bluuebunny/crossref_metadata_2025 huggingface dataset:
THE CENTRAL VASOMOTOR EFFECTS OF 5‐HYDROXYTRYPTAMINE
Authors: BHARGAVA K. P. , TANGRI K. K.
Published: July 2012

In the dog, injection of 5‐hydroxytryptamine into the cerebral ventricles caused hypotension, inhibition of the pressor response to occlusion of the carotid artery and inhibition of the pressor or depressor response evoked by electrical stimulation of the central end of the cut vagus. Hypotension and inhibition of the vagal vasomotor response also occurred in dogs in which the carotid sinuses had been denervated and the vagi cut. The site of action was central. Local cerebral vascular changes could not have been responsible for the action. The central vasomotor effects of 5‐hydroxytryptamine are mediated through the sympathetic outflow. Implications of these findings are discussed in relation to the effects of intravenous 5‐hydroxytryptamine and the mechanism of action of reserpine.
ACTIONS OF DIMETHYLPHENYLPIPERAZINIUM
Authors: LING H. W.
Published: July 2012

The actions of 1,1‐dimethyl‐4‐phenylpiperazinium iodide (DMPP) have been studied to discover under what conditions a blocking action could be seen. Dimethylphenylpiperazinium has a stimulant action on autonomic ganglia, stimulating the superior cervical ganglion and causing contraction of the nictitating membrane. It caused slowing followed by acceleration of the rate of beat of isolated rabbit atria. The denervated gastrocnemius muscle contracted if dimethylphenylpiperazinium was injected intra‐arterially. Under other circumstances a blocking action was seen. It blocked peristalsis in the isolated guinea‐pig ileum stimulated by raising intraluminal pressure and inhibited the response of the rat diaphragm and of the cat gastrocnemius stimulated through the motor nerve. It is suggested that dimethylphenylpiperazinium acts by depolarization, causing stimulation of resting muscle but inhibition by prolonging depolarization.
ANTAGONISM OF THE EFFECTS OF TREMORINE BY TROPINE DERIVATIVES
Authors: FARQUHARSON MURIEL E. , JOHNSTON R. G.
Published: July 2012

Methods of testing new drugs for anti‐Parkinson activity are briefly reviewed. The production in animals of Parkinson‐like effects by Tremorine (1,4‐dipyrrolidin‐1′‐ylbut‐2‐yne), and the inhibition of these effects in mice by a number of tropine derivatives, are described. No correlation was found between the activity against tremor and the anticholinergic, antihistaminic or local anaesthetic properties of the compounds.
COMPARISON OF EFFECTS OF VALYL3— OXYTOCIN AND SYNTOCINON ON THE CARDIOVASCULAR SYSTEM OF MAN
Authors: KITCHIN A. H. , KONZETT H. , PICKFORD MARY
Published: July 2012

Valyl3‐oxytocin has similar circulatory effects in man to those of Syntocinon (synthetic oxytocin). On intravenous administration, it caused a rise in limb blood flow and in pulse rate and a fall in blood pressure. It had a direct vasodilator effect on limb blood vessels. Valyl3‐oxytocin was 1.5 to 2 times more potent than Syntocinon in terms of its circulatory effect in man. The circulatory effects of valyl3‐oxytocin were less readily antagonized by vasopressin than are those of Syntocinon.
THE EFFECT OF ALKYLATING AGENTS ON MALE RAT FERTILITY
Authors: JACKSON H. , FOX B. W. , CRAIG A. W.
Published: July 2012

The effects of tumour inhibitory doses of tretamine (triethylenemelamine), busulphan, and melphalan on the fertility of male rats have been examined. The aromatic nitrogen mustard, melphalan, was inactive, but busulphan has a highly selective action on spermatogenesis which contrasts strikingly with that of tretamine. The main action of tretamine was exerted upon spermatocytes or spermatids, but, with increasing dose, the effects spread to involve a wide range of spermatogenic cells including mature sperm, so that infertility could be induced very rapidly. Busulphan, however, interfered with the development of spermatogonia for several weeks, although other germinal cells were unaffected and continued to develop into mature spermatozoa. This accounted for the continuation of normal fertility for 7 weeks after a dose, before sterility suddenly developed. The antifertility activity of tretamine could be simulated by a variety of other ethyleneimino compounds, potency being greatest in trifunctional and least in monofunctional compounds. The latter were, however, very destructive to the seminiferous epithelium with increasing dose. In the rat, there appeared to be no definite relationship between the ability of alkylating substances to interfere with the activity of normal and pathological proliferating tissues, as represented by the germinal epithelium, haematopoietic, and tumour tissue. Although carcinogenicity was a biological property of alkylating agents, other chemical types of carcinogen did not interfere with fertility.
THE ANTITUBERCULAR PROPERTIES OF A SERIES OF THIOLS AND SULPHIDES
Authors: ACRED P. , BROWN D. M.
Published: July 2012

The antitubercular activity of a series of thiols, dithiolans, thiol esters, dimercaptopropyl esters, and episulphides has been examined in vitro and in vivo in mice infected with the H37Rv strain of Mycobacterium tuberculosis. Most of the thiol compounds were inactive, although dimercaprol (2,3‐dimercaptopropanol; B.A.L.) and a few closely related compounds showed slight activity in vivo, the only exception being 2,3‐dimercaptopropyl chloride which was very active. The dithiolans were inactive, but some of the thiol esters were moderately active, in particular 2,3‐di(acetylthio)propyl acetate and 1,2,3‐tri(acetylthio)propane. The majority of the dimercaptopropyl esters had significant activity, the most active compounds being 2, 3 ‐ dimercaptopropyl benzoate, 1, 3 ‐ dimercapto ‐ 2 ‐ propyl benzoate, 2, 3 ‐ dimercaptopropyl o‐chlorobenzoate, and 2,3‐dimercaptopropyl p‐chlorobenzoate. All the S‐acyl derivatives of 3‐mercaptopropylene sulphide had good antitubercular activity, some being more active than streptomycin. The most active compound of the series was 3‐(2‐furoylthio)propylene sulphide. The activity of the compounds is believed to be due to their conversion in vivo to 3‐mercaptopropylene sulphide and not due to the formation of ethanethiol. Slight deviation from the basic structure abolishes antitubercular activity.
ANALGESIC ANTIPYRETIC DRUGS AS ANTAGONISTS OF BRADYKININ
Authors: COLLIER H. O. J. , SHORLEY PATRICIA G.
Published: July 2012

