bluuebunny/crossref_metadata_2025 huggingface dataset:
Metabolism of cardiac glycosides studied in the isolated perfused guinea‐pig liver
Authors: KOLENDA K.‐D. , LÜLLMANN H. , PETERS T.
Published: July 2012

Metabolic degradation of tritiated ouabain, digoxin, and digitoxin has been investigated quantitatively using the isolated perfused guinea‐pig liver. The cardiac glycosides and their metabolites have been extracted from the plasma, liver, and bile by different solvents and identified as far as possible by radio‐chromatographic analysis.

The total metabolic activity in the experimental system was localized in the liver.

The hydrophilic glycoside ouabain could not penetrate into the metabolically active compartment of the liver and was, therefore, not degraded. The more lipophilic compound digitoxin, however, was completely degraded due to its high affinity for the metabolically active sites. The unchanged digitoxin cannot enter the aqueous bile fluid in contrast to its more hydrophilic metabolites.

The only detectable metabolic degradation of digoxin was a conjugation with glucuronic and/or sulphuric acid, but a cleavage of sugar molecules seemed not to occur.

In the case of digitoxin the metabolic processes are more complicated: sugar cleavage, conjugation, and C‐12 hydroxylation take place simultaneously. An immediate hydroxylation of digitoxin leading to digoxin was not observed. After administration of digitoxin conjugation products as well as digoxigeninbis‐and digoxigenin‐mono‐digitoxosides were present in each of the compartments investigated, but the digitoxosides of digitoxigenin were intermediates in concentrations too low to be determined indicating a very high rate of conjugation and/or C‐12 hydroxylation as compared with the cleavage of the digitoxoses.

A scheme for the metabolic pathways of the cardiac glycosides based on experimental results is presented. The metabolic behaviour of each of the three compounds involved is closely related to their physicochemical properties, especially the lipid solubility.
Importance of noradrenaline found in a functional pool in maintaining spontaneous locomotor activity in rats
Authors: ONN‐LENG CHAN , WEBSTER R. A.
Published: July 2012

Spontaneous locomotor activity (activity) in male Wistar rats was compared with the concentrations of brain noradrenaline (NA), dopamine (DA) and metaraminol.

α‐Methyl‐m‐tyrosine (αMMT) (400 mg/kg) reduced the concentrations of DA as well as NA but activity remained high in the presence of metaraminol formed from the αMMT. When tetrabenazine (TBZ) was given after αMMT pretreatment there was a fall in the levels of activity and in the concentrations of NA, DA and metaraminol.

α‐Methyl‐p‐tyrosine (αMT) produced a fall in activity which was correlated with falls in the concentrations of NA and DA. 5‐Hydroxytryptamine (5‐HT) did not appear to be affected.

After depletion of NA and DA by αMT and TBZ, administration of L‐dopa produced a return in activity which was significantly correlated with the concentration of NA but not DA. When αMMT was given to a similar group of pretreated animals there was no recovery of activity despite high concentrations of DA and metaraminol.

The dopamine β hydroxylase inhibitor, diethyldithiocarbamate (DDC), suppressed activity as well as the concentrations of NA and DA at high doses (750 mg/kg) but smaller doses (400 mg/kg) plus L‐dopa gave high DA concentrations without activity.

It is concluded that NA and not DA is associated with activity but that it is only part of the total NA which is in the biosynthetic storage granule affected by drugs like αMT and TBZ, which controls activity. Drugs that do not affect this pool may lower NA concentrations but not reduce activity.

The replacement of NA by metaraminol in this functional pool does not restore activity.
Cardiovascular pharmacology of quazodine (MJ‐1988), with particular reference to effects on myocardial blood flow and metabolic heat production
Authors: PARRATT J. R. , WINSLOW EILEEN
Published: July 2012

The effects of intravenous infusions of quazodine (6,7‐dimethoxy‐4‐ethyl‐quinazoline; MJ‐1988) on myocardial blood flow, myocardial metabolic heat production and on general haemodynamics have been studied in cats anaesthetized with sodium pentobarbitone.

Quazodine (0·25 and 0·5 (mg/kg)/min for 10 min) decreased diastolic blood pressure, peripheral vascular resistance, systolic ejection time and left ventricular end‐diastolic pressure. Heart rate, cardiac effort, output and external work and left ventricular dP/dt were markedly increased. These changes are indicative of increased myocardial contractility and peripheral vasodilatation.

