bluuebunny/crossref_metadata_2025 huggingface dataset:
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

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.
The effect of age, species and adrenaline on the recovery of isolated atria from anoxia
Authors: PENN R. G.
Published: July 2012

The rate of recovery of the force of contraction of isolated atria from different species of mature animals after 1 hour of anoxia was recorded.

Atria from rabbits of different ages were also exposed to anoxia. Atria from rabbits, ranging in age from 8 days to 3 years, were essentially similar in their recovery from anoxia, which was significantly slower than that of atria taken from rabbit foetuses at the 25th day of gestation.

Atria from human foetuses at 12–16 weeks of gestation recovered from anoxia much faster and more completely than any other atria studied and it is postulated that this may be due, in part, to the concentration of endogenous catecholamines being low.

The addition of propranolol to the organ bath had no effect on the recovery of atria from anoxia but prevented the action of added adrenaline, which manifests itself in a slowing of the rate and incompleteness of the recovery.
The contribution of the sympathetic nervous system to the development and maintenance of experimental hypertension in the rat
Authors: FINCH L. , LEACH G. D. H.
Published: July 2012

Experimental hypertension in the rat, induced either by renal artery stenosis or by treatment with deoxycorticosterone acetate (DCA) developed maximally over a period of 8 weeks. In both types of hypertension the rate of development was unaffected by immunosympathectomy or by chemical sympathectomy following the administration of 6‐hydroxydopamine.

The effect of 6‐hydroxydopamine on chronic renal hypertensive rats was to produce a hypotensive action of longer duration than when similarly administered to DCA‐induced hypertensive or normotensive rats. Reserpine (5–10 mg/kg intraperitoneally) produced a more marked hypotensive effect on both types of hypertensive rats although it was of much shorter duration.

It is concluded that experimental hypertension of renal origin or induced by DCA treatment can develop even though most of the sympathetic nervous system has been destroyed. The maintenance of chronic hypertension in these conditions may depend on the adrenal glands or a hormonal system as yet undetected.
The release of acetylcholine by acetylcholine in the cat's superior cervical ganglion
Authors: COLLIER B. , KATZ H. S.
Published: July 2012

The experiments described in this paper tested the effect of acetylcholine (ACh), carbachol or preganglionic nerve stimulation on the release of ACh from the cat's perfused superior cervical ganglion; radioactive tracer methods were used.

When the ganglion's transmitter store of ACh had been labelled, radioactive ACh was released by nerve stimulation (5 Hz for 2 min), but there was no release by ACh (0.15–15 μg) or by carbachol (1–10 μg) when these drugs were injected close to the ganglion. Perfusion with low or moderate concentrations of ACh (015–5 μg/ml) also failed to release ACh, but high concentrations (15–50 μg/ml) released a small amount of labelled material. There was no correlation between ganglion stimulation by ACh and release of radioactivity.

Ganglion‐blocking concentrations of ACh did not reduce the release of ACh during continuous nerve stimulation.

When resting (unstimulated) ganglia were perfused with 3H‐choline and eserine, the extra ACh synthesized and stored by such ganglia (surplus ACh) was labelled. Preganglionic nerve stimulation (5 Hz for 2 min) did not release surplus ACh, but perfusion with ACh (0.5–15 μg/ml), or injection of carbachol (0.5–2.5 μg) did.

Surplus ACh released by ACh or by carbachol did not contribute to the ganglion stimulating effect of either drug.

It is concluded that the presynaptic effects of ACh are not of physiological importance.
β‐Adrenoceptor stimulating properties of para‐dimethylaminobenzaldehyde
Authors: GHOURI M. S. K. , SHIBATA S.
Published: July 2012

Studies on the various isolated tissues indicate that para‐dimethylaminobenzaldehyde (DMAB) is a β‐adrenoceptor stimulant. DMAB is antagonized by the β‐adrenoceptor blocking agent, MJ 1999, but not by the α‐adrenoceptor blocking agent, phentolamine.

A study of dose‐response relationships suggests a competitive interaction between MJ 1999 and DMAB.

DMAB was about 122 times less potent than isoprenaline on the isolated guinea‐pig tracheal preparation. The effects of DMAB on isolated rabbit atria were not only very weak, but were also very brief. On this tissue, DMAB was respectively 72,000 and 55,400 times less active than isoprenaline in producing positive chronotropic and inotropic effects. DMAB caused the relaxation of the guinea‐pig taenia coli and the rabbit ileum. These actions were very weak in comparison with those of isoprenaline.

These results suggest that a compound (DMAB) structurally different from isoprenaline may mimic isoprenaline responses by stimulating β‐adrenoceptors through different mechanisms.
Long‐lasting convulsant effect on the cerebral cortex of Naja naja venom
Authors: BHARGAVA V. K. , HORTON R. W. , MELDRUM B. S.
Published: July 2012

A neurotoxic fraction has been prepared from Indian cobra venom (Naja naja) by column chromatography on CM Sephadex.

When assayed for lethality in mice, or for neuromuscular blocking potency in the rat phrenic nerve‐diaphragm preparation, this fraction was 2.4–2.9 times as potent as whole venom.

Application of either whole venom (0.5–1.0 mg/ml) or the neurotoxic fraction (0.25–1.0 mg/ml) to the exposed cerebral cortex of the rat led to the appearance in the somatosensory evoked potential of abnormal negative waves, resembling in amplitude and latency those produced by the cortical application of strychnine or curare.

This effect differed from that produced by strychnine or curare in that after washing off the toxin the abnormal responses persisted for as long as the experiment continued (8–9 hours).
Effects of lignocaine and propranolol on experimental cardiac arrhythmias
Authors: ALLEN J. D. , SHANKS R. G. , ZAIDI S. A.
Published: July 2012

The effects of intravenous injection of lignocaine and propranolol were studied in dogs.

Ventricular ectopic beats produced by intravenous injection of adrenaline in anaesthetized dogs respired with halothane were abolished in four out of six dogs by lignocaine. Propranolol was effective in all three dogs tested.

Intravenous infusion of lignocaine at (0·2 and 1·0 mg/kg)/min to total doses of 3·0 ± 1·0 and 2·2 ± 0·5 mg/kg, respectively, abolished the ventricular tachycardia produced in anaesthetized dogs by ouabain. A similar effect was produced by infusion of propranolol at (0·2 mg/kg)/min to a total dose of 1·9 ± 0·4 mg/kg. Intravenous injection of single doses of lignocaine (4·0–8·0 mg/kg) also abolished the arrhythmia.

The frequency of the ventricular ectopic beats occurring in conscious dogs 20–44 h after ligation of the anterior descending branch of the left coronary artery was reduced, with an increase in the number of sinus beats, after intravenous injection of lignocaine (8·0 mg/kg). Larger doses produced excitement. Propranolol (4·0 mg/kg) had a greater effect than the same dose of lignocaine but after 8·0 mg/kg, three of the four dogs died.

Propranolol was more effective than lignocaine in abolishing the three different types of arrhythmia.

Dose‐response curves showed that lignocaine was more active in abolishing the ouabain induced arrhythmia than the halothane‐adrenaline arrhythmia and was least active on the arrhythmia caused by ligation of the coronary artery.
Differentiation between the actions of acetylcholine and tetramethylammonium on the isolated taenia of the guinea‐pig caecum by hemicholinium‐3
Authors: MITCHELSON F.
Published: July 2012

Contractions of the isolated taenia of the guinea‐pig caecum produced by acetylcholine and TMA were examined in the presence of various antagonists and anticholinesterases.

Hemicholinium‐3 (HC‐3) (50–400 μg/ml) inhibited contractions or relaxations produced by TMA but not contractions produced by acetylcholine. The inhibition was rapid in onset and readily reversible. Contractions produced by transmural stimulation were unaffected by HC‐3 but responses produced by nicotine were inhibited.

Low concentrations of hyoscine and benzhexol inhibited responses to acetylcholine to a greater extent than those to TMA.

Morphine, raised concentrations of Mg++ or reduced concentrations of Ca++ inhibited contractions produced by TMA and by acetylcholine to a similar extent.

Edrophonium, in concentrations which preferentially inhibit acetylcholinesterase, increased contractions produced by acetylcholine and converted responses to nicotine or transmural stimulation into contractions or biphasic responses with a marked contraction phase but did not increase contractions produced by TMA.

Iso‐OMPA, in concentrations which preferentially inhibit butyrylcholinesterase, had no effect on responses to acetylcholine, nicotine, transmural stimulation or TMA.

HC‐3 inhibited contractions produced by TMA in the presence of anticholinesterases but had little effect on contractions produced by acetylcholine.

These results suggest that TMA produces contractions by acting directly on receptors of the smooth muscle. An analysis of possible reasons for HC‐3 (in the concentrations used) acting as an antagonist of TMA but not of acetylcholine indicates that the findings do not necessarily contradict the interpretation that both agonists act on the same receptor.
Cardiovascular reactivity in the experimental hypertensive rat
Authors: FINCH L.
Published: July 2012

In pithed preparations, deoxycorticosterone (DOCA)/NaCl‐induced hypertensive rats showed increased cardiovascular reactivity to injected noradrenaline, DMPP, tyramine, angiotensin and to sympathetic nerve stimulation.

Pithed, chronic renal hypertensive rats showed similar hyperreactivity to noradrenaline, DMPP and tyramine but responses to sympathetic nerve stimulation were within normal limits.

In the isolated, Krebs perfused mesentery preparation, vessels obtained from both DOCA/NaCl and renal hypertensive rats showed hyperreactivity to injected noradrenaline. Responses to periarterial nerve stimulation were also markedly increased in preparations from DOCA/NaCl hypertensive rats, while preparations from renal hypertensive rats showed this effect only at higher rates of stimulation (12 and 25 Hz).
Effects of some polymethylene bis(hydroxyethyl) dimethylammonium compounds on acetylcholine synthesis
Authors: HEMSWORTH B. A.
Published: July 2012

The effects of some polymethylene bis(hydroxyethyl)dimethylammonium compounds have been studied on acetylcholine (ACh) synthesis and as substrates for choline acetyltransferase (ChAc).

The decamethylene analogue (C10‐dichol) inhibited ACh synthesis by mitochondrial (P2) fractions of guinea‐pig cerebral cortex suspended in Tris buffer but had no effect on ACh synthesis by P2 fractions when the membranes surrounding the ChAc enzyme were broken down by homogenization in Triton X‐100.

C10‐Dichol was acetylated by ChAc almost to the same extent as choline. The initial rate of acetylation, at a concentration of 10−3m, was more rapid than for choline; however, the apparent Michaelis‐Menten constant for C10‐dichol was greater than the Km for choline, showing a lower affinity for the ChAc enzyme.

All the dicholine compounds were acetylated to some extent by ChAc and the rate of acetylation increased with an increase in the length of the methylene chain between the two quaternary nitrogen atoms in each dicholine molecule.

The rate of acetylation of the dicholine compounds paralleled the activity of these analogues at the prejunctional site at the neuromuscular junction. The possibility is suggested that part of the pharmacological activity of these compounds may be due to their incorporation into cholinergic nerve endings followed by acetylation by ChAc before subsequent release as a false transmitter.
Depletion of brain noradrenaline and dopamine by 6‐hydroxydopamine
Authors: BREESE G. R. , TRAYLOR T. D.
Published: July 2012

After intracisternal administration, 6‐hydroxydopamine had a greater effect on brain noradrenaline than on dopamine.

Administration of two doses of 6‐hydroxydopamine increased the depletion of noradrenaline but not of dopamine.

Small doses of 6‐hydroxydopamine decreased the concentration of noradrenaline with little or no effect on dopamine. Tyrosine hydroxylase activity was not reduced with these treatments.

While pargyline pretreatment offered no advantage in the depletion of brain noradrenaline after 6‐hydroxydopamine, depletion of brain dopamine was greatly potentiated by this treatment. The reduction of striatal tyrosine hydroxylase activity observed after 6‐hydroxydopamine was also potentiated by pargyline pretreatment.

The amounts of labelled noradrenaline and dopamine formed from 3H‐tyrosine were greatly reduced by 6‐hydroxydopamine treatment. After 3H‐DOPA, formation of noradrenaline was greatly reduced while formation of labelled dopamine was only moderately reduced suggesting that decarboxylation of DOPA can occur in other than catecholamine containing neurones.

Desmethylimipramine and imipramine inhibited depletion of noradrenaline produced by 6‐hydroxydopamine but did not alter depletion of dopamine. Reserpine did not inhibit depletion of catecholamines produced by 6‐hydroxydopamine.

Administration of 6‐hydroxydopamine to developing rats lowered both noradrenaline and dopamine concentrations as well as the tyrosine hydroxylase activity in the brains of these animals.
Accumulation of quinidine by human blood platelets: effects on platelet ultrastructure and 5‐hydroxytryptamine
Authors: BOULLIN D. J. , O'BRIEN R. A.
Published: July 2012

We have studied the mechanism of quinidine uptake by normal human blood platelets.

Platelets in plasma or Krebs solution took up quinidine extremely rapidly, the maximal drug concentration ratio of platelet to medium being 24 to 1 after 1 minute.

The effects of metabolic inhibitors on uptake were equivocal. Ouabain had no effect but iodoacetate and dinitrophenol were effective. However, as accumulation was not inhibited by low temperature, it was probably not energy dependent.

Interactions between quinidine and 5‐HT were also investigated.

Quinidine blocked 5‐HT uptake, but conversely, neither 5‐HT itself nor 5‐HT uptake inhibitors, such as cocaine, dexamphetamine, and desipramine interfered with quinidine accumulation.

Electronmicrographs of platelets incubated with 10−5, 10−4 or 2 × 10−3m quinidine in Krebs solution for 2 h showed no changes at the lower concentrations, but gross ultastructural damage, including disintegration of the plasma membrane, at 2 × 10−3m.

Further evidence for intracellular penetration was obtained because quinidine released endogenous 5‐HT and ATP, and also 14C‐5‐HT from loaded cells.

We conclude that quinidine is taken up by the platelet by a passive process, unrelated to the 5‐HT transport mechanism. It is probably accumulated largely in the plasma membrane and outer protein layer, but intracellular penetration and ultrastructural damage may occur.

Although the effects on 5‐HT and ATP were not due to platelet damage, this may occur in vivo and be the cause of quinidine induced thrombocytopenic purpura.
Investigation of central cholinergic mechanisms in the conscious mouse
Authors: ANKIER S. I. , BRITTAIN R. T. , JACK D.
Published: July 2012

An investigation of central cholinoceptors in the mouse has been made by injecting cholinomimetic drugs into the cerebral ventricles and seeing how their effects were modified by prior administration of atropine‐like substances and other drugs.

Carbachol or oxotremorine injected in small doses intracerebroventricularly into conscious mice caused hypothermia, gross tremor and a variety of parasympathomimetic effects including lachrymation and salivation. Acetylcholine injected in this way was active only in much larger doses.

Methacholine and pilocarpine also caused a variety of parasympathomimetic effects after intracerebroventricular injection but virtually no hypothermia or tremor.

Nicotine injected intracerebroventricularly caused mild hypothermia, fine tremor but no parasympathomimetic effects.

Atropine‐like drugs, tricyclic antidepressants and amphetamine antagonized the hypothermia induced by intracerebroventricular carbachol or oxotremorine.

The sites of action of the atropine‐like drugs are in the brain; those of the tricyclic antidepressants and amphetamine are in the periphery probably on heat generating β‐adrenoceptor mechanisms.

It is concluded that the atropine sensitive cholinoceptors in the brain vary in their sensitivities to cholinomimetic drugs, other than acetylcholine, and may exist in isoreceptor forms.

Peripheral atropine sensitive cholinoceptors may also exist in isoreceptor forms.
Cat assay for the emetic action of digitalis and related glycosides (digitoxin, digoxin, lanatoside C, ouabain and calactin)
Authors: PARSONS J. A. , SUMMERS R. J.
Published: July 2012

A titration assay with two end points is described for comparison of the emetic and lethal potencies of digitalis‐like drugs.

A drug was infused at constant rate to a conscious, unrestrained cat, through an indwelling venous cannula. At the moment of vomiting the cat was rapidly anaesthetized and infusion continued at the same rate until the moment of cardiac arrest.

With very slow and very fast infusions, the emetic and lethal doses tended to rise. In the range between these extremes (which varied from drug to drug) they were independent of time.

The observations could be accounted for by analogue computation, assuming that the drugs entered an initial pool and were distributed at finite rates to receptors in the CNS (vomiting centre) and heart.