The antagonism between analgesic antipyretic drugs and bradykinin was examined quantitatively, using the bronchoconstrictor response of guinea‐pigs in vivo. The dose of bradykinin required to overcome antagonism by calcium acetylsalicylate increased with the dose of acetylsalicylate given, the ratio being roughly constant. Fifty times the quantity of acetylsalicylate which just antagonized bradykinin did not modify bronchoconstriction due to small doses of histamine, 5‐hydroxytryptamine, or acetylcholine. A method of measuring the potency of this anti‐bradykinin action was developed. Acetylsalicylic acid, phenylbutazone, amidopyrine, and phenazone had a high potency; paracetamol, cinchophen, sodium salicylate, and acetanilide had a moderate potency; and phenacetin, salicylamide, and 4‐hydroxyisophthalic acid had little or none. Cortisone, hydrocortisone, aldosterone, amodiaquine, and morphine were ineffective or their action was non‐specific. In sensitized guinea‐pigs, an injection of antigen caused bronchospasm. This response was greatly lessened by pretreatment with mepyramine, but was not affected by calcium acetylsalicylate, lysergic acid diethylamide, or atropine. Acetylsalicylic acid, phenylbutazone, and amidopyrine did not specifically antagonize the action of bradykinin on the capillaries of guinea‐pig skin in vivo, on guinea‐pig ileum in vitro or on rat duodenum in vitro.
MEMBRANE POTENTIAL CHANGES ASSOCIATED WITH TACHYPHYLAXIS AND POTENTIATION OF THE RESPONSE TO STIMULATING DRUGS IN SMOOTH MUSCLE
Authors: BÜLBRING EDITH , BURNSTOCK G.
Published: July 2012

Conditions which affect the response of smooth muscle to repeated application of stimulating drugs have been investigated. In guinea‐pig taenia coli, tension changes were recorded simultaneously with membrane potential changes using the sucrose gap technique. Acetylcholine, histamine, and 5‐hydroxytryptamine caused depolarization and, after removal of the drug, hyperpolarization which was followed by a sequence of damped oscillations of the membrane potential. The average rate of depolarization decreased in the order acetylcholine > histamine > 5‐hydroxytryptamine. The readiness with which tachyphylaxis occurred increased in the order acetylcholine <histamine<5‐hydroxytryptamine. When a dose of a stimulating drug was repeated, the response obtained depended on the phase of the oscillatory potential changes during which it was applied. In general the effect was depressed during a phase of polarization and enhanced during a phase of depolarization. The degree of tachyphylaxis—or potentiation—depended not only on the direction in which the membrane potential changed at the moment of drug application, but also on the relation between the rate at which this potential change took place and the rate of depolarization caused by the drug. The results observed are consistent with the hypothesis that the fluctuating excitability and polarization of the smooth muscle membrane is brought about by periodical changes in the rate of active ion transport and other stabilizing processes in the cell membrane which depend on the rate of metabolic energy supply. The muscle was sensitized to acetylcholine and histamine by previous treatment with, or in the presence of, 5‐hydroxytryptamine.
THE PHARMACOLOGICAL ACTIONS OF (m‐HYDROXYPHENETHYL)TRIMETHYLAMMONIUM (LEPTODACTYLINE)
Authors: ERSPAMER V. , GLÄSSER A.
Published: July 2012

Leptodactyline is a naturally occurring quaternary ammonium base, which is found in large amounts in the skin of some South American amphibians of the genus Leptodactylus. It is the first example of a m‐hydroxyphenylalkylamine in the living organism. In vertebrates it had powerful nicotinic actions and a marked neuromuscular blocking effect. This was considered, on the basis of experimental evidence, to be of the “depolarizing” type.
OXIDATION OF 5‐HYDROXYTRYPTAMINE AND RELATED COMPOUNDS BY MYTILUS GILL PLATES
Authors: BLASCHKO H. , MILTON A. S.
Published: July 2012

Homogenates of gill plates of Mytilus edulis L. used oxygen when 5‐hydroxytryptamine was added. The oxidation of 5‐hydroxytryptamine was not due to the presence of an amine oxidase, but to that of an enzyme that catalysed the oxidation of other 5‐hydroxyindoles (5‐hydroxytryptophan, bufotenine). The oxidation was cyanide‐sensitive, but was not inhibited by iproniazid. In the reaction a yellowish‐brown substance was formed. The occurrence of an amine oxidase in the anterior retractor muscle of the byssus and in the digestive gland was confirmed.
THE PHARMACOLOGICAL ACTIONS OF 3,4‐DIHYDROXY‐PHENYL‐α‐METHYLALANINE (α‐METHYLDOPA), AN INHIBITOR OF 5‐HYDROXYTRYPTOPHAN DECARBOXYLASE
Authors: SMITH S. E.
Published: July 2012

α‐Methyldopa (3,4‐dihydroxyphenyl‐α‐methylalanine) is an inhibitor of 5‐hydroxytryptophan decarboxylase which is effective in vitro and in vivo. The inhibition is complex and shows coenzyme reversal. Evidence is presented that it acts by coenzyme inactivation. Its administration to mice reduced brain 5‐hydroxytryptamine but had no effect on noradrenaline. After repeated doses, intestinal 5‐hydroxytryptamine concentrations were also reduced. Co‐ordinated activity was diminished coincidently with the enzyme inhibition and the reduction in brain 5‐hydroxytryptamine. Rectal temperatures were reduced and the possibility that this resulted from inactivity is discussed. Treated animals showed miosis and narrowing of the palpebral fissures. A comparison is drawn between the actions of α‐methyldopa and reserpine. The present results support the idea that the sedative effects of both drugs are due to the fall in brain 5‐hydroxytryptamine concentration that they produce.
UPTAKE OF 5‐HYDROXYTRYPTAMINE BY PLATELETS
Authors: STACEY R. S.
Published: July 2012

