Showing papers in "British journal of pharmacology and chemotherapy in 1949"

The mechanism of action of anticholinesterase drugs.

Abstract: During the past few years much new work on anticholinesterase substances-has been published as a result of the new interest in the subject produced by the discovery of diisopropylfluorophosphonate (DFP) by McCombie and Saunders (1946). Many discrepancies of detail between the behaviour of individual cholinesterase inhibitors have been noted and have occasioned serious doubts as to the validity of the hypothesis that the physiological action of these substances is solely a consequence of cholinesterase inhibition. One source of error was greatly clarified by Mendel and his co-workers (Mendel, Mundell, and Rudney, 1943; Mendel and Rudney, 1943 and 1944; Hawkins and Gunter, 1946; Hawkins and Mendel, 1947), who showed that the term \" cholinesterase \" has been applied in the past to enzymes of two, and possibly more (Augustinsson, 1948), distinct enzymological Species-termed' by them \"true\" and \" pseudo\" cholinesterases, distinguishable by specific substrates. They have shown that these enzyme types differ strikingly in their distribution, their sensitivity to inhibitory agents, and their optimum substrate concentrations, and that the appearance of the pharmacological effects of anticholinesterases is related to inhibition of the \" true\" cholinesterase. Only# when the physiological response measured is that to acetylcholine carried by the blood stream does the pseudocholinesterase in the plasma seem to be important (Heymans, Verbeke, and Votava, 1948) in determining the magnitude of acetylcholine responses. Despite this very important advance many anomalies remain to be explained, and it is the purpose of this paper to discuss the kinetics of cholinesterase inhibition by various agents and the light this sheds on our interpretation of cholinesterase inhibition under strictly physiological conditions. Some aspects of the kinetics of cholinesterase activity and inhibition have been considered by a number of workers (Straus and Goldstein, 1943; Goldstein, 1944; Mazur and

Formation of adrenaline from noradrenaline in the perfused suprarenal gland

Abstract: Observations on the secretion of adrenaline from the perfused suprarenal gland of the dog have been described by Bulbring, Burn, and de Elio (1948). These experiments were carried out before the publication of work by various authors, Schumann (1948), Bflbring and Burn (1949a and b) and v. Euler and Hamberg (1949), showing that the suprarenal medulla contains noradrenaline as well as adrenaline, and no tests were used which would have distinguished between the two substances. The numerous estimations were made with isolated loops of rabbit intestine, comparing the samples with adrenaline only. The main outcome was to show that the liberation of adrenaline-like material in the blood leaving the gland was modified by the presence of adrenaline in the perfusing blood. When this was very small in amount, stimulation of the splanchnic nerve liberated very little adrenaline-like material in the venous blood. When the experiment was performed with progressively larger amounts of adrenaline in the perfusing blood, stimulation of the splanchnic nerve liberated progressively larger amounts ofadrenaline-like material untilanoptimum concentration for adrenaline in the perfusing blood was reached. A further increase of adrenaline in the perfusing blood beyond this optimum produced a steady decline in the amount of adrenaline-like substance liberated by splanchnic stimulation. The work had, however, been begun with the object of studying the formation of adrenaline by the isolated gland, and in the experiments in which less than 1 ,pg. adrenaline per ml. was present in the perfusing blood, an increase in the amount of adrenaline-like material in the system was always observed. Meanwhile West (1947), working in the pharmacological laboratory in Edinburgh, had shown that the rat uterus was much more sensitive to adrenaline than to noradrenaline. When used as described by de Jalon, Bayo, and de Jalon (1945) this test can be used to estimate adrenaline in a mixture of the two drugs (see Gaddum, Peart, and Vogt, 1949). We therefore carried out a series of five perfusion experiments in which we estimated adrenaline and noradrenaline separately throughout each experiment, and we now give a brief description of the results which were obtained.

Studies with a Radioactive Spinal Anaesthetic

Abstract: The need for information about the fate of a spinal anaesthetic after its introduction into the spinal theca was early recognized (Miller, 1901), but many years elapsed before the problem was seriously studied by a number of workers, including Stout (1929), Kustner and Eissner (1930), Koster et al. (1936, 1938, 1939), Bullock and Macdonald (1938), and Shields (1942). In the main these workers agreed that after the intrathecal injection of procaine there was a rapid initial drop in local concentration with a subsequent period of gradual decrement. Evidently an anaesthetic departs from the subarachnoid space, but what is its route of depai ture? There are various theoretical possibilities: