bluuebunny/crossref_metadata_2025_split huggingface dataset:
Studies on the peripheral pharmacology of fenazoxine, a potential antidepressant drug
Authors: BASSETT J. R. , CAIRNCROSS K. D. , HACKET N. B. , STORY MARGOT 
Published: July 2012

. The action of fenazoxine, a cyclized analogue of orphenadrine, has been studied on peripheral tissues innervated by adrenergic and cholinergic nerves. The hypothesis that cyclization of the alkyl amino chain of orphenadrine results in a molecule which retains the noradrenaline sensitizing action of orphenadrine but lacks the antimuscarinic activity has been investigated.
. The antimuscarinic activity of fenazoxine, on guinea pig ileum, was approximately 1/30 that of orphenadrine.
. Fenazoxine, desmethylimipramine and cocaine potentiated the response to noradrenaline and sympathetic nerve stimulation on the cat nictitating membrane, isolated rabbit ear artery and isolated driven atrial strip preparations.
. On the driven atrial strip preparation, fenazoxine at concentrations of 5 × 10−7M and 1 × 10−6M produced a small potentiation of the inotropic response to isoprenaline. At 5 × 10−6M and 5 × 10−5M fenazoxine antagonized the inotropic response to tyramine.
. Chronic denervation of the cat nictitating membrane abolished the potentiating action of fenazoxine.
. The results presented suggest that fenazoxine inhibits the uptake of catecholamines in a manner similar to that reported for desmethylimipramine and cocaine.
. Evidence is also presented which suggests that fenazoxine, like desmethylimipramine, possesses anti‐noradrenaline activity at higher concentrations.
Effects of ganglion blocking agents on nicotine extensor convulsions and lethality in mice
Authors: ACETO M. D. , BENTLEY H. C. , DEMBINSKI J. R. 
Published: July 2012

. The ganglion blocking agents, chlorisondamine, pentamethonium, mecamylamine, decamethonium and hexamethonium all block nicotine extensor convulsions when administered intraventricularly in mice. Tetraethylammonium was inactive.
. For the intraventricular route, there is a relationship between ganglionic blocking potency and blocking of nicotine extensor convulsions. Indirect evidence suggests that the site(s) of action of nicotine extensor convulsions and lethality is central in origin and associated with brain areas near the ventricles.
. When ganglion blocking agents are given orally, subcutaneously or intravenously varying degrees of protection can be observed probably depending on factors such as whether or not the drugs cross the blood‐brain barrier, absorption, etc., and the effectiveness in protecting mice from nicotine is not related to ganglionic blocking potency.
. Atropine and morphine given intraventricularly or subcutaneously did not protect mice from the LD95 of nicotine. Chlorpromazine gave very erratic results and phenobarbitone was effective subcutaneously and to a lesser extent intraventricularly.
Correlation of prostaglandin release from the cerebral cortex of cats with the electrocorticogram, following stimulation of the reticular formation
Authors: BRADLEY P. B. , SAMUELS GILLIAN M. R. , SHAW JANE E. 
Published: July 2012

. Prostaglandin‐like material has been found in superfusates of cerebral cortex in unanaesthetized encéphale isolé cat preparations.
. The material was assayed on the isolated rat uterus and identified by thin‐layer chromatography.
. The level of spontaneous release of prostaglandin‐like material was greater than that which had been found in anaesthetized preparations and it increased further with electrical stimulation of the reticular formation which induced electrocortical arousal.
. Chlorpromazine (1.0–8.0 mg/kg) not only depressed the spontaneous release but blocked the increase evoked by stimulation concomitantly with blocking electrocortical arousal. Increasing the stimulating voltage to restore the arousal response also restored the evoked release of prostaglandins.
. Most of the prostaglandin‐like material released spontaneously was represented by E type compounds, but the increase with stimulation was mainly of F compounds.
The action of glucosulphone [N,N′‐di (glucose sodium sulphonate) of 4,4′‐diaminodiphenyl sulphone] on pancreatic kallikrein
Authors: ABITBOL H. , PIULATS E. , ROSELLó S. 
Published: July 2012

