Showing papers in "British journal of pharmacology and chemotherapy in 1960"
TL;DR: The isolated biventer cervicis nerve-muscle preparation can be used to distinguish between neuromuscular blocking agents which cause depolarization and those which do not.
Abstract: The isolated biventer cervicis nerve-muscle preparation can be used to distinguish between neuromuscular blocking agents which cause depolarization and those which do not Both reduce the contractions caused by nerve stimulation, but depolarizing drugs also cause a contracture of the muscle
310 citations
TL;DR: The antagonism between analgesic antipyretic drugs and bradykinin was examined quantitatively, using the bronchoconstrictor response of guinea-pigs in vivo and a method of measuring the potency of this anti-bradykinIn action was developed.
Abstract: 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.
118 citations
TL;DR: Bradykinin was found to be a potent bronchoconstrictor agent in the guinea-pig anaesthetized with urethane, and the closely related peptide, wasp kinin, was also a potent BronchoconStrictor.
Abstract: Bradykinin was found to be a potent bronchoconstrictor agent in the guinea-pig anaesthetized with urethane. This action was not affected by vagotomy, or by treatment of the animal with mepyramine, atropine, lysergic acid diethylamide, or cortisone. Adrenaline and isoprenaline suppressed the bronchoconstrictor responses to bradykinin and histamine. Small doses of acetylsalicylic acid, however, suppressed only that to bradykinin. Bradykinin also produced bronchoconstriction in the isolated perfused lungs of the guinea-pig. The closely related peptide, wasp kinin, was also a potent bronchoconstrictor.
115 citations
TL;DR: Thalidomide (α-phthalimidoglutarimide, “Distaval,” “Contergan”) is a new sedative hypnotic drug which produces no toxic effects when administered orally to animals in massive doses.
Abstract: Thalidomide (alpha-phthalimidoglutarimide, "Distaval," "Contergan") is a new sedative hypnotic drug which produces no toxic effects when administered orally to animals in massive doses. This lack of toxicity may be due to limited absorption. The drug has a quietening effect on the central nervous system, reducing the voluntary activity of laboratory animals and promoting sleep. Unlike the barbiturate drugs it does not cause an initial excitation in mice, incoordination or narcosis. It potentiates the actions of other central nervous system depressants, in particular the barbiturates. Its sedative effects are counteracted by central nervous system stimulants. It has no deleterious side effects and does not affect the heart, respiration or autonomic nervous system.
100 citations
TL;DR: 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 rates of metabolic energy supply.
Abstract: 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
95 citations
TL;DR: The response was a fall to a level of one-sixth of the original in three weeks, with little change thereafter, in sharp contrast to the action of iproniazid which caused a rise of some 200% in the blood platelet 5-hydroxytryptamine level over the same period.
Abstract: Observations are reported on the blood platelet 5-hydroxytryptamine content of six patients receiving imipramine, N-(γ-dimethylaminopropyl)-iminodibenzyl hydrochloride. The response was a fall to a level of one-sixth of the original in three weeks, with little change thereafter. This is in sharp contrast to the action of iproniazid which caused a rise of some 200% in the blood platelet 5-hydroxytryptamine level over the same period. Imipramine in a concentration of 1 mg./ml. had no inhibitory action on 5-hydroxytryptophan decarboxylase; 8.0 μg./ml. of imipramine suppressed two-thirds of the in vitro uptake of 5-hydroxytryptamine (2.5 μg./ml.) by normal human platelets.
95 citations
TL;DR: The release of acetylcholine from rat and guinea-pig isolated diaphragm preparations stimulated through the phrenic nerve was optimal at 37 degrees in Krebs solution with 5x10(-6) neostigmine methylsulphate but at frequencies of stimulation above 6/sec the release was less than that predicted.
