that contractions induced by such stimulation are "abnormal." The response to nerve stimulation is held, without much evidence, to be different, and in some way superior. It is true that excessive stimuli directly applied to a muscle produce contracture, delayed lactic acid formation and delayed heat-production (see Meyerhof and Lohmann(l), Furusawa and Hartree(2)), and Hartree and Hill(3) have attempted to explain the delayed heat-production of a muscle contracting anaerobically as due to the over-stimulation of a certain number of its fibres, those lying in immediate contact with the electrodes. In a recent paper Fischer (4) claims to have established the existence of such a difference between direct and indirect stimulation. According to Fischer single shocks, or short tetani, directly applied to the muscle, evoke the same tension as, but somewhat more heat than, similar stimuli applied to the nerve of a frog's sartorius preparation. The difference claimed is not large, averaging in one table only 65 p.c. and being rather variable. The accuracy, however, of the myothermic method is relatively so high that the existence of such an error (ranging from 0 to 15 p.c.) would be a definite objection to direct stimulation. The following observations therefore were made in order to test the accuracy of Fischer's conclusions, and to determine whether, in fact, the delayed anaerobic heat can be attributed to over-stimulation of a certain number of the fibres. The experiments proved unexpectedly easy and decisive. Hartree and Hill(3) raised against indirect stimulation of a sartorius preparation the objection that no security exists that any difference which might be observed to occur between direct and indirect excitation could not be attributed to the injury (or asphyxia, if under anaerobic conditions) of a certain proportion of the fibres of the nerve. The present experiments, however, have shown, with surprising sharpness, that no

2 MUSCLE HEAT WITH INDIRECT STIMULUS. 373 such differences do in fact occur, so that the objection has no weight. A sartorius muscle, prepared sufficiently cautiously with its nerve and excited with maximal (but not supermaximal) stimuli, behaves in all respects precisely in the same way whether the stimuli be applied directly to the muscle, or indirectly through the nerve. A suggestion by Prof. Adrian was adopted, that the nerve should be prepared with a small amount of adherent tissue, in order to avoid mechanical strain upon it. The contractions employed were isometric, both for the sake of greater accuracy in the heat measurements and to avoid displacement of the nerve. The muscle (a single sartorius) lay upon a thermopile with its usual electrodes for direct stimulation, and the nerve was placed on a pair of fine electrodes, 2 and 3 mm. respectively from the muscle. Table I shows the initial heat H and the maximum tension T for TABLE I. Initial heat (H) and maximal tension (T) in arbitrary units, in single maximal twitches evoked by direct (M) or indirect (N) stimulation. Mean Temp. Date 0 C. N M N M N M 20. ii H T k ii H k 324 T k 110,, later 0 H k 320 T ii H T k k 137j 7. iii H T 92 91k j 11. iii H k 257k 256k 259 T k 83k 83k 84 several cases of single twitch. Each number entered in the table is the mean of two or three readings of the same kind (nerve or muscle stimulation) and in every case the first kind of stimulus was repeated, after the second kind, so that, by averaging, any progressive change can be eliminated. Preliminary trial ensured that the shocks employed were, in each case, and for both kinds of stimulation, just and only just maximal. In other experiments not quoted the correspondence was as good, and there were no cases showing any marked divergence in the results obtained from the two kinds of stimulation. Similar experiments were PH. LXVII. 26

3 374 W. HARTREE. made for the case tetanus at 00 C.: of tetanic stimulation. For example, for 0x2 sec. Mean M N M N M H T j and for various times of tetanus t, in seconds, at 00 C. in two different experiments: Indirect Direct {~ _ - - )--- t t H H T T Direct Indirect t 0.1 0* t *5 H H T T In these experiments mean values are shown, with "reverse" in respect both of time and of kind of stimulus. It should be noted that the above heat readings have not been corrected for the heat produced by the stimulating current. In the case of a single twitch this is negligible. For a tetanus of 1 second it was estimated as 14 units (about 1 p.c.), by "stimulating" the muscle when dead: allowing for this makes the agreement even better. It is clear that the method of stimulation, if maximal but not too strong, has no detectable effect either on the tension or on the heatproduction. To see if there was any difference in the delayed heat under anaerobic conditions due to the method of stimulation, various experiments were carried out. Ordinary cylinder nitrogen was used, in which asphyxiation of the nerve occurs, if at all, only after a very long time. A certain small amount of recovery heat, due to traces of oxygen, may have appeared in these cases, but since comparison was made directly between the galvanometer deflection-time curves for direct and indirect stimulation, the same error, if any, would occur in each, and would have no effect. To exhibit the results all the curves of galvanometer deflection have been reduced to a maximum of 500 mm.: this was approximately the reading in each case, a resistance being introduced into the galvanometer circuit when the heat-production was larger. In the experiments readings were taken every 5 seconds up to 2 minutes, and then at longer intervals: for the comparison, however, it is sufficient to quote

4 MUSCLE HEAT WITH INDIRECT STIMULUS. only a few readings. One typical experiment gave the following curves: Time: mins i O5sec.tetanus N k 46 32k ,,,,2 M k k 16k 11k 8 5k 3t 2k 1 8shocksinlsec. N k j k 1k 1 M k 24 18k 16 14k k5k This experiment showed, as usual (cf. (3) and (5)), a much greater delayed heat in the case of a tetanus than in that of a set of twitches, but no significant difference between direct and indirect stimulation. In other experiments of this kind it will be sufficient to show the difference between the curves M or N and their mean, to the nearest mm. (maximum.500). All these experiments were at 180 C. Time: mins. *... k 1 1k 2 2k 3 3k shocks sec. tetanus shocks sec. tetanus shocks This fully confirms the statement that there is no observable difference, in the response to a just maximal stimulus, between indirect or direct stimulation. It is not easy to see why Fischer reached the contrary conclusion unless his induction shocks were slightly too strong, and either liberated heat physically or caused an abnormal response to excessive stimuli. The present writer may perhaps be allowed to emphasize that he started with no prejudice in favour of the results recorded here, which in fact contradict the suggestion he made with Hill(3) to explain the delayed anaerobic heat. That heat, whatever be its cause, is not due to excessive direct stimulation of some of the fibres of the muscle, since it occurs equally when stimulation is applied through the nerve. It is satisfactory, however, that direct stimulation with carefully adjusted maximal shocks is justified, since this has been employed in almost all recorded myothermic observations. SUMMARY. The heat-production, initial and delayed, and the tension developed, in the isometric contraction of a frog's sartorius, are precisely the same whether the muscle be excited directly, or through its nerve, provided that the stimuli are carefully set to be just maximal. The suggestion, 26-2

5 376 W. HARTREE. therefore, by Hartree and Hill that the delayed anaerobic heat after a tetanus is due to the excessive stimulation of a fraction of the fibres is incorrect, since this heat appears equally when the muscle is excited indirectly. REFERENCES. 1. Meyerhof and Lohmann. Biochem. Zeitsch p Furusawaand Hartree. ThisJourn. 62. p Hartree and Hill. Proc. Roy. Soc. B, 103. p Fischer. Pfluiger's Arch p Hill. Proc. Roy. Soc. B, 103. p