In a dose of (1·0 mg/kg)/min, quazodine had a more marked hypotensive effect, systolic pressure being significantly reduced, and had less effect on left ventricular dP/dt and cardiac effort. Calculated external cardiac work was slightly reduced and there were very occasional nodal arrhythmias.

Changes in heart rate, aortic dP/dt and diastolic blood pressure induced by quazodine were unaffected by the previous administration of the β‐adrenoceptor blocking agent alprenolol in a dose (1·0 mg/kg) which abolished the effects of isoprenaline.

In all doses, quazodine markedly increased local blood flow (by 70–540%) around an implanted myocardial heated thermocouple recorder. ‘Corrected temperature’, an index of local myocardial metabolic heat production, was almost unchanged and it is suggested that increased myocardial contractility, occurring with unchanged metabolic heat production and oxygen consumption, probably results from a concomitant decrease in intramural wall tension.
3,4‐Dihydroxyphenylacetic acid and 4‐hydroxy‐3‐methoxyphenylacetic acid in the mouse striatum: a reflection of intra‐ and extra‐neuronal metabolism of dopamine?
Authors: ROFFLER‐TARLOV SUZANNE , SHARMAN D. F. , TEGERDINE P.
Published: July 2012

The administration of probenecid to mice increased the concentration of 4‐hydroxy‐3‐methoxyphenylacetic acid (HVA) in the striatum, but did not raise the concentration of 3,4‐dihydroxyphenylacetic acid (DOPAC).

After drug treatments which normally increase the concentration of HVA several‐fold, inhibition of catechol‐O‐methyltransferase (COMT) by tropolone greatly reduced the concentration of HVA but resulted in only a small increase in the concentration of DOPAC in the striatum of the mouse.

These results indicate that HVA and DOPAC do not occur at the same location in the tissue of the striatum and that DOPAC is not normally metabolized to HVA to any great extent in this tissue.

When mice were treated with reserpine, which is thought to prevent the intraneuronal storage of dopamine, there was an increase in the striatal concentration of DOPAC which preceded an increase in the concentration of HVA. Since non‐cholinergic nerve endings of rat brain contain mitochondria and show monoamine oxidase activity, this result suggests that DOPAC is formed intraneuronally.

It is concluded that the DOPAC in the striatum represents intraneuronal metabolism of dopamine and that only the HVA which is sensitive to the action of probenecid represents entirely extraneuronal metabolism of this amine. Some of the HVA is not sensitive to the action of probenecid. This suggests that part of the metabolism of dopamine involves both locations.

A group of drugs which are chemically related to amphetamine were tested for their effects on the concentrations of DOPAC and HVA in the striatum. It is suggested that d‐amphetamine, 2‐aminotetralin and 1,2,3,4‐tetrahydroisoquinoline reduced the intraneuronal metabolism of dopamine whereas adamantanamine did not.
Mediators of the inflammation induced in the rat paw by carrageenin
Authors: CRUNKHORN PEARL , MEACOCK S. C. R.
Published: July 2012

The time course of oedema formation in rats caused by injection of carrageenin into the paw was followed for 5·5 hours. Intact or adrenalectomized rats which had previously been injected with ellagic acid or saliva to reduce considerably the concentration of blood kininogens, or with methysergide to antagonize 5‐hydroxytryptamine (5‐HT) showed a reduced inflammatory response. It was concluded that kinins and 5‐HT contributed significantly to oedema formation during this period.

Mepyramine alone had no effect on oedema formation, but in combination with ellagic acid treatment, with or without methysergide, it caused a reduction suggesting that histamine played a minor role in oedema formation during the first 3 hours.

Vascular permeability studies indicated that injection of ellagic acid did not interfere with the normal responses in skin to intradermal injections of histamine, 5‐HT, bradykinin or compound 48/80. Mepyramine and methysergide, at the doses used in the carrageenin experiments, completely antagonized histamine and 5‐HT, respectively, and did not affect the skin responses of bradykinin.

Treatment in vivo with ellagic acid or rat saliva was equally effective in reducing plasma kininogen concentrations by an amount equivalent to more than 10 times the quantity of substrate 1 measured by Gautvik & Rugstad (1967).

Rat saliva, but not ellagic acid, lowered complement levels by approximately 20%.
Destruction of chlorpromazine during absorption in the rat in vivo and in vitro
Authors: CURRY S. H. , D'MELLO A. , MOULD G. P.
Published: July 2012

Concentrations of total radioactivity in plasma of rats given intravenous and oral 35S‐chlorpromazine, were similar. Concentrations of unchanged drug, however, were lower after oral doses.