Abstract: The release of acetylcholine from rat and guinea-pig isolated diaphragm preparations stimulated through the phrenic nerve was optimal at 37 degrees in Krebs solution with 5x10(-6) neostigmine methylsulphate. The amount of acetylcholine released by a 20 min. tetanus was reduced by cooling. At frequencies of stimulation above 6/sec. the release was less than that predicted. This "failure" was unaffected by the addition of 1x10(-6) choline. The acetylcholine release declined with continued stimulation at 25/sec. In the absence of nerve stimulation, there was a small continuous resting release of acetylcholine which seemed to originate in the muscle fibres. These results are discussed in the light of current electrophysiological knowledge of the quantal release of acetylcholine.
92 citations
TL;DR: It was concluded that the phenomenon described by Straub (1911) was produced mainly by the action of the sacro-coccygeus dorsalis muscle, and that it was also necessary that the lumbo-sacral cord with its peripheral nervous outflow should be intact and that these functioning units should have an adequate circulation.
Abstract: The administration of morphine was followed in white mice by a typical Straub reaction which consisted of the tail becoming rigid and erected across the back of the animal in an S-shaped curve. This reaction was accompanied by restlessness, excitability, extension rigidity of the hindlimbs, forcible viodance of faeces and prominence of the perineum. The Straub reaction was abolished by general anaesthesia with pentobarbitone or ether, by administration of tubocurarine, by bilateral section of the muscles causing extension to the tail, and by the removal of the circulation to the lower extremity. The reaction was modified by unilateral section of the extensor muscles of the tail. Section of the spinal cord, decortication, division of the anal sphincter and perineal floor, or ablation of the pelvic splanchnic nerves did not suppress the appearance of the Straub response. It was concluded that the phenomenon described by Straub (1911) was produced mainly by the action of the sacro-coccygeus dorsalis muscle, and that it was also necessary that the lumbo-sacral cord with its peripheral nervous outflow should be intact and that these functioning units should have an adequate circulation.
74 citations
TL;DR: The potentiation of responses to sympathetic stimulation by antiadrenaline drugs, which also possess anticholinesterase activity, can be explained on the basis of a cholinergic sympathetic mechanism.
Abstract: The contractions of the isolated guinea-pig vas deferens in response to stimulation of the sympathetic hypogastric nerve were potentiated by low concentrations and inhibited by high concentrations of the antiadrenaline agents tolazoline, yohimbine, ergotamine, phenoxybenzamine and piperoxan. Eserine potentiated the contractions of the vas deferens produced by hypogastric nerve stimulation. The cholinesterase activity of an extract of vas deferens was decreased by the antiadrenaline agents. The potentiation of responses to sympathetic stimulation by antiadrenaline drugs, which also possess anticholinesterase activity, can be explained on the basis of a cholinergic sympathetic mechanism.
72 citations
TL;DR: A study of the distribution of bretylium in cat tissues at various times after subcutaneous injection suggests that the specificity of its blocking action on adrenergic neurones may be related to its selective accumulation in these neurones.
Abstract: A study of the distribution of [14C]-labelled bretylium (N-o-bromobenzyl-N-ethyl-N,N-dimethylammonium) in cat tissues at various times after subcutaneous injection suggests that the specificity of its blocking action on adrenergic neurones may be related to its selective accumulation in these neurones. The rate of rise and fall of concentration in sympathetic ganglia and postganglionic sympathetic nerves showed a close similarity to the time course of the blocking adrenergic neurones as manifested by relaxation of the nictitating membranes. Concentrations found were similar to those in adrenergic nerve trunks when topical application of the drug had caused a local block of conduction. Conduction in other types of nerve could be blocked by topical application, but in general they were less sensitive, heavily myelinated nerves being the most resistant.
71 citations
TL;DR: It is concluded that the effect of antihistamines in anaphylaxis is possibly due both to their competitive inhibition of histamine on smooth muscle receptors and to their inhibition of mast cell damage and histamine release by antigen.