. The effects of sulphone have been studied on kinin production in dog plasma and on capillary permeability in the skin of rabbits.
. Dog plasma was used as a substrate for pancreatic kallikrein in vitro and the addition of sulphone caused an inhibition of kinin production, which was dependent on the concentration of the drug.
. The increased vascular permeability produced in vivo by intradermal injections of kallikrein was partially inhibited by sulphone injected intravenously. The same doses of sulphone also inhibited the increase in permeability produced by bradykinin and histamine in the skin of rabbits.
Stimulant action of tetraethylammonium on the peristaltic reflex of the guinea‐pig isolated ileum
Authors: BELESLIN D. B. , RAKIĆ M. M. 
Published: July 2012

. Tetraethylammonium (TEA) in concentrations below 0.5 mg/ml. depressed or blocked the peristaltic reflex of the guinea‐pig isolated ileum: in concentrations above 0.5 mg/ml. it caused a contraction of the longitudinal muscle and restored the peristaltic reflex previously blocked by the lower concentrations.
. The peristaltic reflex, when blocked by ganglion‐blocking agents, morphine and morphine‐like agents, 5‐hydroxytryptamine, catecholamines or atropine, was restored by high concentrations of TEA.
. The possible mechanisms of these effects are discussed.
Myocardial and haemodynamic effects of the beta‐adrenoceptor blocking drug alprenolol (H56/28) in anaesthetized cats
Authors: PARRATT J. R. , WADSWORTH R. M. 
Published: July 2012

. The effects of the beta‐adrenoceptor blocking drug alprenolol (H56/28) on myocardial and general haemodynamics were studied in anaesthetized cats.. Alprenolol (0·5 mg/kg and 1·0 mg/kg) reduced femoral systolic and diastolic pressures, heart rate and left ventricular systolic pressure. The rate of rise of the left ventricular pressure pulse (dp/dt) was reduced despite a significant elevation of left ventricular end‐diastolic pressure. This is evidence for decreased myocardial contractility. On some occasions there was a transient initial increase in +ve dp/dtmax. possibly indicative of moderate β‐adrenoceptor stimulant activity.. Myocardial and liver blood flows were measured using a heated thermocouple technique. Alprenolol slightly decreased both myocardial and liver blood flows (mean of 17% and 15% respectively with a dose of 1·0 mg/kg). Myocardial and liver vascular resistances were only very slightly increased.. Alprenolol had no direct effect on calculated myocardial and liver metabolic heat production.. In doses up to 1·0 mg/kg alprenolol had no effect on airway resistance but occasionally decreased (in vivo) intestinal muscle movement.. Since alprenolol (although reducing calculated myocardial oxygen consumption and the myocardial and metabolic heat stimulant effects of catecholamines) has no significant effect on myocardial vascular resistance, it is suggested that it would be a useful adjunct in the therapy of angina pectoris.
The synthesis and pharmacology of some 1,4,5,6‐tetrahydropyrimidines
Authors: BRIMBLECOMBE R. W. , HUNT R. R. , RICKARD R. L. , TAYLOR JOAN V. 
Published: July 2012

. Several 1‐ and 2‐substituted, and 1,2‐disubstituted, 1,4,5,6‐tetrahydropyrimidines have been prepared and their toxicological and pharmacological properties have been investigated.
. In general the compounds were neuromuscular blocking agents with the monosubstituted members of the series showing a depolarizing type of activity and the disubstituted compounds a non‐depolarizing type.
. The toxicity to mice of some of the monosubstituted compounds was increased by pretreatment of the animals with SKF 525A, but the toxicity of the disubstituted compounds was unaffected.
. The results obtained with these compounds are not at variance with a suggestion made previously that nicotinic action at the neuromuscular junction can result from an interaction between drug and receptor at two points separated by about 4 Å.
Tremor induced by tetrabenazine
Authors: CALNE D. B. , WEBSTER R. A. 
Published: July 2012

. Acute administration of tetrabenazine produced tremor in cats, in doses which caused sedation but not hypothermia.
. The pattern of movements resembled shivering rather than Parkinsonism, and warming the skin suppressed the tremor.
. The tremor was not influenced by hyoscine.
. Tremor produced by amylobarbitone was essentially similar to that induced by tetrabenazine.
Effect of spironolactone and norbolethone on the toxicity of digitalis compounds in the rat
Authors: SELYE H. , MÉCS I. , TAMURA T. 
Published: July 2012