Chlorpromazine circulated in solution through isolated loops of rat intestine was rapidly absorbed by the tissue. Measurements of glucose transport and histological examination indicated that the tissue was intact. In these in vitro experiments some of the chlorpromazine was converted to products, which together with unchanged drug, were partly retained in the intestinal wall and partly transferred to the serosal side of the tissue. Observations at three concentrations supported the hypothesis that transfer of unchanged drug occurred by passive diffusion.

Conversion of chlorpromazine to metabolites in the intestine in vivo, would account for the differences in concentrations of chlorpromazine and total radioactivity in plasma after oral doses.
Some observations on the estimation of 3‐methoxytyramine in brain tissue
Authors: GULDBERG H. C. , SHARMAN D. F. , TEGERDINE P. R.
Published: July 2012

A new method for the estimation of 4‐hydroxy‐3‐methoxyphenylethylamine (3‐methoxytyramine) in brain tissue is described. This is based on the formation of a fluorescent derivative by oxidation with potassium ferricyanide in ammonium hydroxide solution.

The effects of some drugs on the concentration of 3‐methoxytyramine in the brain are reported.

The significance of changes in the striatal concentration of 3‐methoxytyramine is discussed.
Studies on prostaglandin antagonists
Authors: BENNETT A. , POSNER J.
Published: July 2012

Three prostaglandin antagonists have been examined for their ability to block PGE2 and PGF2α on human, guinea‐pig and isolated rat gastrointestinal muscle.

7‐oxa‐13‐Prostynoic acid was either a non‐selective antagonist, or was ineffective on the tissues studied; it had marked spasmogenic activity on the rat fundus.

1‐Acetyl‐2‐(8‐chloro‐10,11‐dihydrodibenz (b,f)(1,4) oxazepine‐10‐carbonyl)hydrazine selectively antagonized the excitatory effects of PGE2 and PGF2α in guinea‐pig and rat tissues, but not in human muscle.

Polyphloretin phosphate selectively antagonized the excitatory effects of prostaglandins in both human and guinea‐pig muscle preparations, but it caused stimulation of the rat fundus.

All the antagonists lowered the tone in many tissues. They also reduced contractions caused by potassium.

None of the compounds blocked the inhibitory effect of PGE2 on intestinal circular muscle.

The implication of these results on the nature of prostaglandin receptors, and the value of each compound as a prostaglandin antagonist are discussed.
Antagonism by β‐adrenoceptor blocking agents of the antianaphylactic effect of isoprenaline
Authors: ASSEM E. S. K. , SCHILD H. O.
Published: July 2012

β‐Adrenoceptor blocking agents antagonized the inhibitory (antianaphylactic) effect of isoprenaline on antigen‐induced histamine release in isolated, passively sensitized, human lung and actively sensitized guinea‐pig lung suggesting that the effect is exerted through β‐adrenoceptors. No antagonism was obtained with the human allergic leucocyte preparation.

The antianaphylactic effect of isoprenaline was antagonized not only by propranolol but also by the ‘selective’ β‐adrenoceptor blocking agents, practolol and butoxamine.

The classification of β‐adrenoceptors is discussed. Certain similarities between antianaphylactic and lipolytic β‐adrenoceptors are noted.
Effects of narcotic analgesics and antagonists on the in vivo release of acetylcholine from the cerebral cortex of the cat
Authors: JHAMANDAS K. , PHILLIS J. W. , PINSKY C.
Published: July 2012

In cats under light allobarbitone anaesthesia, the effects of intravenous injections of narcotic and non‐narcotic analgesics, of a general depressant, and of narcotic antagonists were investigated on the spontaneous release of acetylcholine (ACh) from the surface of the sensorimotor cortex.

The narcotic analgesics morphine (0·1, 1·0 and 5 mg/kg), meperidine (1·0 and 2·0 mg/kg), methadone (1·0 mg/kg) and codeine (5·0 and 10·0 mg/kg) greatly reduced ACh release.

The non‐narcotic analgesics pentazocine (1·0 and 2·0 mg/kg) and propoxyphene (5·0 and 10·0 mg/kg) as well as the depressant chlorpromazine (0·25, 0·5 and 1·0 mg/kg) also greatly reduced ACh release.