Abstract: It has been shown that, depending upon their concentration, antihistamines act in three different ways: (a) by competitive inhibition of histamine as already known; (b) by destroying mast cells and releasing histamine; and (c) by preventing mast cell damage and histamine release in anaphylaxis. Furthermore, antihistamines potentiated mast cell damage and histamine release by compound 48/80, when acting on guinea-pig tissues, and inhibited these same phenomena when acting on rat tissues. It is concluded that the effect of antihistamines in anaphylaxis is possibly due both to their competitive inhibition of histamine on smooth muscle receptors and to their inhibition of mast cell damage and histamine release by antigen.
TL;DR: A number of tryptamine analogues and other exciter agents have been tested on the heart of Venus mercenaria and suggestions are made concerning the effective conformation of the 5-hydroxytryptamine molecule and the nature of its receptor.
Abstract: A number of tryptamine analogues and other exciter agents have been tested on the heart of Venus mercenaria. The method of estimation of potency, especially for irreversibly acting compounds, is discussed. Specificity of action with respect to the site of action of 5-hydroxytryptamine is defined experimentally. The specific activity of tyramine and phenethylamine and the non-specific excitatory action of indole and skatole indicate that the indole ring is neither necessary nor sufficient for 5-hydroxytryptamine-like activity. Tryptamine analogues differ in mode of action as well as potency. Congeners without a 5-hydroxyl group tend to act more slowly and irreversibly as well as less strongly than 5-hydroxytryptamine. Methyl substitution also increases the time of action and difficulty of reversal. However, the potency of such compounds may be increased or decreased depending upon the position of substitution and the presence of the 5-hydroxyl group. The relations between structure and potency and mode of action are discussed. Suggestions are made concerning the effective conformation of the 5-hydroxytryptamine molecule and the nature of its receptor.
TL;DR: In this article, a compound of established antiviral activity, isatin beta-thiosemicarbazone, has been subjected to systematic structural modification and a 4-point parallel-line assay of in vivo chemotherapeutic activity has been developed.
Abstract: As part of an investigation devoted to the development of new antiviral agents a compound of established antiviral activity has been subjected to systematic structural modification. The structure-activity data so obtained have been used in the design of new compounds, some of which are described. The compound chosen was isatin beta-thiosemicarbazone, which has high activity against neurovaccinia infection in mice, and a 4-point parallel-line assay of in vivo chemotherapeutic activity has been developed, which has enabled the activity of the derivatives to be determined against isatin beta-thiosemicarbazone as a standard. The overall dimensions of the isatin beta-thiosemicarbazone molecule appear to be nearly maximal for the retention of high activity, as all substituents in the aromatic ring decrease the activity irrespective of their nature or position. The projection of the -CS.NH(2) group in relation to the ring nitrogen was found to be critical, as the alpha-thiosemicarbazone was inactive. A number of modifications of the side-chain were investigated:all led to reduction or loss of antiviral activity. The antiviral activity showed a positive correlation with chloroform solubility over a considerable range. The most active compound encountered was 1-ethylisatin beta-thiosemicarbazone, with an activity of 286 (isatin beta-thiosemicarbazone identical with100). Isatin beta-thiosemicarbazone showed no activity against 15 other viruses, and 20 related compounds showed on activity against ectromelia.
TL;DR: The data from this investigation were personally precommunicated to Elliott, Lewis, and Horton, who have since found that the structure of pure trypsin-bradykinin is identical with theructure of the nonapeptide A, therefore, this synthetic nonAPEptide is in fact synthetic bradykinIn.