. In the rat, both spironolactone (an antimineralocorticoid) and norbolethone (an anabolic steroid) inhibit the characteristic neuromuscular disturbances and the mortality produced by digitoxin, gitalin, proscillaridin, digoxin and digitalin. The corresponding effects of strophanthin K, ouabain and digitoxigenin could not be prevented.
. It may be concluded that, in our experimental conditions, both spironolactone and norbolethone counteract the toxicity of some, but not all, digitalis compounds tested and that both the protective steroids affect the toxicity of the same digitalis derivatives.
. This antidigitalis effect is not merely a secondary consequence of either antimineralocorticoid or anabolic potency because spironolactone lacks anabolic and norbolethone lacks antimineralocorticoid properties. Indeed, it appears that the ability to antagonize the toxicity of digitalis compounds represents a pharmacological property independent of all known steroid hormone actions, since spironolactone is virtually devoid of these.
Enhancement of inflammation and histamine formation by actinomycin D
Authors: REILLY MARGARET A. , SCHAYER R. W. 
Published: July 2012

. An inflammation model developed in other laboratories was used in this study. Mice given endotoxin intranasally develop lung inflammation which progresses in intensity for several days. Lung weight is a satisfactory measure of inflammation.
. In lungs of mice treated intranasally with endotoxin, histidine decarboxylase was activated within 6 hr, before lung weight had increased substantially. Enzyme activity was near maximal at 24 hr but had dropped by 48 hr, at which time inflammation was increasing. The data are consistent with an early role for histamine in mediating inflammation, but not with an essential role in the later stages.
. When actinomycin D, an inhibitor of RNA synthesis, was mixed with endotoxin solution and given to mice intranasally, both lung inflammation and histidine decarboxylase activation were markedly enhanced at 24 and 48 hr, relative to effects produced by endotoxin alone.
. Evidence is presented that intranasal instillation of endotoxin into mice increases histamine formation in lung in vivo.
. We previously found protein synthesis inhibitors, the only drugs shown capable of blocking histidine decarboxylase activation, to be powerful anti‐inflammatory agents. Now we have found that actinomycin D, the only drug shown capable of enhancing histidine decarboxylase activation, to be strongly pro‐inflammatory. These observations support a causative role for histamine in slowly‐developing inflammation, and also provide a rigorous test for the participation of other mediator candidates.
Relaxations of the isolated portal vein of the rabbit induced by nicotine and electrical stimulation
Authors: HUGHES J. , VANE J. R. 
Published: July 2012

A pharmacological analysis of the inhibitory innervation of the isolated portal vein of the rabbit has been made.
In untreated preparations, transmural stimulation elicited a long‐lasting relaxation at low frequencies (0·2–1 Hz); at higher frequencies a contraction followed by a prolonged after‐relaxation occurred. Tetrodotoxin abolished the contractions but a higher dose was required to abolish the relaxations. Veratrine lowered the threshold of stimulation for producing relaxations in the untreated vein. The relaxations were unaffected by hyoscine or hexamethonium. They were reduced or altered by antagonists of α‐adrenoceptors for catecholamines and by adrenergic neurone blockade. They were sometimes slightly reduced by antagonists of β‐adrenoceptors.
In the presence of antagonists of α‐adrenoceptors, electrical stimulation elicited relaxations which increased with frequency of stimulation and became maximal at 20–30 Hz. These relaxations were partially reduced by antagonists of β‐adrenoceptors, or by adrenergic neurone block; the antagonisms were more pronounced at the higher frequencies of stimulation. Noradrenaline also caused relaxations which were abolished by β‐adrenoceptor blocking drugs. Cocaine increased the sensitivity to noradrenaline by 7–8 fold after α‐adrenoceptor blockade but had little or no effect on the relaxations induced by electrical stimulation at high frequencies.
In the presence of antagonists of α‐ and β‐adrenoceptors, or adrenergic neurone blocking agents, or in veins taken from rabbits pretreated with reserpine, electrical stimulation elicited rapid relaxations which were greatest at 20–30 Hz. These relaxations were increased by veratrine and abolished by tetrodotoxin or by storing the vein for 9 days at 4° C. They were unaffected by antagonists of acetylcholine, or by dipyridamole.
Prostaglandins E1, E2 and F2α inhibited contractions elicited by electrical stimulation and noradrenaline, but in higher doses caused contractions themselves.
Nicotine (10−6–10−5 g/ml) relaxed the portal vein; higher concentrations elicited mixed inhibitory and excitatory effects. All these effects were abolished by tetrodotoxin, cocaine, hexamethonium or storage. The contractor effects were abolished by drugs or procedures that blocked adrenergic mechanisms.
The relaxations produced by nicotine in untreated preparations and in veins from rabbits pretreated with reserpine were mediated mainly by a non‐adrenergic non‐cholinergic nervous mechanism. Relaxations induced by nicotine in the presence of antagonists of α‐adrenoceptors were only partially antagonized by antagonists of β‐adrenoceptors.
It was concluded that all the effects of nicotine and transmural stimulation were mediated by nerves. Part of the inhibitory effects was mediated by non‐adrenergic, non‐cholinergic nerves.
Oxotremorine‐induced hypertension in the anaesthetized rat
Authors: WALKER JOYCE L. , WEETMAN D. F. 
Published: July 2012

