their action (14). The values of Q10 in all these cases are higher for temperatures near zero and decrease as the temperature is raised. The following table (table 5) gives in terms of beats per minute the average rates of heart-beat from a large number of observations. Previous to making the observations the embryos were kept in a thermostat at the desired temperature for from fifteen to twenty minutes. The temperature coefficients are calculated for 10 degree intervals. The resemblance of these values to the temperature coefficients of enzyme action is obvious. In this connection it is interesting that E. N. Harvey (15) determined the effect of temperature on the pulsations of the medusa Cassiopea xamachana, and found that the temperature coefficient resembles closely that of an enzyme action. HEART-BLOCK 1 If the temperature of the heart is gradually raised, a point is reached at which the normal rhythmical sequence of the parts no longer occurs. G. N. Stewart (16) observed heart-block as the result of heat in the case of the frog. With Fundulus embryos a block develops so that regularly not all of the beats of the auricle are followed by ventricular contractions. If the heart is not heated too suddenly, the block develops in well-defined steps. The ratio of auricular to ventricular beats may be successively, 6/5, 5/4, 4/3, 3/2, 2/1, 3/1, etc., until the ventricle stops beating altogether. If the temperature is then slowly lowered, the reverse changes in the ratios take place until the normal sequence is resumed. The temperature at which the block appears is two or three degrees above that at which the block disappears upon lowering the temperature. The exact point at which the block appears depends upon the former treatment of the embryo. Embryos which had been kept in a refrigerator with a temperature of from 8° to 10° for several days, when gradually heated developed heart-block at from 28° to 29° in every instance. Embryos which had been kept at room temperature developed block at from 34° to 35°, while embryos which had been kept at 34° to 35° for an hour and had recovered from the block at that temperature, had normally beating hearts up to 41° or 42°. If the embryo is kept for some few minutes at the temperature at which the block appears, the heart recovers its normal beat, and in order to produce block again, the temperature must be further raised. I never observed a recovery above 39°, howOne embryo was kept at 39° without affecting the block, for an hour and a quarter, when the experiment was discontinued. After a half hour, during which the temperature had fallen to that of the room, the heart had completely recovered its normal beat. The ventricle is unable to beat at temperatures above 42°. The auricle stops beating at from 44° to 46°, according to the length of time exposed, and the sinus stops immediately after the auricle. It was difficult to determine this point exactly since the beats of the sinus, besides being very rapid at high temperatures, become weak and almost indistinguishable. In several experiments the sinus was seen to beat two or three times immediately after the auricle had ceased beating, and then to come to rest, relax and fill with blood from the auricle and ventricle. In every case after standstill of the heart, the sinus was full of blood so that the spot was visible to the naked eye. CONCLUSIONS 1. The changes in the rate of the heart-beat of the Fundulus embryo at high temperatures are such as would be expected in case the rhythmical contractions of the heart depend upon the velocity of an enzyme reaction. 2. With high temperatures the length of time exposed is an important factor. The longer the time exposed, the lower the temperature necessary to bring about standstill of the heart, indicating a temperature coefficient of the destruction of the enzyme. 3. The values of Q10 are shown to be higher at temperatures near zero and to decrease, as is the case with enzymes, when the temperature is raised. 4. Auriculo-ventricular block was observed as a result of high temperature. The ventricle is first affected by the high temperature, and finally the auricle and sinus. I wish to thank Professor A. R. Moore for constant encouragement and many helpful suggestions in carrying out this work. BIBLIOGRAPHY (1) CYON: Gesammelte Physiologische Arbeiten, Berlin, 1888. (5) MARTIN: This Journal, 1904, xi, 370. (6) ROBERTSON: Biol. Bull., 1906, x, 242. SNYDER: This Journal, 1906, xvii, 350. (7) SNYDER: Univ. Cal. Publ. Physiol., 1905, ii, 125. ROGERS: This Journal, 1911, xxviii, 81. (8) SNYDER: Zeitschr. allg. Physiol., 1913, xv, 72. (9) LOEB: Comparative physiology of the brain, New York, 1900, 23. (10) TAYLOR: Univ. Cal. Publ. Path. 1907, i, 112. EULER: General chemistry of the enzymes, (transl. by Pope), New York, 1912, v. (11) LOEB AND EWALD: Biochem. Zeitschr., 1913, lviii, 177. (12) ROGERS: Loc. cit. (13) LOEB AND CHAMBERLAIN: Journ. Exper. Zoöl., 