Human blood platelets were incubated with 5‐hydroxytryptamine and with tryptamine and the uptake of each amine measured. The uptake of tryptamine, unlike that of 5‐hydroxytryptamine, was linearly related to the concentration of the amine in the surrounding fluid, was similar in amount at 0° and 37° C and varied directly with the pH of the solution. When both amines were present together the uptake of 5‐hydroxytryptamine was depressed. The antagonism of tryptamine was found to be competitive, and the possible site of its action is discussed. The effect of a number of other substances on the uptake of 5‐hydroxytryptamine by platelets was examined; of these imipramine, cocaine and chlorpromazine were more potent and dihydroergotamine and lysergic acid diethylamide somewhat less potent than tryptamine in inhibiting uptake.
SUPPRESSION OF OUABAIN‐INDUCED ATRIAL ARRHYTHMIAS BY CAROTID SINUS STIMULATION
Authors: SCHOTT A.
Published: July 2012

In dogs anaesthetized with chloralose ectopic atrial arrhythmias were produced by subepicardial injection of ouabain. Stimulation of the right carotid sinus abruptly suppressed the ectopic arrhythmias. They returned on cessation of stimulation and sometimes already during the period of stimulation. It is suggested that in view of its response to carotid sinus stimulation the ouabain‐induced arrhythmia resembles paroxysmal atrial tachycardia and that it is distinct from the aconitine‐induced arrhythmia which on account of its response to vagal stimulation has been classified as atrial flutter.
COMPARISON OF THE FUNCTIONAL EFFECTS OF DYFLOS, TRI‐O‐CRESYL PHOSPHATE AND TRI‐p‐ETHYLPHENYL PHOSPHATE IN CHICKENS
Authors: CAVANAGH J. B. , DAVIES D. R. , HOLLAND P. , LANCASTER M.
Published: July 2012

Tri‐p‐ethylphenyl phosphate is unique amongst the organophosphorous compounds which produce neurotoxic effects in not being an inhibitor of cholinesterase. The dysfunction it produces is also marked by some unusual features. Thus it produces a characteristic high‐stepping gait which develops at varying periods after intramuscular injection but more regularly following oral administration. A careful comparison of the character, onset and development of the effects of diisopropyl phosphorofluoridate (dyflos), tri‐o‐cresyl phosphate and tri‐p‐ethylphenyl phosphate has illustrated the differences between the two former substances and tri‐p‐ethylphenyl phosphate. It has also confirmed a previous suggestion that this substance acts in a different manner from the other two, a suggestion supported by the histological evidence.
SENSITIVITY OF THE HYPERTHYROID AND HYPOTHYROID MOUSE TO HISTAMINE AND 5‐HYDROXYTRYPTAMINE
Authors: SPENCER P. S. J. , WEST G. B.
Published: July 2012

Injections of thyroxine sodium increased the sensitivity of mice to histamine, the maximal effect occurring after 6 days. The sensitivity to 5‐hydroxytryptamine was increased to a lesser extent. Hydrocortisone antagonized this effect of thyroxine, whereas anti‐thyroid drugs alone decreased the sensitivity to histamine. Treatment with thyroxine also raised the metabolic rate, the peak again being reached after 6 days. As treatment was continued beyond 6 days, the adrenal gland enlarged and its secretion probably accounted for the decline in the histamine sensitivity.
RELATIVE ACTIVITY OF SOME INHIBITORS OF MONO‐AMINE OXIDASE IN POTENTIATING THE ACTION OF TRYPTAMINE IN VITRO AND IN VIVO
Authors: MAXWELL D. R. , GRAY W. R. , TAYLOR E. M.
Published: July 2012

Several known inhibitors of mono‐amine oxidase (iproniazid, isocarboxazid, nialamide, phenelzine, pheniprazine and tranylcypromine) were tested for their ability to (i) inhibit the mono‐amine oxidase activity of a rat brain mitochondrial preparation in vitro; (ii) potentiate the action of tryptamine on the isolated rat fundal strip preparation; and (iii) potentiate the acute toxicity of tryptamine in mice. There was some correlation between the order of potency of the drugs in the three tests, particularly in inhibiting the enzyme activity in the Warburg and in the tryptamine toxicity test in mice. Exceptions to this were isocarboxazid which had unexpectedly high activity on the rat fundal strip preparation, and tranylcypromine which was devoid of tryptamine‐potentiation action on the rat fundus preparation although it inhibited rat brain mono‐amine oxidase in vitro and potentiated the action of tryptamine in vivo. Tranylcypromine was considerably less active in inhibiting the mono‐amine oxidase of rat fundus than rat brain tissue in vitro, while iproniazid and isocarboxazid had about the same potency on the enzyme from the two tissues.
SIMILARITY BETWEEN RECEPTORS RESPONSIBLE FOR THE PRODUCTION OF ANALGESIA AND LENTICULAR OPACITY
Authors: WEINSTOCK MARTA
Published: July 2012

Evidence is presented that the receptors responsible for the mediation of analgesia by morphine‐like drugs are similar to those which are involved in the production of a reversible lenticular opacity. The activity of a number of compounds in mice on the lens was closely correlated with analgesic potency in this species. Stereospecificity for isomers with d configuration was demonstrated for both effects. Nalorphine only antagonized the lenticular opacity activity of those drugs the analgesic action of which it abolished.
EFFECT OF l‐TRYPTOPHAN ON DIURESIS AND 5‐HYDROXYINDOLEACETIC ACID EXCRETION IN THE RAT
Authors: BERTACCINI G. , NOBILI M. B.
Published: July 2012