Oxotremorine exerts an action on peripheral cholinoceptors in the anaesthetized rat. After the blockade of peripheral cholinoceptors with the quaternary atropine derivative, atropine methylbromide, oxotremorine produced a rise in arterial blood pressure and tachycardia.
The rise in arterial pressure and tachycardia was absent in rats that had been pithed or had undergone high spinal cord transection.
A non‐quaternary atropine derivative antagonized these cardiovascular effects.
Drugs which inhibit activity of the sympathetic nervous system antagonized the oxotremorine‐induced hypertension and tachycardia.
It is concluded that the rise in arterial pressure and tachycardia seen in the anaesthetized rat treated with a quaternary derivative of atropine is due to an action of oxotremorine on the central nervous system at a supraspinal level, resulting in an increase in activity of the efferent sympathetic nervous system.
Cardiovascular effects of prostaglandins mediated by the central nervous system of the dog
Authors: LAVERY HELEN A. , LOWE R. D. , SCROOP G. C. 
Published: July 2012

Prostaglandins A1, E1, F1α and F2α were infused into the vertebral artery of the chloralose‐anaesthetized greyhound and the resulting cardiovascular responses were compared with those obtained on intravenous and intracarotid infusions in the same dose range.
Infusions of PGF2α intravertebrally (4–64 (ng/kg)/min) caused an increase of blood pressure, tachycardia and a fall of central venous pressure. Cardiac output was increased and peripheral resistance was essentially unchanged. There was never any response to intravenous or intracarotid PGF2α infusions in this dose range.
PGF1α was found to have similar effects to PGF2α but it was much less potent.
PGE1 infusions (4–360 (ng/kg)/min) into the vertebral artery caused a tachycardia which was greater than that obtained with intracarotid or intravenous infusions, but there was no significant effect on blood pressure.
Infusions of PGA1 caused a small fall of blood pressure accompanied by an increase of heart rate and the dose response relationships were similar for all three routes of administration.
It is concluded that some prostaglandins can activate cardioregulatory centres within the territory of distribution of the vertebral artery. Prostaglandin F2α is the most potent of these.
The kinetics of amylobarbitone metabolism in healthy men and women
Authors: BALASUBRAMANIAM K. , LUCAS S. B. , MAWER G. E. , SIMONS P. J. 
Published: July 2012

Sodium amylobarbitone (3·54 mg/kg) was given by intravenous injection to seven healthy men and nine healthy women who were not receiving other drugs. Serum amylobarbitone and urine hydroxyamylobarbitone concentrations were measured by gas‐liquid chromatography. There was no significant difference between the groups either in the serum amylobarbitone concentration/time curves or in the urinary excretion of hydroxyamylobarbitone.
The serum amylobarbitone concentration decayed over 48 h as a double exponential function of time; the first exponential component had a mean half‐time of 0·6 h (males 0·56 ± 0·06 h, females 0·62 ± 0·08 h, ± s.e.) and the second exponential component had a mean half time of 21 h (males 22·7 ± 1·6 h, females 20·0 ± 1·0 h, ± s.e.).
The urinary excretion of hydroxyamylobarbitone over 48 h accounted for 34% of the dose (males 33·8 ± 3·2%, females 35·2 ± 3·0%, ± s.e.). One male and two female subjects excreted hydroxyamylobarbitone partly as a conjugate which was readily hydrolysed in acid.
An elimination constant (kel) derived from the serum concentration/time curve by the application of a two compartment model was approximately proportional to β (h−1), the rate constant of the second exponential component. There was a positive correlation (r=0·78, P<0·001) between β and the mean rate of urinary excretion of hydroxyamylobarbitone during the 24 to 48 h period.
The effects of calcium and magnesium on the response of intestinal smooth muscle to drugs
Authors: BURGEN A. S. V. , SPERO L. 
Published: July 2012