Half times of metabolic loss derived from this computation for digitoxin, digoxin and ouabain (17, 9·9 and 1·8 h, respectively) were in the same ratio as the threefold longer half times reported for these drugs in man.

When measured with infusion rates in the time independent range, the ratio of lethal to emetic doses did not vary between the drugs studied. All caused vomiting at 40% of the lethal dose.

From a review of the literature, the emetic and cardiotoxic actions of digitalis‐like drugs appear inseparable and probably share a common biochemical mechanism.

It is concluded that foreseeable improvements in digitalis‐like drugs are small and would depend on the elimination of any local emetic effect on gut receptors which they may have.
Effects of adrenoceptor blocking agents on body temperature
Authors: FELDBERG W. , SAXENA P. N.
Published: July 2012

The effect on rectal temperature of adrenoceptor blocking agents, injected through a cannula chronically implanted into a lateral cerebral ventricle, was examined in unanaesthetized rabbits, cats and rats, kept at room temperature (19–22° C).

In rabbits, the α‐adrenoceptor blocking agent phenoxybenzamine (50 or 100 μg) produced marked hypothermia when injected intraventricularly but not when injected intravenously. In some rabbits as little as 1 μg was effective on intraventricular injection. Phentolamine and ergotamine, the other α‐adrenoceptor blocking agents examined, had a much weaker hypothermic action when injected intraventricularly, whereas the β‐adrenoceptor blocking agents propranolol, pronethalol and Trasicor had no effect.

In rabbits in which the noradrenaline stores of the hypothalamus were depleted by intraventricular injections of reserpine, the hypothermic effect of phenoxybenzamine was abolished and remained abolished for a few days.

In cats, an intraventricular injection of phenoxybenzamine (200 μg) produced long‐lasting hyperthermia, but not in all cats, and only with the first, or the first two or three injections. Injected intraperitoneally, this dose had no effect on temperature. Phentolamine (100 or 200 μg) had a very weak hyperthermic effect and phentolamine (500 μg), a hypothermic effect, but only on intraventricular injection, whereas ergotamine (100 and 200 μg) had a weak hyperthermic effect both on intraventricular and intraperitoneal injection. Propranolol and Trasicor had no effect on temperature when injected intraventricularly.

In rats, phenoxybenzamine (5 or 20 μg) produced long‐lasting hypothermia on intraventricular injection.

Some of the temperature effects produced by intraventricular injections of the α‐adrenoceptor blocking agents are explained on the assumption that they prevent the effect on temperature produced by a continuous release of noradrenaline from adrenergic neurones innervating the anterior hypothalamus.
3H‐Noradrenaline‐accumulating ability of cholinergic nerve terminals in cat sympathetic ganglia
Authors: GRAHAM J. D. P. , IVENS CAROLINE , JOÓ F. , LEVER J. D. , MOTTRAM D. R. , SPRIGGS T. L. B.
Published: July 2012

After incubation of pieces of cat posterior mesenteric ganglion in [3H]‐noradrenaline solution, the localization of the isotope was assessed by electronautoradiography.

Significantly higher concentrations of [3H]‐noradrenaline were found over acetylcholinesterase‐positive axons terminal on ganglion cells than in adjacent background areas.

[3H]‐Noradrenaline was not accumulated by ganglion cells under these circumstances.

The significance of these findings in relation to previous physiological and pharmacological investigation is discussed.
Comparison of the effects of drugs on the aggregation of hamster platelets in vivo and in vitro
Authors: BEGENT NICOLA A. , BORN G. V. R.
Published: July 2012

A method is described for measuring the inhibitory effectiveness of drugs on the aggregation by ADP of hamster platelets in vivo.

The method was used to compare the effects of several drugs, viz. adenosine, imipramine, desmethylimipramine and aspirin, on platelet aggregation in vivo with their in vitro effects measured photometrically.

The concentrations of adenosine and imipramine present in the cheek pouch after 10 min infusions were measured using radioactively labelled drugs.

The results show that adenosine (0·4 μm) inhibited platelet aggregation in vivo by 43%, whereas several times this concentration was required to produce the same inhibition in vitro.

Imipramine and desmethylimipramine (0·4 μm) did not inhibit platelet aggregation in vivo; in vitro, however, desmethylimipramine caused up to 34% inhibition at concentrations as low at 0·25 μm.