Oral administration of l‐tryptophan to rats produced two main biochemical and pharmacological effects: a marked increase in urinary 5‐hydroxyindoleacetic acid excretion, and a significant reduction in the urine flow after a water load. Urinary 5‐hydroxyindoleacetic acid excretion reached its maximum 2 to 6 hr after the administration of tryptophan, and it increased with the dose of the amino acid. Antidiuresis was seen after the administration of l‐tryptophan, 200 mg/kg, or more. The effect appeared promptly and it was roughly proportional to the dose of the amino acid administered. Both antidiuretic effect and increase in urinary 5‐hydroxyindoleacetic acid excretion were more intense after oral than after parenteral administration of l‐tryptophan. d‐Tryptophan, in oral doses up to 1,000 mg/kg, produced neither an increase in urinary 5‐hydroxyindoleacetic acid nor a reduction of diuresis. Available evidence suggests that reduction of urine flow is a consequence of biosynthesis and release of 5‐hydroxytryptamine by the gastrointestinal mucosa. Tryptamine produced by direct decarboxylation of l‐tryptophan does not seem to play any important role.
TOXICOLOGICAL AND PHARMACOLOGICAL EFFECTS OF GADOLINIUM AND SAMARIUM CHLORIDES
Authors: HALEY T. J. , RAYMOND K. , KOMESU N. , UPHAM H. C.
Published: July 2012

A study has been made of the toxicology and pharmacology of gadolinium and samarium chlorides. The symptoms of acute toxicity following intraperitoneal injection are described. The chronic oral ingestion of both chemicals for 12 weeks produced no effects on growth or the blood picture, and only the male rats receiving gadolinium chloride showed liver damage. The pharmacological responses to both chemicals were mainly depressant on all systems studied, and death was associated with cardiovascular collapse coupled with respiratory paralysis. The greatest damage seen was on abraded skin, where non‐healing ulcers were produced by both chemicals, whereas irritation of intact skin and ocular tissues was only transient in nature.
MECHANISM OF INCREASED SUSCEPTIBILITY TO FIBRILLATION OF THE HYPOTHERMIC MAMMALIAN HEART IN SITU
Authors: SZEKERES L. , MÉHES J. , PAPP J.
Published: July 2012

The susceptibility of auricles and ventricles to fibrillation during hypothermia of isolated hearts, and of heartsin situin anaesthetized cats, was estimated by measuring the threshold for the production of fibrillation by electrical stimulation. Hypothermia reduced the threshold ofin situhearts, but increased the threshold of isolated perfused hearts and of heart‐lung preparations. The increased sensitivity ofin situhearts to fibrillation could be induced by cooling the head only, and was abolished by cutting the vagi. At normal body temperature, section of the vagi had no influence on the fibrillation threshold. In contrast, cutting the sympathetic increased the fibrillation threshold ofin situhearts at normal temperature, but had no influence on the threshold during hypothermia. It was concluded that the increased susceptibility of anaesthetized animals to fibrillation could be attributed to changes in the central nervous control of the heart induced by the cooling of the head.
STRUCTURE‐ACTIVITY RELATIONSHIPS IN A SERIES OF 6‐THIOXANTHINES WITH BRONCHODILATOR AND CORONARY DILATOR PROPERTIES
Authors: ARMITAGE A. K. , BOSWOOD JANET , LARGE B. J.
Published: July 2012

The bronchodilator activity of 47 compounds on the isolated guinea‐pig tracheal ring preparation and the coronary dilator activity on the dog heart‐lung preparation is described. 1,3‐Disubstituted xanthines and 6‐thioxanthines (theophyllines and 6‐thiotheophyllines) were more active as bronchodilators and as coronary dilators than were 3,7‐disubstituted 6‐thioxanthines (6‐thiotheobromines) or 1,3,7‐trisubstituted 6‐thioxanthines (6‐thiocaffeines). None of the 6‐thioxanthines was of any interest as a diuretic and none of the 6‐thiocaffeines was of any interest as a central stimulant. Structure‐activity requirements for potent bronchodilator and coronary dilator activity are discussed.
ON THE METABOLISM OF METHYLATED DISULPHONAMIDES WITH A DIURETIC ACTION—A CONTRIBUTION TO THE MECHANISM OF ACTION OF CHLOROTHIAZIDE AND SIMILAR COMPOUNDS
Authors: LOGEMANN W. , GIRALDI P. N.
Published: July 2012

The metabolism of two substances possessing a diuretic action, 4‐amino‐6‐chloro‐benzene‐1,3‐disulphonmethylamide (III) and 6‐chloro‐3,4‐dihydro‐2‐methyl‐7‐methyl‐sulphamoyl‐2H‐1,2,4‐benzo[e]thiadiazine‐1,1‐dioxide (IV), has been studied on rats and human subjects. It has been shown that these compounds are not demethylated in the –SO2.NHCH3 group. They therefore do not act through liberation of substances with unsubstituted sulphonamido‐groups which might inhibit carbonic anhydrase, and their mechanism of diuretic action cannot be considered due to inhibition of this enzyme.
SITE OF ACTION OF CHLORPROMAZINE AND MEPHENESIN IN EXPERIMENTAL TETANUS
Authors: WEBSTER R. A.
Published: July 2012

The anti‐tetanus activities of chlorpromazine and mephenesin have been determined quantitatively in intact, spinal and decerebrate rabbits with local tetanus. The activity of chlorpromazine in the spinal animal differed from that in the intact and decerebrate animal and depended on the level of brain‐stem section. Mephenesin was equally effective in all preparations and probably suppressed tetanus by blocking transmission in motor pathways in the spinal cord.
ACTIONS OF BRETYLIUM AND GUANETHIDINE ON THE UPTAKE AND RELEASE OF [3H]‐NORADRENAUNE
Authors: HERTTING G. , AXELROD J. , PATRICK R. W.
Published: July 2012