Two of the three narcotic antagonists examined, levallorphan (0·1, 1·0 and 5 mg/kg) and nalorphine (1·0 mg/kg) had the property of reducing ACh release. They were thus partial agonists. With levallorphan the greatest reduction occurred with the smallest dose injected and the effect was regularly obtained, whereas with nalorphine a reduction was obtained in some experiments only. The third, naloxone, was a specific narcotic antagonist and did not reduce the ACh release in any dose (0·01, 0·1, 0·5 and 1·0 mg/kg) examined. In a dose of 1·0 mg/kg it actually produced a small increase in Ach release.

Naloxone (0·1–1·0 mg/kg) restored the reduction in ACh release produced by the narcotic analgesics and by the partial agonist levallorphan. It partially restored the reduction produced by the non‐narcotic analgesics and by nalorphine, but had no effect on the reduction produced by chlorpromazine.

The relevance of these results with regard to analgesia and to the narcotic abstinence syndrome is discussed.
Biliary excretion of barbiturates
Authors: KLAASSEN C. D.
Published: July 2012

Pentobarbitone and phenobarbitone are excreted into the bile of rats.

The concentration of pentobarbitone and/or its metabolites in the bile is 22‐fold higher than in the plasma; the concentration of phenobarbitone and/or its metabolites in bile is 10‐fold higher than in the plasma.

Probenecid decreases the excretion of the barbiturates into the bile.

Twenty‐eight per cent of a 35 mg/kg dose of pentobarbitone and 18% of a 75 mg/kg dose of phenobarbitone is excreted in the bile in 6 hours.

Most of the pentobarbitone and phenobarbitone excreted into the bile is not in the form of the parent compound but rather as a more polar metabolite or metabolites.
Comparison of human serum, parotid and mixed saliva levels of phenoxymethylpenicillin, ampicillin, cloxacillin and cephalexin
Authors: SPEIRS C. F. , STENHOUSE D. , STEPHEN K. W. , WALLACE EDITH T.
Published: July 2012

A study has been made of serum, mixed and parotid salivary levels attained in normal volunteers following oral dosage of 500 mg phenoxymethylpenicillin tablets, 500 mg crushed phenoxymethylpenicillin tablets in capsules, 500 mg ampicillin, 500 mg cloxacillin and 500 mg cephalexin.

High mixed saliva levels were obtained with phenoxymethylpenicillin tablets and it is considered that these were due to rapid intra‐oral dissolution of surface powder from friable tablets. No saliva levels were detected when tablets from the same batch were put into capsules.

Low or no saliva levels were achieved with ampicillin, cloxacillin and cephalexin.

The mode of action of antibiotics in oral infections is discussed.
Effects of some sympathomimetic drugs and their antagonists on afterdischarges elicited in chronically isolated slabs of cerebral cortex
Authors: KRIP G. , VÁZQUEZ J.
Published: July 2012

The role of sympathomimetic agents in the maintenance and termination of induced cortical epileptiform activity was studied in chronically neuronally isolated slabs of cerebral cortex in the suprasylvian gyrus of unanaesthetized, unrestrained cats.

The administration of the sympathomimetic agents (+)‐amphetamine, methamphetamine, tyramine, and ephedrine resulted in a highly significant decrease in the duration of epileptiform afterdischarge (EADs).

The α‐adrenoceptor blocking drugs phenoxybenzamine, phentolamine and tolazoline did not significantly alter the duration of EADs but prevented the decrease in duration of EADs produced by the sympathomimetic drugs.

The effect of atropine and arecoline on the duration of EADs, previously described, were not modified by the α‐adrenoceptor blocking drugs, but atropine prevented and reversed the inhibitory action of amphetamine.

It is suggested that (1) in the chronically neuronally isolated cortical slab there is normally no spontaneous adrenergic activity, (2) a cortical, cholinergic inhibitory mechanism, previously described, is modulated by ascending adrenergic influences, (3) adrenergic cholinergic linkages might be arranged in the cortex in an alternating network, as proposed by Feldberg.
Effect of reserpine on the activity of adrenal enzymes involved in the synthesis of adrenaline
Authors: BHAGAT B. , BURKE W. J. , DAVIS J. W.
Published: July 2012

After administration of reserpine to rats, the tyrosine hydroxylase (TH) and phenylethanolamine‐N‐methyl transferase (PNMT) activity in their adrenal glands was found to be increased under in vitro conditions.

The increase in TH activity occurred at 12–18 h after reserpine whereas the PNMT activity increased at 30 hours. Unlike the TH, the increase in PNMT activity did not appear to be neuronally mediated since ganglion blockade by chlorisondamine failed to antagonize the reserpine‐induced increase in PNMT activity. The increase in PNMT activity may be a response to increased utilization of catecholamines.

