A PRELIMINARY note on the phenomena dealt with more completely in this paper was entitled, " The Physiological Action of Chrysotoxin'." Since the date of that publication further experiment has shown that the action is due to a principle, or combination of principles, which, by the aid of the physiological test, can be recognised in the various substances for which the title of "active principle" has been claimed, and indeed in all preparations of ergot possessing therapeutic activity. The active resin extracted from chrysotoxin, and called by Jacobj2 " sphacelotoxin," gives the effect in doses of a few milligrammes. So also do preparations corresponding in mode of extraction and solubility to the " cornutine" of Kobert, and differing from that substance only in their failure to elicit the spasms in frogs, described by Kobert3 as characteristic-a failure by no means unique in the experience of those who have worked with "cornutine" since Kobert. A resinous substance separated from commercial ergotinine also gives the reaction very typically and in small dosages; while, in larger quantities, many specimens of the ordinary pharmacopceial extracts produce the same effects, complicated only by the' presence of depressant impurities.These facts make it impossible to speak of the action any longer as that of chrysotoxin. On the other hand, the wide acceptance of Kobert's4 view as to the difference between spbacelotoxin (in -sphacelinic acid) and cornutine would render the attribution of the effects to either of those substances misleading. The introduction of new names on the strength of physiological results, and in default of chemical isolation of principles, would inevitably add to the existing confusion, 1

IMINAZOLYLETHYLAMINE is the amine which is produced when carbon dioxide is split off from histidine. It was first prepared synthetically by Windaus and Vogt'. Recently Ackermann2 obtained a large yield of the base by submitting histidine to the action of putrefactive organisms. It has been shown that several of the amines thus related to amino-acids possess marked physiological activity. The activity of j8-iminazolylethylamine was discovered in the course of the investigation of ergot and its extracts by G. Barger and one of us3, who attributed this structure to a base which they obtained, and which in minute doses produced tonic contraction of the uterus. The synthetic substance, and the base produced by splitting off carbon dioxide from histidine by bacterial action or by chemical means, were found to have an identical action. Meanwhile Kutscher4 had simultaneously and independently described the isolation from ergot of a base having this action and presumably identical with that obtained by Barger and Dale. By its chemical properties this first ergot base of Kutscher was not distinguishable from 8-iminazolylethylamine; but certain apparent differences in the physiological action of the two bases, observed by Ackermann and Kutscber-5, led them to the conclusion that the ergot base, though closely related to 8-iminazolylethylamine, is not identical with it. The alleged difference in action, on the existence and cause of which our experiments throw light, was as follows: the 1 Ber. d. deutsch. chem. Gesell. xi,. p. 3691. 1907.

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IN a note published some time ago [Dale and Feldberg, 1934] [1932] and Plattner [1932, 1933] found that the substance present in such extracts was rapidly inactivated by fresh blood, like acetylcholine, and that the quantity present had a general correspondence to the wide differences in sensitiveness of different muscles to the stimulating action of acetylcholine. Faradic stimulation of the nerve increased the yield; but P1 attn e r associated the apparent presence of the acetylcholine in the muscle, and its increase on mixed nerve stimulation, with a "parasympathetic" innervation of the blood vessels. In the tongue, excised from a cat treated with eserine, and divided longitudinally into halves, he found that stimulation of the chorda-lingual nerve caused increase of acetylcholine in the extract from one half, while stimulation of the hypoglossal nerve did not significantly increase the yield of the other.Hess [1923], Brinkman and Ruiter [1924, 1925]

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A PAPER recently published by one of us with H. W. Dudley [Dale and Dudley, 1929] described the isolation and identification of acetylcholine from the perfectly fresh spleens of certain animals. The occasion of the first chemical recognition of this substance, as a natural constituent of the body, was taken to review the evidence suggesting its connection with certain normal effects of parasympathetic nerves, and also with the contractures produced in denervated voluntary muscles by stimulating parasympathetic and other nerves having, normally, only vasodilator actions. The possibility of explaining this association, between the normal vaso-dilator actions and the effects on motor denervated muscles, by attributing both to the peripheral liberation of a substance having both types of action, had presented itself to several who have worked on these phenomena. It was mentioned by Bremer and Rylant [1924] and again by Hinsey and Gasser [1928]. The view published from this laboratory differed from these only in suggesting acetylcholine, which produces both types of effect with unique intensity, as most likely to be the substance in question. The recent careful review by Gasser [1930] of work on these contracture responses of denervated muscles, from their first discovery by Philip eeaux and Vulpian [1863] to the present day, makes it unnecessary for us to give a connected historical survey; we need only refer, in their proper places, to earlier observations bearing on our own.Gasser, in his review, mentions some difficulties in the way of accepting acetylcholine as the common mediator of these effects, in particular the well-known ease with which the vaso-dilator effect of acetylcholine is obliterated by small doses of atropine, which leave the otherwise similar vaso-dilator effects of the chorda tympani and of PH. LXX.8/'

IN our earlier papers (1, 2, 3) on the action of histamine we have been chiefly concerned with the physiological analysis of the evanescent effects of smaller doses, though mention was made in our first paper of the phenomena of fatal histamine-poisoning in rabbits and guinea-pigs and of the prolonged collapse and coma caused by injecting large doses into the unansesthetised cat. The essential difference between its actions in rodents and carnivXora is well illustrated by the modifications introduced by anaesthesia. The normal rabbit or guinea-pig is easily killed by a relatively small intravenous injection of histamine, but suffers little harm from a much larger injection when deeply under the influence of an anaesthetic. We have shown that the cause of death in the guinea-pig is bronchial constriction, in the rabbit obstruction of the pulmonary circulation leading to acute dilatation of the right ventricle, and have pointed out that the reaction of plain muscle to histamine, on which the effects depend, is weakened by an anaesthetic. The unanaesthetised cat, on the other hand, recovers from the depressant effects even of very large doses, while in the same species under an anaesthetic even moderate injections of histamine often produce a fatal circulatory collapse and respiratory failure, from which the animal does not recover even after prolonged application of artificial respiration. E. Mellanby(4) has studied the onset of this condition in ansesthetised cats as the result of absorption of histamine from the small intestine. Our object in this paper is to examine the nature and the mode of production of this "histamine-shock" in ansesthetised cats. The fact that the condition has many features in common with a number of pathological conditions, loosely classified as "shock," gives to its analysis a more than immediate interest.Methods. Most of our experiments have been made on cats, a few only on dogs. It will be clear from what has been said above that the

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