The effect of bretylium and guanethidine has been studied on the uptake and the spontaneous and reserpine‐induced release of [3H]‐noradrenaline in the rat heart and in the splenic nerve endings of the cat. Bretylium and guanethidine inhibited the uptake by the heart of circulating [3H]‐noradrenaline. Bretylium blocked spontaneous and reserpine‐induced release of [3H]‐noradrenaline, while guanethidine caused release and partially antagonized the reserpine‐induced release. Both compounds produced a transient liberation of [3H]‐noradrenaline from splenic nerves, but blocked the release of the [3H]‐catechol amine following stimulation of the splenic nerve.
A COMPARISON OF THE RESPONSES OF THE TENUISSIMUS MUSCLE TO NEUROMUSCULAR BLOCKING DRUGS IN VIVO AND IN VITRO
Authors: MACLAGAN JENNIFER
Published: July 2012

In view of the differing responses to decamethonium which have been reported for the isolated tenuissimus muscle on the one hand and the tibialis muscle of the cat on the other hand, the responses of the tenuissimus muscle to neuromuscular blocking drugs were studied bothin vivoandin vitroand compared with those of the tibialis anterior muscle. In both musclesin vivo, the block produced by decamethonium had all the well‐known characteristics of blockade due to long‐lasting depolarization, independent of the number of doses given. However, when the tenuissimus muscle was studiedin vitroits responses were considerably altered. When decamethonium was left in contact with the isolated muscle, maximum paralysis developed quickly, but then the muscle recovered despite the continued presence of the drug in the bath. This contrasts with the effect obtainedin vivo, where a steady application of decamethonium produced steady blockade. This spontaneous recoveryin vitrooccurred to a smaller extent with each successive dose. In addition, the usual antagonism between depolarizing and competitive drugs was only seen during the earlier part of an experiment and rarely occurred after several doses. It is suggested that the differences betweenin vivoandin vitroresponses of the tenuissimus muscle to decamethonium could be due to detrimental changes in ionic concentration gradients resulting from immersion in an artificial fluid.
NEUROTOXIC SYNDROME PRODUCED IN CHICKENS BY A CYCLIC PHOSPHATE METABOLITE OF TRI‐o‐CRESYL PHOSPHATE—A CLINICAL AND PATHOLOGICAL STUDY
Authors: BARON R. L. , BENNETT D. R. , CASIDA J. E.
Published: July 2012

A clinical and neuropathological comparison was made between chickens poisoned with tri‐o‐cresyl phosphate and those treated with the major cyclic phosphate metabolite of tri‐o‐cresyl phosphate. Ataxia was evident with both materials, and the degree of peripheral neuropathy increased with higher doses of these agents. Morphological changes were evident with the onset of symptoms and increased in number as the neurological signs progressed. Demyelination of the spinal cord following administration of the metabolite occurred at doses considerably below those necessary to effect peripheral nerve degeneration. Axon and myelin damage was prominent with both agents. The relationship between these effects and those produced by certain other organophosphates such as dyflos (diisopropyl fluorophosphonate) is discussed.
ACTION OF SOME GANGLION‐STIMULATING SUBSTANCES ON THE SECRETION OF SALIVA FROM THE SUBMANDIBULAR GLAND
Authors: DE LA SIERRA B. GOMEZ ALONSO
Published: July 2012

An attempt has been made to determine whether the ganglionic actions of pilocarpine and of 4‐(m‐chlorophenylcarbamoyloxy)‐2‐butynyltrimethylammonium chloride (McN‐A‐343) contribute to their effect on salivary secretion. Salivary flow was measured from the submandibular glands of spinal cats. Destruction of the superior cervical ganglion and adrenalectomy failed to reduce the stimulant effect of pilocarpine and McN‐A‐343. Substances known to interfere with the ganglionic actions of pilocarpine (cocaine, methadone and choline 2:6‐xylyl ether bromide) likewise failed to modify the response. It is concluded that stimulation of autonomic ganglia and of the adrenal medulla does not contribute to the salivary secretion observed after intravenous injections of pilocarpine and of McN‐A‐343. Dimethylphenylpiperazinium, a nicotine‐like ganglion‐stimulating substance, causes salivary flow by stimulating the adrenal medulla as well as parasympathetic ganglion cells; stimulation of the superior cervical ganglion by this substance does not contribute to the salivary response.
DEPOLARIZING ACTION OF NEOSTIGMINE AT AN AUTONOMIC GANGLION
Authors: MASON D. F. J.
Published: July 2012

The actions of neostigmine have been examined using electrical recording from normal and denervated superior cervical ganglia from rat and kitten. Neostigmine produced a rapid and reversible depolarization of the ganglion cells, both in vitro and in vivo. This depolarization could be antagonized by hexamethonium, and was not related to an anticholinesterase action. Eserine blocked transmission and only produced a small depolarization of slow onset and development. This depolarization was reversible, but could not be antagonized by hexamethonium.
EFFECT OF RESERPINE PRETREATMENT ON THE RESPONSE OF ISOLATED PAPILLARY MUSCLE TO EPHEDRINE
Authors: CAIROLI V. J. , REILLY J. F. , ROBERTS J.
Published: July 2012

Reserpine pretreatment of cats abolished the action of ephedrine to induce spontaneous beating in papillary muscles obtained from these animals. This spontaneous beating was viewed as resulting solely from catechol amine release. The positive inotropic action of ephedrine was diminished but not abolished by reserpine pretreatment. Reserpine reduced the heart rate in vivo, but it did not affect the peak contraction height or the rate of failure of the isolated papillary muscle. The contractile response to adrenaline (0.1 μg/ml.) was not affected by reserpine pretreatment. However, in this concentration adrenaline induced spontaneous beating only after reserpine.
EFFECT OF TYRAMINE ON ISOLATED GUINEA‐PIG ATRIA IN RELATION TO THEIR NORADRENALINE STORES
Authors: CROUT J. R. , MUSKUS A. J. , TRENDELENBURG U. , HOBBS RONEEN D.
Published: July 2012