1915, xix, 559. (14) SLATOR: Journ. Chem. Soc., 1906, lxxxix, 128. VAN SLYKE And Cullen: Journ. Biol. Chem., 1914, xix, 174. (15) HARVEY: Carnegie Inst. of Wash. Publ. no. 132, Papers from the Tortugas Laboratory, III, 1911, 29. (16) STEWART: Loc. cit. VASODILATOR REACTIONS. Į REID HUNT From the Laboratory of Pharmacology, Harvard Medical School, Boston Received for publication December 7, 1917 The experiments described in the following resulted from an endeavor to discover the cause of the marked fall of blood pressure following the administration of certain drugs; they have led to the conclusion that there is present in mammals (and perhaps other animals) a vasodilator mechanism not recognized, or only vaguely recognized, capable of responding with more intense reactions than any of the mechanisms generally recognized and one which may be more perfectly controlled than the latter. The present work began with the discovery by Taveau and myself in 1906 of the intense blood pressure lowering action of acetyl-cholin.1 In our first publication (1) on this subject I said, I think it safe to state that, as regards its effect upon the circulation it (acetyl-cholin) is the most powerful substance known. It is one hundred thousand times more active than cholin, and hundreds of times more active than nitroglycerin; it is a hundred times more active in causing a fall of blood pressure than is adrenalin in causing a rise. In our paper in 1906 Taveau and I described a physiological test for cholin, based upon its conversion into the acetyl compound, by means of which 0.0001 mgm. or less of cholin could be detected. This method was later elaborated (2) using the isolated frog heart as a test object so that 0.00001 mgm., and probably less, cholin could be detected; a number of applications of the method were described. Ten years after our first description of this method Guggenheim and Loeffler (3) without knowing of my work (as stated in a letter from Doctor Loeffler) published a similar method making use of the guinea pig intestine as a test object. This method seems ( I have not seen the original paper) to be far less sensitive than mine; but although these authors do not seem to have taken the precautions I did to avoid splitting off cholin from the lecithin of the serum the figures given for the cholin content of the blood serum (from 0.2 to 2.0 mgm. per 100 cc.) are similar to those I found. Their observations upon the rapid disappearance of cholin from the blood and upon the amount present in the urine also agree with mine. Fühner (4) is quoted as having emphasized the superiority of the frog heart as a test object. These results were fully substantiated in subsequent work and were confirmed eight years later by Dale (13). Figure 1 shows the effect. of 0.000,000,002,4 mgm. of acetyl-cholin per K upon the blood pressure when injected intravenously into a cat. The response was, I believe, more active in this experiment than in any other; the stated dose caused the same fall of pressure repeatedly. Injections of equal amounts of the 0.9 per cent sodium chloride solution used in making the acetyl-cholin solution, had no effect. In order to avoid the possibility of an error in the dilution a fresh series of dilutions was made; the results were the same. 3-15 B.L 3-32 10" Fig. 1. Experiment 359. Cat, 4.16 K; paraldehyde; vagi cut. Blood pressure from left femoral artery; injections into right saphenous vein. 3-15, 1 cc. of acetyl-cholin 1: 100,000,000,000. 3-32, 1 cc. 0.9 per cent sodium chloride solution. Taveau and I also described in 1906 a chemical test for cholin based upon its conversion into the benzoyl compound and the precipitation of the latter with platinum chloride; this test seemed to have advantages over the tests then in use (cf. 5). My work on the cholin esters was suggested by some work I had done previously which had resulted in the isolation of cholin from adrenal extracts and the identification of it as the chief substance causing the fall of blood pressure of such extracts after the removal of the epinephrin (6)—an observation frequently ascribed to Lohmann, but the publication of my work antedated that of Lohmann by seven years. At that time no one, apparently, except MarinoZucco (who had reported finding "neurin," evidently cholin, in the adrenal glands) had isolated cholin from any organ extract and the thought at once occurred to me that possibly this substance might represent an internal secretion of the cortex in the same way that epinephrin was supposed to be an internal secretion of the medulla. Further work (7) (1) suggested that there may be present in the adrenal glands compounds of cholin much more active than cholin itself and this led me to prepare and study pharmacologically a few cholin esters already known and later, in collaboration with Taveau and Menge to prepare and study a large number of new cholin and analogous compounds (1), (8), (9), (PO), (11), (12). |