Abstract: The biological activity of synthetic polypeptides containing the amino acids of natural pure trypsin-bradykinin and snake-venom-bradykinin has been investigated. A series of tests for bradykinin-like activity in stimulating plain muscle, depressing the blood pressure and increasing capillary permeability was used on various species. A nonapeptide with the following structure: H-L-Arg-L-Pro-L-Pro-Gly-L-Phe-L-Ser-L-Pro-L-Phe-L-Arg-OH elicited qualitatively and quantitatively the effects of the pure natural bradykinins. An octapeptide with the following structure: H-L-Arg-L-Pro-Gly-L-Phe-L-Ser-L-Pro-L-Phe-L-Arg-OH also exerted bradykinin-like effects but was 50 to 100 times less active than the nonapeptide. Three other octapeptides and a heptapeptide were without any significant effect. Further work will demonstrate if the nonapeptide A is synthetic bradykinin or a peptide with bradykinin-like activity.
Note added since submission of this paper: The data from this investigation were personally precommunicated to Elliott, Lewis, and Horton, who have since found that the structure of pure trypsin-bradykinin is identical with the structure of the nonapeptide A. Therefore, this synthetic nonapeptide is in fact synthetic bradykinin.
TL;DR: It is suggested that in rats the histamine-releasing mechanism of the antigen-antibody reaction in anaphylaxis is very similar to that of compound 48/80.
Abstract: In vitro anaphylactic reaction causes mast cell damage and histamine release from rat tissue. Histamine release is correlated with mast cell damage and both phenomena are simultaneously inhibited by various metabolic inhibitors, antipyretics, calcium lack and previous heating of the tissue at 45 degrees . The mast cell damage produced by antigen in sensitized rat tissues is morphologically similar to that caused by compound 48/80, both agents causing extrusion of granules. Mast cell damage and histamine release induced by antigen or by compound 48/80 are inhibited alike by several substances and conditions. It is suggested that in rats the histamine-releasing mechanism of the antigen-antibody reaction in anaphylaxis is very similar to that of compound 48/80.
TL;DR: The catechol amines excite the isolated heart of Venus mercenaria in a characteristic manner as discussed by the authors, and the response to high concentrations was dominated by an increase in muscle tone.
Abstract: The catechol amines excite the isolated heart of Venus mercenaria in a characteristic manner. This response was not obtained with phenethylamine, tyramine, ephedrine, or mescaline, nor with histamine, nor with the basic n-alkylamines. 5-Hydroxytryptamine had a distinctive effect at high concentrations (above 3×10-6 M) different from that at lower doses. The response to high concentrations was dominated by an increase in muscle tone. Hearts exposed to high concentrations of 5-hydroxytryptamine and other tryptamine analogues for long periods became tachyphylactic to low doses of these substances. However, high doses of 5-hydroxytryptamine (about 2×10-5 M) still excited the tachyphylactic heart, but the response was then like that to the catechol amines. When high bath temperatures rendered the heart insensitive to 5-hydroxytryptamine, high concentrations of this compound again had the catechol amine effect. The possibility of a physiological role for the catechol amines or high 5-hydroxytryptamine concentrations is discussed.
TL;DR: An infusion of noradrenaline appeared to increase the effect of sympathetic stimulation of the hypogastric nerves to the uterus of the virgin cat about as much as an infusion of adrenaline.
Abstract: Previous observations have shown that the effects of sympathetic stimulation and of tyramine were absent in the organs of animals treated with reserpine, but that they were restored by an infusion of noradrenaline. Observations are described showing that an infusion of adrenaline did not restore the pressor action of tyramine in the cat or in the rat, but that in the rat the pressor action was restored by an infusion of dopamine, or of (—)-dopa, or of m-tyrosine, or of phenylalanine. Observations are also described showing that the effect of postganglionic stimulation of the fibres to the nictitating membrane and to the iris was restored by an infusion of dopamine or of (-)-dopa; it was restored less well by an infusion of noradrenaline. An infusion of noradrenaline did not restore the action of tyramine on the denervated iris or on the denervated vessels of the cat's foreleg. An infusion of noradrenaline appeared to increase the effect of sympathetic stimulation of the hypogastric nerves to the uterus of the virgin cat about as much as an infusion of adrenaline. An infusion of noradrenaline restored the constrictor action of nicotine on the perfused vessels of the rabbit ear.
