PHYSIOLOGICAL Nov. 21, SOCIETY, PROCEEDINGS. Bandages soaked in a solution of common salt were then tied round

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1 PROCEEDINGS OF THE PHYSIOLOGICAL Nov. 21, SOCIETY, The frequency of the heart-beat in the mouse. By F. BUCHANAN. Wbile it is generally recognised that small mammals have a more frequent pulse than large ones, the actual frequency in very small mammals seems never to have been determined, probably on account of the difficulty in counting it by the ordinary method of palpation. My attention was drawn to this fact by being told by Dr Haldane that in view of the extremely high respiratory exchangre per unit bodyweight in the mouse, a pulse frequency of over 500 per minute was to be expected. It seemed to me of interest to ascertain whether it was so, not only from the point of view of the mouse's internal economny, but also because such a fact might help to throw light uipon what it is iii cardiac muscle which determines the frequency of the rhythm. As a simple way of doing so Waller's method of registering the electrocardiogram suggested itself, and I have by its means determined the frequency of the heart-beat in six mice, one of which however was evidently not in a good state of health, so that the records obtained with it will not be considered here. The mouse was suspended by a dry bandage passing round its waist. Bandages soaked in a solution of common salt were then tied round each of its feet. The ends of these bandages dipped into vessels of salt solution, those from the two fore-feet into one, those from the two hindfeet into another. In each vessel was a zinc rod, the one connected with the acid, the other with the mercury of a quick capillary electrometer. The movements of the meniscus were then photographed on plates moving at the rate of about 4 cm. a second, the time being marked on each plate by the shadow of an electromagnetic signal driven by a tuning fork of 100 d.v. per sec. The movements indicating negativity of the base of the ventricle, each announcing the beginning of a systole, recurred with great regularity. They can be easily f

2 lxxx PROCEEDINGS OF THE PHYSTOLOUJCAL counted on the photographs and their frequency, for 2-3 seconds at a time, determined. With each of the five healthy mice the frequency soon became fairly constant and remained so for an hour or more. Just at first it was always higher, owing probably to the animal being somewhat excited by the unwonted treatment. The average for each mouse, determined from records taken after the first ten minutes, is shown in the following table: Weight Number Frequency Date (in grammes) of records per minute A. Oct Nov B. Aug C. Nov. 2 21P D. Nov E. Nov. 6 (Albino) The frequency during the first few minutes was as much as 810 in C and 800 in D. These two mice, in which throughout the highest frequencies were observed, were both of them known to be only about 8 weeks old, and therefore, although adult, were young. If we calculate the average for the five mice we find it to be about 670 per minute. The respiration frequency was counted in A (the second time), C and E. It was 160 per minute in A and C, 140 in E. Its ratio, therefore, to pulse rate is of the same order as in man. The respiratory exchange in grammes CO per kilogramme bodyweight per hour is 8&4 in the mouse (Pembrey), and therefore about 7 times as great as in the rabbit and about 14 times as great as in man. The frequency of the heart-beat seems to be about 4 times what it is in the rabbit, about 10 times what it is in man (or sheep). That the pulse frequency is not as much greater as the respiratory exchange is greater, may be correlated with the fact that the ratio of heart-weight to bodyweight is greater in the mouse (than in man). This ratio was determined in mouse B and found to be as 1 to 127. It was also determined in a six weeks old mouse and found to be as 1 to 88. With regard to what determines frequency in heart muscle, it seems to me that a comparison, by histological or by chemical methods, of two hearts the one of which beats 10 times more quickly than the other at the same temperature, ought to give uis some definite information in the place of much which is at present merely speculative. Such a comparison will I hope soon be made. The expenses of this research have been defrayed out of the Government Grant administered by the Royal Society.

3 SOCIETY, NOV. 21, Ixxxi Action of some alkaloids upon striated muscle. I. Muscarine and atropine. By A. D. WALLFER. In previous communications to the Society, the comparative action of some alcohols' and salts2 and ana-sthetics3 upon the sartorius muscle has been described. The present communication gives an account of experiments made in order to ascertain whether the method is applicable to the study of alkaloids. I selected for the purpose alkaloids with whose action upon isolated nerve miy observations had made rne familiar, and I paid particular attention to such of them as have been closely investigated by other physiologists. I chose the case of muscarine and its antagonism by atropine as being the most familiar and therefore the most favourable for my present purpose. Moreover the action of muscarine and the quiestion of its antagonism by atropine in the case of ordinary striated muscle submitted to direct excitation is of interest in connection with the formerly vexed question whether cardiac ganglia or cardiac muscle is the seat of such antagonism. In so far as the present experiments bear upon the case of the heart, they prove that skeletal muscle exhibits the antagonism, and render probable therefore that cardiac muscle is also directly subject to the contrary influences of the two substances, I have so far had three samples of "muscarine" at my disposal, viz. (1) half a gramme of synthetic muscarine hydrochloride (Grubler), (2) a natural muscarine " not warranted pure," and (3) an alcoholic extract of muscarus due to the kindness of Professor Marshall, confessedly impture. Of the three samples the second was inactive, and served only as a tcrm of comparison. The third was moderately active. The first was active-i.e. muscular contractility was nearly abolished by 15 minutes' immersion in a 1 per 1000 solution (in 0-6 0/o NaCl in tap-water)-and supplied 50 c.c. of a 1 per 100 solution with which the present series of experiments were made. 1 H. P. Kemp. "Demonstration of the physiological effects of the propyl and butyl alcohols," Proc. Physiol. Soc., July 18, A. D. Waller. "Action of salts upon the contractility of isolated muscle," Proc. Physiol. Soc., July 18, A. D. Waller. "The comparative effect upon striped muscle of alcohol ether and chloroform." Proc. Physiol. Soc., October 17, 1908.

