Bradford N. Craver

Influence of Female Hormones on Motility of Cat's Uterus and Its Responses to Oxytocics

Summary A method has been described of treating cats with an estrogen plus progesterone to assure uteri in vivo highly responsive for hours to oxytocics. Modifications of this method applied to juvenile and castrated cats indicated that either type of hormone would establish some brief uterine responsiveness but that both together were required to give a maximal and prolonged sensitivity to drugs. The two hormones in the cat are synergistic, or at least mutually complementary, and not antagonistic in respect to their effects upon the sensitivity of the cats uterus in vivo to drugs.

THE PHARMACODYNAMICS OF HISTAMINE

To make understandable the case history, as it were, of allergy, one must be familiar with the characteristics of the “skeleton in the closet.” Histamine plays the role of such a “skeleton” in relation to allergy. Since the papers dealing with the peculiar problems of allergy have clarified this relationship, we shall confine ourselves purely to the characteristics of that “skeleton,” save for minimal references to the earliest papers suggesting a connection between allergy and histamine. Histamine was first synthesized in 1907 by Windaus and Vogt.‘ In 1909, Biedl and Kraus2 advanced the hypothesis, based upon their studies of peptone-shock and anaphylaxis, that the symptoms resulting therefrom might be attributable to the release of a toxic substance within the organism. In 1910, Kutscher3 and Barger and Dale4 announced their independent isolation of histamine from ergot. In the same year, Dale and laid la^,^ after a careful study of the physiological effects of histamine, suggested that this substance might be responsible for the symptoms of peptone-shock. The comprehensive investigations of Dale and Laidlaw concerning the physiological effects of histamine clearly delineated the major actions of the drug. The hundreds of papers concerned with histamine that have been published since that time have added details to the picture ’sketched by Dale and Laidlaw. We can consider the present state of that picture, but it would be impossible to trace the history of every detail. Such histories are readily available in the two able monographs by Feldberg and Schilfs and by Gaddum and Dale7 and in the four excellent reviews by Best and McHenry? Rose; Dragstedt,’O and Selle.’l Of the many investigations in recent years that have been concerned primarily with the metabolism of histamine, only a partial review will be possible. Histamine is readily absorbed after injection and rapidly exerts its effects. Histamine administered enterally is slowly and poorly absorbed, although slight absorption does occur from the small intestine.12 Histamine must be reasonably well absorbed from the oral cavity, since, when administered lingually, it has been lethal to guinea pigs.13 Best and his associates14 first definitely established the presence of histamine in most, if not all, tissues of the body. Earlier workers had isolated histamine from various tissues,ls but the demonstration by Ackermann16 in 1910 that bacteria could produce histamine from histidine had raised the question of whether the histamine subsequently isolated was a natural constituent of the tissues or was produced by decomposition. The analytical method devised by Best and his associates eliminated this doubt. In general, its concentration is particularly high in lung, intestine, and skin and usually particularly low in the blood and kidneys; but there are considerable variations among species. In 1935, Barsoum and Gaddum’7 devised a more sensitive analytical procedure. It still employed, however, essentially the same principles incor-

Pharmacological properties of a new antispasmodic N, N-Dimethylthymyloxyacetamidine hydrochloride

1. The activities of a new antispasmodic, N, N-di-methylthymy loxyacetamidine hydrochloride and of its diethyl congener have been compared with the corresponding activities of Trasentine, Trasentine-6H, and atropine sulfate in respect to the following: a. Antagonism of a histamine-induced spasm of the ileum of the guinea pig. b. Antagonism of an acetylcholineinduced spasm of the ileum of the guinea pig. c. Antagonism, of a barium chloride-induced spasm of the small intestine of the rabbit. d. Actions on the feline uterus in vitro and in vivo. e. Actions on the nictitating membrane of the cat and on salivation induced by drugs and by stimulation of the chorda tympani nerve. f. Paralysis of the peripheral cut vagus in the cat. g. Antagonism of Mecholyl-induced hypotension in the cat. h. Intravenous LD50 in white rats. i. Chronic toxicological studies in dogs and rats. 2. The effects of Su-198 upon the intestines of dogs with Thiry-Vella loops and upon the bronchioles of the perfused guinea pig’s lung have been described. 3. Some of the problems have been discussed which must be solved before an objective evaluation of an antispasmodic becomes possible.

The effects of variable intervals of cooling upon the responses of the lapin intestine and uterus and the feline intestine to histamine, acetylcholine pituitrin and barium chloride

A study was made of the effects of cooling upon the response of the isolated uterus of the rabbit to acetylcholine, histamine, Pituitrin, and barium chloride. Since the responses of the tissues to the last spasmogenic agent were characterized by marked tachyphylaxis and an earlier loss than were the responses to the first two, it has been suggested that the focus of the barium ion’s action is relatively far removed from the final contractile response. It may lead to an alteration in the local concentration of some other cation such as potassium.