The relation between the noradrenaline content of isolated guinea‐pig atria and the rate‐increasing action of tyramine was studied by the use of pretreatment with reserpine as a pharmacological tool for graded depletion of the noradrenaline stores. Reserpine was more potent in depleting the stores than in reducing the biological response to tyramine; 50% depletion had little effect on the response to tyramine; 50% reduction of the response to tyramine occurred when the noradrenaline content fell to about 10% of normal. Depletion of the stores of guinea‐pig atria did not result in supersensitivity to noradrenaline. Exposure of heavily pretreated atria to 3 × 10−6 noradrenaline for 10 min (followed by repeated washing for 45 min) restored the response to tyramine to 70% of normal; it failed, however, to restore the noradrenaline content to the level expected from the experiments with reserpine alone. Restoration of the response to tyramine was accompanied by a small but significant increase in the noradrenaline content of the atria; a change in sensitivity to added noradrenaline did not occur. The results are consistent with the view that (a) the noradrenaline stores consist of two compartments the smaller of which is important for the action of tyramine, that (b) this smaller compartment can be at least partially refilled by exposure of the atria to noradrenaline, and that (c) there is no direct relationship between the noradrenaline content and the sensitivity to noradrenaline in guinea‐pig atria.
INHIBITION OF PLASMA KININASE ACTIVITY AT SLIGHTLY ACID pH
Authors: EDERY H. , LEWIS G. P.
Published: July 2012

Kinins, like bradykinin, are rapidly inactivated in blood and interstitial fluid by an enzyme called kininase. The action of this enzyme was found to be inhibited at slightly acid pH although the formation of kinins proceeded normally. Thus a slightly acid pH which is known to occur in inflamed and damaged tissue is a suitable environment to allow accumulation of kinins which are thought to be the mediators of the inflammatory response.
RELATIONSHIP BETWEEN ANTI‐ACETYLCHOLINE AND ANTI‐TREMORINE ACTIVITY IN ANTI‐PARKINSONIAN AND RELATED DRUGS
Authors: AHMED A. , MARSHALL P. B.
Published: July 2012

The anti‐acetylcholine potency of a number of anti‐Parkinsonism drugs and related phenothiazine compounds was determined using the isolated guinea‐pig ileum. The antagonism was assessed by the difference between the pA2 and pA10 values and by log concentration‐response curves for acetylcholine in presence and absence of the antagonists. All compounds except chlorpromazine showed some evidence of competitive antagonism to acetylcholine. The anti‐tremor potency of the compounds was assessed from suppression of Tremorine‐induced tremors in mice. There was a relation between anti‐acetylcholine and anti‐Tremorine potency among the anti‐Parkinsonism drugs, but not among the phenothiazine compounds. Some implications of the findings are discussed in relation to the mode of action of anti‐Parkinsonism drugs.
EFFECT OF NICOTINE, NORNICOTINE AND ALLYLNORNICOTINE ON THE DIURETIC RESPONSE TO WATER IN RATS
Authors: REES A. H. , SCHNIEDEN H.
Published: July 2012

The LD50 in mice for nicotine, (—)‐nornicotine and allylnornicotine given intraperitoneally was respectively 10 mg/kg, 18.8 mg/kg and 93.3 mg/kg. Whilst nicotine inhibited the renal response in rats to water, (—)‐nornicotine and allylnornicotine were without effect. Nicotine antidiuresis was not antagonized by (—)‐nornicotine or by allylnornicotine.
EFFECT OF TYROSINASE PREPARATIONS ON OXYTOCIN, VASOPRESSIN AND BRADYKININ
Authors: BISSET G. W.
Published: July 2012

On incubation with a tyrosinase preparation at pH 7.5, oxytocin and vasopressin were inactivated. The loss of oxytocic activity did not differ significantly from that of milk‐ejecting activity in oxytocin, nor the loss of pressor activity from that of antidiuretic activity in vasopressin. Oxytocin was inactivated less rapidly at pH 6.6 than at pH 7.5. At pH 3.9 neither oxytocin nor vasopressin was inactivated. Analogues of oxytocin and vasopressin, in which tyrosine is replaced by phenylalanine, were not inactivated by the tyrosinase preparation used. On incubation of bradykinin with two different tyrosinase preparations, there was no loss of oxytocic activity at pH 7.5 but an almost total loss at pH 3.9. In the presence of p‐nitrophenol, ascorbic acid, sodium diethyldithiocarbamate and during incubation under anaerobic conditions the inactivation of oxytocin at pH 7.5 was inhibited, but not that of bradykinin at pH 3.9. It is concluded that the tyrosinase preparations used contain two distinct enzymes or activities, the one inactivating oxytocin and vasopressin at pH 7.5 and the other bradykinin at pH 3.9.
TRIETHYLCHOLINE COMPARED WITH OTHER SUBSTANCES AFFECTING NEUROMUSCULAR TRANSMISSION
Authors: BOWMAN W. C. , HEMSWORTH B. A. , RAND M. J.
Published: July 2012

Triethylcholine (triethyl‐2‐hydroxyethyl ammonium) has been compared, in its actions on neuromuscular transmission, with the motor end‐plate blocking drugs tubocurarine and decamethonium, with the anticholinesterase neostigmine, and with the closely related drug tetraethylammonium. The experiments were carried out on conscious rabbits and mice, on the tibialis anterior muscle of cats under chloralose anaesthesia and on the isolated phrenic nerve‐diaphragm preparation of the rat. Anticholinesterase activity was determined manometrically using the Warburg apparatus. Triethylcholine possessed a slight curare‐like action, but this effect was shown to be too weak and transient to contribute to the slowly developing and long‐lasting transmission failure which occurs selectively in frequently excited nerve‐muscle preparations and in exercised conscious animals. It was confirmed that the site of the blocking action of triethylcholine was pre‐junctional. Triethylcholine often produced a slight potentiation of the contractions before blocking them. This effect was not due to a depolarizing or an anticholinesterase action, and it was concluded that the slight initial facilitating action of triethylcholine on neuromuscular transmission was due to an increase in the quantity of acetylcholine released by the nerve impulse. Tetraethylammonium was much more powerful than triethylcholine in this respect. The pre‐junctional transmission failure produced by triethylcholine could not be explained simply on the basis that an initial excessive release led to exhaustion of transmitter.
HISTAMINE AND 5‐HYDROXYTRYPTAMINE IN THE INTESTINAL TRACT OF GERM‐FREE ANIMALS, ANIMALS HARBOURING ONE MICROBIAL SPECIES AND CONVENTIONAL ANIMALS
Authors: BEAVER MARGARET H. , WOSTMANN B. S.
Published: July 2012