TL;DR: Thirty-six alkyl organophosphorus compounds have been tested for neurotoxicity in the chicken and certain predictions have been made about the chemical structure of compounds which would be expected to be neurotoxic.
Abstract: Thirty-six alkyl organophosphorus compounds have been tested for neurotoxicity in the chicken The individual compounds were chosen to enable the importance of each portion of the molecule to be assessed in relation to the property of neurotoxicity Seventeen substances were found to be neurotoxic, fifteen for the first time All of these contained fluorine On the basis of the results reported, certain predictions have been made about the chemical structure of compounds which would be expected to be neurotoxic The importance of fluorine suggests that it plays a direct role in the development of the biochemical lesion, and this may occur as the result of its being carried by the molecule as a whole to specific areas in the nervous system By the action of cholinesterase, the P-F bond may be ruptured and ionic fluorine liberated where it blocks some metabolic cycle
TL;DR: The results support the hypothesis that histamine stimulates the myocardium by a direct action on specific receptors.
Abstract: Histamine stimulated the isolated auricles and heart of the guinea-pig. The effect was best seen in auricles which had been previously depressed by treatment with reserpine. Ganglionic blocking drugs (hexamethonium and pempidine), applied to auricles which had been previously treated with reserpine, abolished the diphasic effect of nicotine, but did not alter the response to histamine. Dichloroisoproterenol did not modify the stimulant action of histamine in isolated auricles, either before or after treatment with reserpine; nor did it alter the response of the isolated heart. Diphenhydramine reduced or blocked the stimulant action of histamine in auricles which had been previously treated with reserpine. The results support the hypothesis that histamine stimulates the myocardium by a direct action on specific receptors.
TL;DR: The blocking action of hemicholinium on the responses to postganglionic sympathetic stimulation resembles its blocking action against cholinergic nerve stimulation observed on rabbit isolated atria with vagus nerves, rabbit isolated vagina with pelvic nerves, and guinea-pig isolated diaphragm with phrenic nerve.
Abstract: It has been shown by others that hemicholinium (α,α'-dimethylethanolamino-4,4'-biacetophenone) inhibits the synthesis of acetylcholine, an effect which is reversed by choline. Hemicholinium produces a failure of response to nerve stimulation in the following sympathetically innervated preparations: guinea-pig isolated vas deferens, rabbit isolated uterus, rabbit isolated colon, perfused rabbit ear, cat isolated atria and the piloerector muscles in the cat's tail. The blocking action of hemicholinium on the responses to postganglionic sympathetic stimulation resembles its blocking action against cholinergic nerve stimulation observed on rabbit isolated atria with vagus nerves, rabbit isolated vagina with pelvic nerves, and guinea-pig isolated diaphragm with phrenic nerve. The failure of transmission produced by hemicholinium in sympathetic nerves and in cholinergic nerves can be reversed by choline. It is suggested that if there were a cholinergic junction at sympathetic nerve endings the mechanism of the blocking action of hemicholinium at these endings could be explained by inhibition of acetylcholine synthesis.
TL;DR: The blood and urine of mice and rats infected with Babesia rodhaini contain substances which stimulate the isolated guinea-pig ileum and rat duodenum and are probably peptides, which are unaffected by trypsin or pepsin.
Abstract: The blood and urine of mice and rats infected with Babesia rodhaini contain substances which stimulate the isolated guinea-pig ileum and rat duodenum. The amount of active material excreted increases as the infection increases. The active substances are stable to boiling with hydrochloric acid but not with alkali; they pass through a cellophane membrane and are soluble in hot ethanol. They are destroyed rapidly by papain and less rapidly by chymotrypsin, but are unaffected by trypsin or pepsin. Their action on smooth muscle is not affected by atropine, eserine, antihistamines, iproniazid, bretylium or by lysergic acid diethylamide. The active substances are probably peptides and there is evidence that the urine contains a mixture of peptides, some of which relax and some of which contract the rat duodenum. Similar active peptides appear in the urine of mice infected with Plasmodium berghei, Trypanosoma rhodesiense, Streptococcus pyogenes and Rift Valley fever virus.