Aspirin (estimated 0·2 mm) inhibited platelet aggregation in vivo by 37% whereas similar inhibition in vitro required about 1 mm aspirin. Sodium salicylate was several times less potent than aspirin in vivo.
Effects of isoxazolium cations on some isolated muscle preparations
Authors: MITTAG T. W. , TORMAY ANNE
Published: July 2012

The quaternary ammonium compound, N,t‐butyl‐5‐methyl isoxazolium perchlorate (BIP), an anionic group reagent, initially causes contractions of the rat phrenic‐nerve diaphragm, guinea‐pig ileum and rabbit aortic strip preparations in vitro.

In addition, the drug produces an irreversible block of indirectly elicited twitch responses in the diaphragm and of contractions induced by acetylcholine, methylfurmethide, dimethyl‐phenylpiperazinium, 5‐hydroxytryptamine (5‐HT), histamine, angiotensin and pilocarpine in the ileum, while direct electrical stimulation of the diaphragm and contractions of the ileum to Ba and K ions are relatively unaffected.

BIP is also an irreversible inhibitor of acetylcholinesterase but not of butyrylcholinesterase.

On rabbit aortic strip preparations, responses to histamine, noradrenaline and 5‐HT were differentially sensitive to irreversible blockade by BIP.

Diphenhydramine, used in conditions which gave complete protection of the histamine response to irreversible block by dibenamine, did not protect against the blocking action of BIP but increased the blockade.

These results suggest that BIP reacts covalently with anionic groups which mediate receptor initiated stimuli. The isoxazolium group may be useful in conferring irreversible properties by its substitution in drug molecules for the pyrrole or pyrrolidine group.
Effect of M & B 17803A, a new β‐adrenoceptor blocking agent, on the cardiovascular responses to tilting and to isoprenaline in man
Authors: CUTHBERT M. F. , OWUSU‐ANKOMAH K.
Published: July 2012

dl‐1‐(2‐acetyl‐4‐n‐butyramidophenoxy)‐2‐hydroxy‐3‐isopropylaminopropane hydrochloride (M & B 17803A) was given to four healthy volunteers in single oral doses of up to 300 mg. There were no subjective effects and no significant alterations in the heart rate, systolic and diastolic blood pressure in the seated position or in the forced expiratory volume or in the electrocardiogram within 6 h of the dose. There were no abnormalities in haematological tests and estimations of the serum glutamyloxaloacetic transaminase.

Oral doses of both M & B 17803A and propranolol inhibited the increase in heart rate which occurs on tilting from the supine to the 80° head up position. The results suggest that the degree of β‐adrenoceptor blockade produced by M & B 17803A (100 and 300 mg) is comparable to that of propranolol (10 and 40 mg) respectively. Propranolol is 7·5–10·0 times as potent as M & B 17803A when compared by this method. There were no significant changes in the systolic or diastolic blood pressure after any of the treatments, in either of the positions studied.

M & B 17803A was also effective in inhibiting the increase in heart rate produced by the intravenous infusion of isoprenaline and in two subjects the degree of β‐adrenoceptor blockade produced by M & B 17803A (300 mg) was comparable to that of propranolol (40 mg). M & B 17803A is a competitive β‐adrenoceptor blocking agent and the duration of the pharmacological activity of both M & B 17803A and propranolol appeared to be very similar as assessed by this method.

In separate experiments with small oral doses of M & B 17803A no evidence of a selective action on myocardial β‐adrenoceptors was obtained from the study of changes in heart rate and diastolic blood pressure (sphygmomanometric recording).
Central components of the renin‐angiotensin system
Authors: HAYDEN J. , TARGETT MARGARET A.
Published: July 2012

Re‐establishment of renal blood flow after total renal ischaemia of 4 h duration causes a pressor response in pentobarbitone anaesthetized rats and cats.

The pressor response is related to the release of renin from the ischaemic kidney.

Spinal section at any cervical level or stellate ganglionectomy abolishes the pressor response but spinal section caudad to the thorax or vagotomy and treatment with hexamethonium have no effect.

Spinal section and stellate ganglionectomy interfere with the release of renin and with the pressor response to angiotensin.