SUMMARY

It has been shown in the above that acetyl-cholin has an intense vasodilator action on the vessels of the skin and of the ear; the action on the skeletal muscles is slight. It dilates the vessels of the penis, of the submaxillary gland and of the spleen; it seems also to dilate the vessels of the intestines and liver. Only slight evidence of a dilator action was found in the case of the kidney and none in that of the lung. The nasal mucosa seemed relatively less sensitive to the vasodilator action of acetyl-cholin than many other vascular areas. The vasodilation in all of these cases was diminished or prevented by atropine. As little as 0.000,000,002,4 mgm. acetyl-cholin per K caused a pronounced fall of blood pressure.

Acetyl-cholin injected into the trachea or applied to the surface of the lung, kidney, liver, adrenal and various muscles was very active in causing a fall of blood pressure; similar doses applied to the surface of the stomach, spleen and small intestine had no effect on the blood pressure.

BIBLIOGRAPHY

(1) HUNT AND TAVEAU: Brit. Med. Journ., 1906, ii, 1788.

(2) HUNT: Journ. Pharm. Exper. Therap., 1915, vii, 301.

(3) GUGGENHEIM AND LOEFFLER: Biochem. Zeitschr., 1916, lxxiv, 208; quoted from Chem. Abst., 1916, x, 2754.

(4) FÜHNER: Biochem. Zeitschr., 1916, lxxvii, 408; quoted from Chem. Abst., 1917, xi, 616.

(5) KAUFFMANN AND VORLÄNDER: Ber., 1910, xliii, 2735.

(6) HUNT: This Journal, 1900, iii, 18.

(7) HUNT: This Journal, 1901, v, 6.

(8) HUNT AND TAVEAU: Journ. Pharm. Exper. Therap., 1909, i, 303.

(9) HUNT AND TAVEAU: Bull. 73, Hygienic Laboratory, U. S. Public Health Service, 1911.

(10) MENGE: Journ. Biol. Chem., 1911, x, 399; 1912, xiii, 97.

(11) Menge: Bull. 96, Hygienic Laboratory, U. S. Public Health Service, 1914. (12) HUNT: Journ. Pharm. Exper. Therap., 1915, vi, 477.

(13) DALE: Journ. Pharm. Exper. Therap., 1914, vi, 147.

(14) BAYLISS: Journ. Physiol., 1902, xxviii, 220.

(15) HARTMAN: This Journal, 1915, xxxviii, 438.

(16) HOSKINS, GUNNING AND BERRY: This Journal, 1916, xli, 513.

(17) DALE: Journ. Physiol., 1906, xxxiv, 163.

(18) BARGER AND DALE: Biochem. Journ., 1907, ii, 240.

(19) GUNNING: This Journal, 1917, xliii, 395.

(20) GUNNING: This Journal, 1917, xliv, 215.

(21) TSCHALUSsow: Pflüger's Arch., 1913, eli, 524.

(22) FOFANOW AND TSCHALUSSOW: Pflüger's Arch. 1913, cii, 551. (23) HOSKINS AND GUNNING: This Journal, 1917, xliii, 298. (24) HARTMAN AND MCPHEDRAN: This Journal, 1917, xliii, 311. (25) Edmunds: Journ. Pharm. Exper. Therap., 1915, vi, 569. (26) MAUTNER AND PICK: Münch. Med. Wochenschr., 1915, 1141. (27) MACHT: Journ. Pharm. Exper. Therap., 1914, vi, 13.

VASODILATOR REACTIONS. II

REID HUNT

From the Laboratory of Pharmacology, Harvard Medical School, Boston

Received for publication December 7, 1917

1. THE RELATION OF THE ACETYL-CHOLIN VASODILATOR REACTION TO

VASOMOTOR NERVES

It has been shown by the work of Dale (1) and also by that reported in the preceding paper that acetyl-cholin causes vasodilation in many organs and that this action is prevented by atropine. It is usually assumed that a drug, the effect of which is prevented by atropine, acts upon "nerve endings" or upon "receptive substances" in connection with nerve endings; moreover, such an antagonism is often interpreted as showing the presence in an organ of a parasympathetic nerve innervation. Hence it was of interest to see if this vasodilator reaction could be correlated with the action of any of the nerves to which vasodilator actions have been attributed. "Vasodilator nerves" have been described for many organs; but in nearly every case their presence has been questioned. In fact the existence of "vasodilator" nerves (in the usual sense in which the term is employed) often has been the subject of discussion (2), (3), (4). Further, some authors believe that certain "vasodilator nerves" should be classed with one group of nerves, others that they should be placed in a different category. For present purposes we may consider the following groups of alleged vasodilators and see what evidence there is that they are involved in the action of acetyl-cholin: (a) Parasympathetic vasodilators, (b) Posterior root vasodilators, (c) Sympathetic vasodilators.