Hypophysectomy resulted in a diminution of the activities of both enzymes; the activity of TH, but not of PNMT, could be partially restored by reserpine. ACTH restored the activities of both enzymes almost to normal.

The differential effect of reserpine suggests that the activities of these two enzymes are controlled by different mechanisms.
Factors influencing the aggressiveness elicited by marihuana in food‐deprived rats
Authors: CARLINI E. A. , HAMAOUI A. , MÄRTZ REGINA M. W.
Published: July 2012

Aggressive behaviour was elicited in rats that had been deprived of food for 20 h daily (starved), by chronic administration of Cannabis sativa extract or (—)‐Δ9‐trans‐tetrahydrocannabinol.

The influence of intraperitoneal (i.p.) or oral glucose administration, cold environment, acidosis, and corn, and protein‐free diets on this aggressiveness was studied.

Intraperitoneal injections of glucose (100–1,600 mg/kg) did not alter the aggressiveness induced by marihuana in starved rats; glucose given orally, however, blocked this behaviour.

Low temperature (14° C) strongly potentiated the aggressive behaviour induced by marihuana in the starved rats.

Lactic acid in doses capable of potentiating thiopental anaesthesia, failed to alter the marihuana‐aggressiveness of starved rats or to facilitate this effect of marihuana in rats fed ad libitum. The same negative results were obtained with ammonium chloride.

In rats fed ad libitum with protein‐free or corn diets, marihuana administered chronically did not elicit aggressive behaviour. However, aggressiveness appeared when rats were fed for only 2 h daily on those diets.

The results suggest that the stress of hunger (and not hypoglycaemia, acidosis or lack of specific nutrients due to starvation) is the factor that facilitates the development of aggressive behaviour by chronic administration of marihuana.
Prostaglandins, oxygen tension and smooth muscle tone
Authors: ECKENFELS A. , VANE J. R.
Published: July 2012

By using indomethacin to inhibit their intramural synthesis, we have investigated the contribution of prostaglandins to the maintenance of (a) the intrinsic tone of isolated smooth muscle preparations and (b) contractions produced by drugs or high oxygen concentration.

When treated with indomethacin, the rat stomach strip and chick rectum preparation slowly relaxed, whether they were bathed in Krebs solution or blood. Although their sensitivity to added prostaglandin was somewhat enhanced, they became insensitive to changes in oxygen or glucose concentration. However, another smooth muscle preparation, the rat colon, was neither relaxed by indomethacin nor contracted by high oxygen concentration.

These results support the hypothesis that intramural generation of prostaglandin maintains the tone of some smooth muscle preparations.

Contractions of the guinea‐pig isolated colon were induced by histamine. These contractions were normally well maintained but in Krebs solution lacking either oxygen or glucose, only the initial spike contraction remained. In the presence of indomethacin the histamine contraction was also poorly sustained, but maintenance was restored by a low concentration of prostaglandin E2.

Thus, the effects on smooth muscle of oxygen or glucose lack may also be mediated by reduction in the synthesis or effects of an intramural prostaglandin. Extension of this hypothesis to intestinal and vascular smooth muscle in vivo is discussed.
A method for measuring human behavioural and physiological responses at different stress levels in a driving simulator
Authors: ASHTON HEATHER , SAVAGE R. D. , THOMPSON J. W. , WATSON D. W.
Published: July 2012

A method is described by which a car simulator can be used to measure, simultaneously, motor‐perceptual performance and physiological responses of human subjects under different levels of task difficulty or stress.

Motor‐perceptual performance was measured in terms of reaction times taken by subjects to carry out steering, braking and operation of traffic indicators in the simulator. Subjects were instructed to carry out the different driving manoeuvres by means of a command panel containing five coloured lights. Three levels of task difficulty or stress were devised. In level 1 only the light signals were used. In level 2 the driving simulator film was shown and all of the light signals reinforced the movements of the car in the film. Level 3 was similar to level 2, with the exception that whilst some of the light signals reinforced the movements of the car, others deliberately conflicted with it.

Physiological responses measured were heart rate, blood pressure, respiration and calf blood flow. Personality was also measured by means of the Cattell 16 personality factor questionnaire.

Analysis of variance of the performance of 15 subjects showed significant variation between the three task levels (P = <0·001 for steering reaction times; P = <0·01 for brake and indicator reaction times). In all cases the reaction times were longest for level 3, indicating that this was the most difficult task. The number of anticipated responses to steering, braking and traffic indicator signals was highest in level 2, while the number of corrections to steering and braking responses was lowest in level 2. None of these differences was statistically significant.