TL;DR: It was concluded that bretylium can selectively block the activity of sympathetic noradrenergic fibres without causing a similar block of sympathetic cholinergic fibre.
Abstract: After intra-arterial infusion of bretylium tosylate (12.5 mg.), the reflex changes in vasoconstrictor tone which normally occur in the forearm with body cooling, positive pressure breathing, the Valsalva manoeuvre and postural change were greatly reduced or abolished. Reflex vasodilatation mediated by cholinergic fibres in response to body heating or to emotional stress was little affected. It was concluded that bretylium can selectively block the activity of sympathetic noradrenergic fibres without causing a similar block of sympathetic cholinergic fibres. As the responses to intravenous or intra-arterial infusions of adrenaline or noradrenaline were not reduced after bretylium, it was concluded that bretylium interferes with the activity of noradrenergic fibres rather than with the activity of the noradrenaline released at the nerve ending. After bretylium infusion, forearm and hand blood flow did not often rise to levels characteristic of full release of vasoconstrictor tone. As infusion of bretylium into a nerve-blocked forearm resulted in a pronounced reduction in flow, it is concluded that bretylium also has a constrictor effect on blood vessels. The state of the vessels following an infusion of bretylium appears to depend on the balance between this constrictor action and the longer-acting sympathetic blocking effect.
TL;DR: Ferguson's principle of using thermodynamic activity instead of concentration as an index of activity was applied to the present results and it was found that the log-concentration action curves of alcohols on all four systems were straight over most of their range and, for any one system, parallel throughout the series.
Abstract: Experimental results relating to the unspecific depressant action of normal primary alcohols from methanol to octanol on four separate biological systems are presented. It was found that the log-concentration action curves of alcohols on all four systems were straight over most of their range and, for any one system, parallel throughout the series. With arithmetic increase in the alcohol chainlength the concentration required to produce a given effect diminished logarithmically. The rate of this decrease varied in different biological systems, and was always less than the rate of decrease of solubility with chainlength. In two of the systems investigated alcohols beyond octanol failed to show any activity (cut-off phenomenon). The implications of these findings are discussed, with reference to the mechanism of action of unspecific depressants. Ferguson's principle of using thermodynamic activity instead of concentration as an index of activity was applied to the present results. In an appendix, the results are compared with predictions according to Mullins' hypothesis of narcotic action, and found not to agree well.
TL;DR: The present experiments show thatorphine and related analgesics also depress the responses to smooth muscle stimulants which act directly on the smooth muscle fibres.
Abstract: Morphine and related analgesics depress the responses of the isolated guinea-pig ileum to nervous stimulation and to drugs which act by stimulating the nervous structures of the intestinal wall. The present experiments show that these analgesics also depress the responses to smooth muscle stimulants which act directly on the smooth muscle fibres.
TL;DR: The uncertain emetic effect of apomorphine in pigeons has been confirmed and Ten other centrally acting agents tested (caffeine, cocaine, 5-hydroxytryptamine, lysergic acid diethylamide, methamphetamine, morphine, nalorphine, pentylenetetrazol, strychnine, and yohimbine) failed to produce similar effects in pigeon.
Abstract: Apomorphine produced persistent pecking in pigeons, the latent period, intensity and duration of which were related to the dose. The ED50 was estimated as 78.1±11.1 μg./kg. On chronic administration of apomorphine there was a significant decrease in latent period and weight which quickly returned to normal on stopping the drug. No conditioning and no tolerance were observed. The uncertain emetic effect of apomorphine in pigeons has been confirmed. Ten other centrally acting agents tested (caffeine, cocaine, 5-hydroxytryptamine, lysergic acid diethylamide, methamphetamine, morphine, nalorphine, pentylenetetrazol, strychnine, and yohimbine) failed to produce similar effects in pigeons.