. The sensitivity of the longitudinal muscle of the guinea‐pig ileum to muscarinic drugs producing contraction depends on optimum concentrations of calcium and magnesium. It can also be reduced by changes in sodium concentration and osmolality.
. The rubidium efflux response to these same drugs is insensitive to any of these changes in the external medium.
. Raised calcium or magnesium concentration has the effect of largely annulling the differences in structure‐activity relationships of the two responses as they exist in optimal media.
. The effects are explained in terms of a labile coupling process between a single receptor and the contractile process compared with a stable coupling process of the efflux process.
Diffusion of drugs through stationary water layers as the rate limiting process in their action at membrane receptors
Authors: CUTHBERT A. W. , DUNANT YVES 
Published: July 2012

. Preparations bathed in a well stirred solution have been considered as heterogeneous systems in which the solid phase is enveloped by a thin layer of stationary liquid. Any substance applied into the bulk solution must pass through this layer by diffusion before reaching the receptors.
. The rate of diffusion through the stationary layer can govern the time course of the cellular responses to applied drugs provided that (i) all receptors involved in the response are situated at an equal distance from the solution and (ii) interaction with the receptor and consequent cellular events are very rapid.
. These conditions have been verified for two responses: the contraction of guinea‐pig ileum by acetylcholine (ACh), carbamylcholine (CCh), histamine and KCl, and the depolarization of the rat isolated sympathetic ganglion by ACh in the presence of eserine. A method of analysis has been applied which allows a complete dose‐response curve to be obtained from only two responses.
. Diffusion half‐times measured for pieces of ileum were 4·13 ± 0·13 s (s.e. of mean) for ACh, 3·60 ± 0·05 s for CCh and 1·01 ± 0·05 s for KCl. The equivalent thickness of the stationary layer calculated from these values was respectively 93 μm, 87 μm and 70 μm. The average diffusion half‐time for ACh in sympathetic ganglia was 14·19 ± 1·05 s. This gives an equivalent thickness of 173 μm.
. Diffusion half‐times were increased by increasing the viscosity of the bathing solution without changing the concentration response relationship.
. The time course of contractions of guinea‐pig ileum are no longer diffusion limited in the presence of a competitive antagonist or when the temperature is lowered from 35° to 25° C.
Inotropic effects of thyroxine and related compounds on guinea‐pig left atria in vitro
Authors: Baird J. R. C. , Spilker B. A. 
Published: July 2012

Triiodothyronine, diiodothyronine and di‐iodotyrosine have positive inotropic activity on normal guinea‐pig left atria in vitro. The increases produced by triiodothyronine and diiodothyronine are small but their detection shows that the inotropic responses to these agents can be studied in vitro. Thyroxine, thyronine and monoiodotyrosine are inactive.Reserpine pre‐treatment reduces the inotropic effect of diiodotyrosine but does not reduce those of triiodothyronine and diiodothyronine.
The effect of “selective”β‐adrenoceptor blocking drugs on the myocardial circulation
Authors: PARRATT J. R. , WADSWORTH R. M. 
Published: July 2012

Summary
A comparison has been made of the effects of a relatively specific β1‐adrenoceptor blocking drug (practolol) and a relatively specific β2‐adrenoceptor blocking drug (butoxamine) on myocardial and general haemodynamics in anaesthetized cats.
Practolol, in a dose (10 mg/kg, intravenously) which had little effect on arterial pressure, heart rate, myocardial blood flow or myocardial vascular resistance, markedly reduced the effects of isoprenaline infusions on heart rate, aortic dp/dt, myocardial blood flow, vascular resistance and metabolic heat production, and the cardiac effort index. Isoprenaline induced vasodepression was unaffected.
Butoxamine (5 mg/kg, intravenously) decreased heart rate, aortic dp/dt, the cardiac effort index and myocardial blood flow and increased myocardial vascular resistance. This is taken as further evidence for the existence of β2‐adrenoceptors in the myocardial microcirculation.
After butoxamine, the effects of isoprenaline on myocardial blood flow, myocardial vascular resistance and heart rate were unaffected but the peripheral vasodilator effect was abolished. The effects on aortic dp/dt and the cardiac effort index were potentiated.
It is concluded that the effect of isoprenaline in increasing myocardial blood flow is due predominantly to increased cardiac work and oxygen consumption and that practolol, since it has little direct effect on myocardial blood flow yet abolishes the cardiac stimulant and oxygen wasting effects of released catecholamines, has properties which indicate that it should be an effective and safe anti‐anginal drug.