Histamine and 5‐hydroxytryptamine were determined in the intestinal tract of germ‐free and conventional rats and mice. Comparable histamine data were collected in Clostridium perfringens mono‐associated rats, while 5‐hydroxytryptamine determinations were extended to include the chicken. In rats and mice harbouring an intestinal microflora, bacterial formation of histamine occurs mainly in the caecum. Compared to values found in germ‐free animals, histamine levels in the wall of the small intestine of the conventional animal tend to be higher, though in the rat the data are not consistent. Mono‐association (harbouring of one microbial species) of germ‐free rats with a histamine‐producing strain of Clostridium perfringens resulted in high histamine concentrations in the caecal contents, but failed to increase the histamine levels in the wall of the small intestine. 5‐Hydroxytryptamine levels in the intestinal wall in the presence of an intestinal flora were generally lower than those in germ‐free animals. Modification of the flora by dietary administration of penicillin to mice partly abolished its depressing effect.
PREVENTION OF INDIUM INTOXICATION BY FERRIC DEXTRAN
Authors: GABBIANI G. , SELYE H. , TUCHWEBER BEATRIZ
Published: July 2012

Experiments on the rat indicate that intravenous administration of indium chloride produces severe hepatic necroses with fatal icterus within a few days. These actions can be prevented by the prophylactic administration of ferric dextran. This protective effect of the iron compound must be largely specific since it could not be duplicated by pretreatment with any of a large series of other agents. The possible mechanism of the protective effect is briefly discussed.
RELATIONSHIP BETWEEN STRUCTURE AND ANTI‐COAGULANT ACTIVITY OF COUMARIN DERIVATIVES
Authors: ARORA R. B. , MATHUR C. N.
Published: July 2012

Thirty‐five coumarin derivatives have been examined for their anticoagulant activity in rabbits by determining the prothrombin time by a modification of Quick's one‐stage method, in order to find out the structural features eliciting the activity. The compounds include methoxylated dicoumarols, substituted 4‐hydroxycoumarins, coumarins devoid of a 4‐hydroxyl group, such as 3‐ and 4‐phenylcoumarins and 4‐methylcoumarins, and some complex coumarin derivatives having additional rings. The results show the complexity of the problem and the involvement of various factors. Among these the importance of molecular geometry is emphasized by the high activity of calophyllolide (31)* and a new synthetic compound, 4‐methyl‐2,5‐dioxo‐3‐phenyl‐2H, 5H‐pyrano[3,2‐c][1]‐benzopyran (30). The importance for the anticoagulant activity of a substituent in position 8 of the coumarin moiety, and the role of ability to ionize with regard to the vitamin‐K‐like property of some hydroxylated phenylcoumarins, are also indicated.
FACILITATION OF NEUROMUSCULAR TRANSMISSION BY ANTICHOLINESTERASE DRUGS
Authors: BLABER L. C.
Published: July 2012

A close correlation has been shown to exist between the in vitro anticholinesterase potencies of ambenonium, neostigmine, methoxyambenonium and edrophonium chloride and their abilities to increase muscle contractions produced by close‐arterial injections of acetylcholine. No correlation was found between the anticholinesterase potencies of the drugs and their potentiations of the maximal twitch in response to electrical stimulation, or their antagonisms of tubocurarine. It is concluded that some action, in addition to inhibition of cholinesterase, contributed to their facilitation at the neuromuscular junction, and it is suggested that this action may be at the pre‐junctional site.
A METHOD FOR ASSESSING THE EFFECTS OF DRUGS ON THE CENTRAL ACTIONS OF 5‐HYDROXYTRYPTAMINE
Authors: CORNE S. J. , PICKERING R. W. , WARNER B. T.
Published: July 2012

Injection of 5‐hydroxytryptophan into mice produces a characteristic head‐twitch. For a given period of observation this response may be assessed quantitatively either by observing the proportion of mice showing at least one head‐twitch (a quantal response) or by counting the number of head‐twitches for each mouse (a graded response). A method, based on the quantal response, of investigating the effect of centrally acting compounds on the head‐twitch response is described. Evidence is presented that the head‐twitches are due to a central action of 5‐hydroxytryptamine formed by decarboxylation of 5‐hydroxytryptophan. Head‐twitches are potentiated by monoamine oxidase inhibitors and by Phenytoin. Antagonists tested include an inhibitor of decarboxylase, antagonists of 5‐hydroxytryptamine, some antihistamines, major tranquillizers and analgesic and sympathomimetic drugs. Drugs which neither potentiate nor inhibit the response include barbiturates and minor tranquillizers. The method may be valuable in the preliminary examination of compounds likely to have a central action.
A STUDY OF THE β‐ADRENERGIC RECEPTORS IN RAT KIDNEYS
Authors: LEES P. , LOCKETT MARY F.
Published: July 2012

Dichloroisoprenaline (1 mg), injected intramuscularly into the rat, retarded the elimination of water and retained sodium, depressing both glomerular filtration rate and renal blood flow. A dose of 4 mg had a similar but more intense action. These actions of dichloroisoprenaline resembled those of 2 or 4 μg of (±)‐isoprenaline given subcutaneously. Dichloroisoprenaline and (±)‐isoprenaline summed in salt retaining effect but competed in renal vascular action. 2‐Isopropylamino‐1‐naphth‐2′*ylethanol hydrochloride (nethalide, 1 mg intramuscularly) was without action during water diuresis. A dose of 4 mg inhibited solely the excretion of water. Nethalide (1 mg) completely antagonized the antidiuretic and vascular actions of 2 μg of (±)‐isoprenaline; antagonism of the salt retention caused by (±)‐isoprenaline was less complete. A dose of 4 mg of nethalide antagonized both the salt retaining and the vascular actions of 4 μg of (±)‐isoprenaline.
THE ACTION OF GUANETHIDINE WITH PARTICULAR REFERENCE TO THE SYMPATHETIC NERVOUS SYSTEM
Authors: ABERCROMBIE G. F. , DAVIES B. N.
Published: July 2012