4 lxxxii PROCEEDINGS OF THE PHYSIOLOGICAL The solutions of muscarine and of atropine in which the muscles were immersed were taken at strengths between 1 and 01 per 100, and their effects were studied separately and successively and mixed. Muscarine hydrochloride (Grubler) in 1 0/o and 0 5 0/0 solution gave temporary contracture and almost immediate and comeplete abolition of contractility. After replacing the muscarine solution by saline the contractility gradually reappears. In /0 solution of muscarine the decline of contractility is more gradual and sometimes incomplete. In 0-1 0/0 solution of muscarine the muscular contraction is at first increased, then it gradually declines. These statements refer to first trials of fresh muscle not previously drugged. Atropine sulphate in 1 0/o solution gradually reduces the contraction without producing contracture. Urider the present conditions of observation, the contraction is abolished in between 10 and 15 minutes. Actual times of abolition in three different muscles were 11, 11 and 13 minutes. In another experiment with a 0 5 0/0 solution, the abolition of contraction was all but quite complete in 25 minutes. In 0-1 0/0 solution atropine produced no marked effect-if anything a slight augmentation. Both muscarine and atropine act thus as paralysants of muscular contraction, the former rather more powerfully than the latter, but even this difference disappears if we take the drugs on their molecular scale (muscarine= 137, atropine= 289). The chief feature of difference between the two drugs is that mnuscarine produces a temporary contracture, not unlike that caused by nicotine and by caffeine, whereas atropine does not cause contracture. The recovery in saline is less complete after atropine than after muscarine. The action of atropine after muscarine varies with the strength of solution; with strong solution (1 0/o) there is no recovery of contraction; with weak solution (0-1 0/s) there is recovery, but in this case we cannot be certain that the recovery is other than a recovery in ordinary saline. The action of muscarine is modified by the previous action of atropine, but this can only be witnessed in the case of weak solutions, since strong solutions of atropine abolish muscular contraction. The contraction of a previously atropinised muscle is augmented by weak (0-1 to 0-2 0/,) miuscarine solution. After a muscle has recovered from depression by muscarine, it does not exhibit a second contracture in consequence of a second muscarine bath, but the contractions decline at least as rapidly as in the first bath.

5 SOCIETY, NOV. 21, lxxxiii The antagonism of mnuscarine by atropine is best observed by comparing the action of muscarine alone with that of muscarine plus atropine in solutions of appropriate strength, changing over the two solutions to the two muscles, so that we have simultaneous effects compared on both muscles and successive effects on the same muscles. My supply of muscarine was unfortunately limited, so that I did not compare on a similar plan the effect of atropine alone with that of muscarine alone, nor was I able to repeat experiments as often as I should have wished. I have made only seven complete comparisons between muiscarine alone and nmuscarine plas atropine with the following results. Exp. 1 Oct Musc. versus 0125 Musc Atr. Fairly clear antagonism. 2,, 22 Do. do. Doubtful result.,, 3,, Musc. versus 025 Musc Atr. Clear antagonism. 4,, 23 Do. Do. Do. 5,, 26 Do. Do. Do.,t 6 Nov Musc. versus Musc Atr. Antagonism once only. 7,, 11 Do. Do. Do. For the last two observations all that remained was a small quantity of /0 solution of active muscarine. The antagonism by atropine came out clearly in both experiments at the first pair of trials, but failed at the second pair of trials. The comparison was between muscarine an equal volume of saline and muscarine an equal voltume of atropine solution At this strength the muscarine acted a first but not a second time. It will be sufficient to give details of Exp. 1 and the records of Exp. a. Exp. 1. Oct. 21. Time Left Sartorius Right Sartoriuis 0 to 35 mins. In muscarine /0 the contrac- In muscarine /0+ atropine tion fell from 12 mm. to 5 mm /0 the contraction fell from 11 mm. to 10 mm. 40 to 90 mins. In muscarine /o+tropine In muscarine /0 the con / the contraction rose from traction fell from 10 mm. to 5 mm. to 10 mm. 5 mm.

6 lxxxiv PROCEEDINGS OF THE PHYS. SOC., NOV. 21, EXP. V. Oct. 26, First simultaneous record. Left sartorius. Muscarine, /0. Right sartorius. Time in minutes. t _ L Muscarine, 025 /0 + Atropine, /0. Second simultaneous record (same muscles, solutions reversed). Left sartorius. 111 ii l L mllll!' u. m.zw M u ca in,* Atropine, I1 _ 11 Muscaflue, /0 + Atropine, /,. I Right sartorius. i #. ~~~~~~la iad Musearine, l02 liti.b.0 A_ 11kUpL IIL. a li W. Muscarine, /0.