a. Parasympathetic vasodilators. The chorda tympani, stimulation of which causes a dilatation of the vessels of submaxillary gland, and the pelvic nerve, the stimulation of which causes, among other effects, dilatation of the vessels of the penis, have long been considered typical examples of parasympathetic vasodilators. It has been shown in the preceding paper that acetyl-cholin causes vasodilation in the submaxillary gland and in the penis; does it act upon the "nerve-endings"

of the parasympathetic nerves? That this is not the case (at least in the conventional sense) is shown by the different effects of atropine in the two cases: the action of acetyl-cholin is easily prevented by atropine; that of the stimulation of the nerves is not. Thus it was shown in the preceding paper that a small dose of atropine (2 mgm., for example) prevented the marked dilator effect of acetyl-cholin upon the penis; Langley and Anderson (5), Piotrowski (6) (and others cited by Piotrowski) found that atropine (even up to 60 mgm.) did not prevent the vasodilator action of the pelvic nerve.

As regards the chorda tympani: I found, for example, that 0.05 mgm. atropine prevented the vasodilator action of acetyl-cholin upon the submaxillary gland, whereas stimulation of the chorda continued to cause a marked vasodilation after more than 5 mgm. atropine. It has long been a common physiological demonstration that atropine while "paralyzing the secretory fibers" of the chorda tympani does not paralyze its vasodilator fibers (7). It has however been shown (8) (and I have confirmed the results) that atropine does diminish the "vasodilator" action of the chorda tympani and some, Barcroft for example, are inclined to hold that the vasodilation is the result of the secretory processes caused by the stimulation of the nerve. (See (2), (3), (4)). Of course, an interpretation could be placed upon my results with acetyl-cholin, similar to that given by Henderson and Loewi (8) for pilocarpine, namely, that the vasodilation from this was simply the result of increased secretory activity; but similar relations between atropine and acetyl-cholin hold for organs in which an analogous explanation can scarcely be offered. Since, when comparable degrees of vasodilation are caused on the one hand by acetyl-cholin and on the other by stimulation of the chorda tympani, the action of the latter is not perceptibly impaired by an amount of atropine a hundred times greater than that which suffices to prevent the action of the former it seems simpler to suppose that the vasodilation caused by acetyl-cholin is not the result of a stimulation of the chorda "nerveendings."

It has also been shown that the vasodilators to the tongue are not paralyzed by atropine (6).

b. Posterior root dilators. The most widely distributed and apparently the most powerful vasodilator nerves described are those in the posterior roots which were discovered by Stricker but which have been investigated with especial care by Bayliss (9). Bayliss considers that the vasodilator supply to the limbs, skin of the trunk and probably

of the ears and face, and of the intestine belong to this system. It is in these regions that acetyl-cholin exerts its most pronounced vasodilator action; is this the result of the stimulation of the "endings" of these nerves? Atropine prevents the action of acetyl-cholin upon the vessels in this area, as in all other cases. So far as I can learn the effect of atropine upon the vasodilator action of the posterior roots has not been directly tested. There is, to be sure, some evidence that atropine does not paralyze these nerves. Thus Ostroumoff (10) reported that the vasodilation resulting from weak or slow stimulation. of the peripheral end of the sciatic was not prevented by atropine; Pick (11) found that whereas large doses of atropine diminished the action of the vasoconstrictors of this nerve that of the vasodilators was not affected. Bayliss believes that the only sources of vasodilators to the limbs are the posterior root fibers, but others have described. sympathetic vasodilators to the limbs, and Gaskell (4) has recently stated that he thinks it impossible to consider that the posterior root fibers are the same as those found in the sciatic by slow stimulation. It seemed desirable therefore to test the effect of atropine upon the result of the direct stimulation of the posterior root fibers. This seemed especially desirable in view of Gaskell's suggestion that the posterior roots affect the metabolism of the skin as the chorda tympani controls the cells of the submaxillary gland and that the vasodilation from the stimulation of the nerves is, in both cases, the indirect result of changes in metabolism (production of "metabolites" which cause vasodilation.) The acceptance of this suggestion would not necessarily lead to the expectation that atropine would prevent the vasodilation caused by the posterior roots for there is no information as to the character of the metabolites supposed, on the above hypothesis, to be produced. But if atropine does not prevent the vasodilator action of the posterior roots whereas it does prevent the action of acetyl-cholin the conclusion would be justified that the vasodilation in the two cases is different.

As a matter of fact, I found that when comparable degrees of vasodilation were caused in a posterior extremity of a dog by stimulation of a posterior lumbar root on the one hand and by acetyl-cholin on the other, the effect of the latter was completely prevented by a small dose of atropine whereas that of the former was not diminished even by large doses (fig. 1, exp. 476).

According to the current conceptions of the posterior root vasodilators (3), (9), (see however, (12)), the nerve fibers of these divide, one