It has been suggested that guanethidine can release and then deplete postganglionic sympathetic nerve endings of noradrenaline. However, no release of noradrenaline from postganglionic nerve endings or from the adrenal medulla by guanethidine was found by direct experiment. Although release of noradrenaline from postganglionic sympathetic nerve endings in response to nerve stimulation was rapidly reduced and finally abolished by guanethidine, the drug did not appear to affect the release of catechol amines from the adrenal medulla in response to splanchnic nerve stimulation. The nature of the action of guanethidine is discussed, and it is concluded that it blocks the effect of postganglionic sympathetic nerve stimulation by interfering with the synthesis of transmitter and that it also has a direct sympathomimetic effect.
CHEMOTHERAPY OF EXPERIMENTAL LEPTOSPIRAL INFECTION IN MICE
Authors: SPRADBROW P. B.
Published: July 2012

A strain of Leptospira zanoni was used to produce chronic renal infections in young white mice. A variant of this strain produced an acute disease with over 50% mortality. The responses of both forms of disease to chemotherapy were studied. When treatment of the acute disease was initiated before jaundice occurred, suitable single doses of streptomycin, chlortetracycline, tetracycline, erythromycin, oxytetracycline and oxytetracycline (in oil) prevented death and chronic renal infection in a high percentage of mice. Bicillin, a long‐acting penicillin preparation, was more effective than other penicillins, but it prevented the development of chronic renal infection in only half the treated mice. Streptomycin was the only antibiotic of which a single administration regularly cured the chronic renal infections: chlortetracycline, tetracycline and oxytetracycline (in oil) were partially effective. Oxytetracycline, chloramphenicol, Bicillin, fortified penicillin, procaine penicillin and potassium penicillin had no permanent action. The suitability of mice as laboratory animals in the study of experimental leptospirosis and the need for complete cure of carriers of chronic renal infection are emphasized. The above findings indicate that streptomycin is the drug of choice for the treatment of leptospirosis in animals, and that it is worthy of further trial in man.
EFFECTS OF ASARONE AND β‐ASARONE ON CONDITIONED RESPONSES, FIGHTING BEHAVIOUR AND CONVULSIONS
Authors: DANDIYA P. C. , MENON M. K.
Published: July 2012

In the Ayurvedic system of medicine, the roots and rhizomes of an indigenous Indian plant Acorus calamus are used together with the roots of Rauwolfia serpentina for treating many mental ailments. The influence of asarone and β‐asarone (the trans and cis forms of 2,4,5‐trimethoxy‐1‐propenyl benzene), two active principles of Acorus calamus, when given alone and together with either reserpine or chlorpromazine, has been studied on the conditioned avoidance response of trained rats, on the fighting behaviour of paired mice subjected to mild foot shock and on electro‐convulsions. Except for electro‐convulsions, asarone in small doses potentiates the effects of reserpine and of chlorpromazine; β‐asarone has no such effect. Estimation of the 5‐hydroxytryptamine content of rat brain showed that neither acorus oil nor its active principles increase the concentration of 5‐hydroxytryptamine; nor do these compounds cause an additional decrease in the 5‐hydroxytryptamine content of the brains of animals treated with reserpine. It is concluded that the potentiating effect of these principles is unrelated to 5‐hydroxytryptamine concentration. In experiments using electro‐convulsions, asarone increased the percentage mortality of animals treated with chlorpromazine but not of those treated with reserpine.
ACTIONS OF CERTAIN AMINES ON CEREBRAL CORTICAL NEURONES
Authors: KRNJEVIĆ K. , PHILLIS J. W.
Published: July 2012

A number of derivatives of tryptamine and phenethylamine, and certain other compounds, were tested on neurones in the cerebral cortex of cats by iontophoretic release from micro‐pipettes. The characteristic action of many of these compounds was a depression of the neuronal discharge initiated by synaptic activity or by the application of l‐glutamate; imidazolylacetic acid, dopamine, ephedrine and ergometrine were particularly effective. Catechol amines, hydroxytryptamines and imidazolylacetic acid had a relatively quick and rapidly reversible action, not unlike that of γ‐aminobutyric acid, whereas ephedrine and derivatives of lysergic acid diethylamide caused a slower and more prolonged depression of the amplitude of spikes, rather like atropine. Several compounds, including 5‐hydroxytryptamine, adrenaline and ergometrine, could also excite the same neurone when larger amounts were applied. A few substances, such as dopa and methylergometrine, had a predominantly excitant action.
CARDIAC NORADRENALINE STORES
Authors: FAWAZ G. , SIMAAN J.
Published: July 2012

The effects of single doses of reserpine or of guanethidine in increasing the heart rate of the dog heart‐lung preparation have been studied. Compared with reserpine, guanethidine increased heart rate more and more rapidly, and the increase lasted longer. When the effects of reserpine had subsided, guanethidine now caused a similar rate of change and maximum increase in heart rate, but recovery was quicker. Guanethidine given alone caused less release of noradrenaline in the right atrium than did reserpine alone, but both drugs together caused greater release than did either alone. Thus liberation of noradrenaline in the right atrium was unrelated to the effectiveness of either drug to increase heart rate. Guanethidine and reserpine did not increase the heart rate of heart‐lung preparations from dogs which had received reserpine for 2 days and which contained no noradrenaline. Guanethidine had similar actions on the heart rate of preparations either given a slow intravenous infusion of noradrenaline or a single dose of reserpine. Treatment of a normal heart‐lung preparation with noradrenaline increased the atrial noradrenaline content, but subsequent addition of reserpine or of guanethidine changed heart rate in the same manner as for preparations not given noradrenaline. Treatment with reserpine increased the heart's sensitivity to noradrenaline without changing initial heart rate. These results are discussed in relation to the idea that there may be more than one noradrenaline compartment in the heart.