TL;DR: There was an increase however, in the amine contents of the stomach of rats; the sex hormones were weaker in these effects while deoxycortone and corticotrophin were inactive.
Abstract: Daily intramuscular injections of cortisone, prednisolone, triamcinolone, dexamethasone, fludrocortisone and 2-methylfludrocortisone markedly reduced the histamine and 5-hydroxytryptamine contents of the skin and small intestine of rats; there was an increase however, in the amine contents of the stomach. The sex hormones were weaker in these effects while deoxycortone and corticotrophin were inactive. When the skin was depleted of half of its 5-hydroxytryptamine by prolonged treatment with polymyxin B, the rate of recovery of this amine was retarded by the glucocorticoids. The glucocorticoid activity of a steroid and its ability to produce changes in the histamine and 5-hydroxytryptamine contents of tissues are related.
TL;DR: A preparation is described of isolated rabbit atria with both vagus and sympathetic nerves that abolished the constrictor effect of nervous stimulation and of acetylcholine, but increased that of tyramine in the vessels of the perfused rabbit ear.
Abstract: A preparation is described of isolated rabbit atria with both vagus and sympathetic nerves. The action on it of bretylium and of choline 2,6-xylyl ether bromide (TM10) was studied. A concentration of breylium sufficient to abolish the response to sympathetic stimulation also depressed the response to vagal stimulation. The effect was reversible, though more easily with choline xylyl ether. Both drugs abolished the accelerating action of acetylcholine in the presence of atropine, but they augmented the action of tyramine, and did not reduce that of amphetamine. In the vessels of the perfused rabbit ear they abolished the constrictor effect of nervous stimulation and of acetylcholine, but increased that of tyramine.
TL;DR: 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.
Abstract: 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.
TL;DR: In cats, tremor produced by intraperitoneal pentobarbitone sodium or by intramuscular chlorpromazine was abolished by injection into the cerebral ventricles of a few gamma of adrenaline or noradrenaline, but not of other sympathomimetic amines or of anti-Parkinsonian drugs.
Abstract: In cats, tremor produced by intraperitoneal pentobarbitone sodium or by intramuscular chlorpromazine was abolished by injection into the cerebral ventricles of a few gamma of adrenaline or noradrenaline, but not of other sympathomimetic amines or of anti-Parkinsonian drugs Chloralose, urethane, calcium chloride, and magnesium chloride produced anti-tremor activity when administered in this way When adrenaline or noradrenaline was perfused from a lateral ventricle to the aqueduct during pentobarbitone sodium tremor, tremor was inhibited when less than 1 mug had been perfused Adrenaline was at least four times as active as noradrenaline Isoprenaline inhibited tremor when perfused in higher concentrations, but perfusion of ephedrine, amphetamine or of the anti-Parkinsonian drugs in high concentrations was ineffective Perfusion of 2 mug of chloralose or of 20 mug of calcium chloride was sufficient to inhibit tremor Intraventricular injections of 250 to 500 mug of 5-hydroxytryptamine initiated tremor Possible physiological implications of these findings are discussed
TL;DR: The catabolism of histamine was studied in three female psychiatric patients by analysis of the [(14)C]-labelled metabolic products occurring in the urine after a subcutaneous injection of [( 14)C]histamine.
Abstract: The catabolism of histamine was studied in three female psychiatric patients by analysis of the [14C]-labelled metabolic products occurring in the urine after a subcutaneous injection of [14C]histamine. Each patient was studied before and during treatment with aminoguanidine or iproniazid.
Without treatment the patients had a normal histamine catabolism. Aminoguanidine and iproniazid inhibited the oxidation of histamine to imidazoleacetic acid; iproniazid produed a 50% inhibition of the oxidation of methylhistamine to methylimidazoleacetic acid. After iproniazid a large proportion of the injected [C14]histamine was excreted as methyl [14C]histamine.