Of the physiological variables, the heart rate showed a progressive increase from task levels 1 to 3 but only those between levels 1 and 3 were statistically significant (P<0·05).

The results are discussed in relation to the validity of the method. It is concluded that by means of this method it is possible to produce controlled and reproducible degrees of stress and under conditions which are also suitable for the investigation of pharmacological agents upon it.
The effects of some phosphodiesterase inhibitors on the conductance of the perfused vascular beds of the chloralosed cat
Authors: HAMILTON T. C.
Published: July 2012

The vasoactivity of a number of phosphodiesterase inhibitors in the autoperfused splanchnic region and hindquarters of the cat have been investigated.

Theophylline, dipyridamole and 4‐(3,4‐dimethoxybenzyl)‐2‐imidazolidinone (Ro 7–2956) and its analogues were more potent vasodilators in the splanchnic region than in the hindquarters, whereas papaverine was a potent vasodilator in both these vascular beds.

The vasodilator response to the phosphodiesterase inhibitors in the splanchnic region and hindquarters was not susceptible to β‐adrenoceptor blockade.

Infusion of dibutyryl cyclic AMP into the superior mesenteric artery increased vascular conductance of the splanchnic region. This effect was enhanced by Ro 20–1724 in doses below those in which this compound affected conductance.

These results are consistent with the hypothesis that accumulation of cyclic AMP in vascular smooth muscle mediates the vasodilator response to phosphodiesterase inhibitors.
Effects of an isolated toxin from Australian Tiger snake (Notechis scutatus scutatus) venom at the mammalian neuromuscular junction
Authors: HARRIS J. B. , KARLSSON E. , THESLEFF S.
Published: July 2012

The acute effects of a purified toxin from Australian Tiger snake (Notechis scutatus scutatus) venom have been investigated at the mammalian neuromuscular junction.

The toxin was injected into the tail vein of mice. Death was due to respiratory paralysis.

The resting membrane potential, and action potential of muscle fibres in muscles from in vivo intoxicated animals were normal.

The frequency of miniature end plate potentials (m.e.p.p.s) from intoxicated nerve‐muscle preparations was reduced, although m.e.p.p. amplitude was unaltered.

Nerve stimulation resulted in end plate potentials (e.p.p.s) of quantal amplitude; only rarely was the e.p.p. large enough to give rise to an action potential.

High (20 mm) K+ did not increase m.e.p.p. frequency in intoxicated preparations.

The toxin was largely ineffective in vitro.

The similarities and differences between this toxin, β‐bungarotoxin and botulinum toxin are discussed.
N,O‐di andN,N,O‐tri [3H] acetyl α‐bungarotoxins as specific labelling agents of cholinergic receptors
Authors: CHANG C. C. , CHEN T. F. , CHUANG SING‐TAI
Published: July 2012

α‐Bungarotoxin isolated from the venom ofBungarus multicinctuswas acetylated with [3H] acetic anhydride andN‐[3H] acetyl imidazole. Tri‐N‐acetyl and hexa‐N‐acetyl derivatives were obtained from the former, andN,O‐di,N,N,O‐tri andN,N,N,O‐tetraacetyl derivatives from the latter reaction, respectively.

There were parallel decreases in both neuromuscular blocking action in the phrenic nerve—diaphragm preparation of rats and depression of acetylcholine response of the rectus abdominis muscle of frogs with increased acetylation. Also, a parallel but greater decrease of toxicity in mice was found.

N,O‐Di andN,N,O‐triacetyl toxins were localized mostly in the motor endplate region of the rat diaphragm, whereas a slight nonspecific binding along the whole muscle fibre in addition to the peak in the endplate region was observed withN,N,N,O‐tetraacetyl and tri‐N‐acetyl toxins. In contrast, there was a marked nonspecific binding with hexa‐N‐acetyl toxin and no peak was observed at the endplate zone.

The specific binding was saturable and irreversible. The number of toxin‐receptive sites in one endplate was 1·9–2·2 × 107for all of the labelled toxins irrespective of their potency.

(+)‐Tubocurarine protected effectively against the binding as well as the irreversible neuromuscular blocking effect of the toxins.

Denervation of the rat diaphragm caused an increase of toxin‐receptive sites beginning from the endplate zone at 1–2 days and then along the whole muscle fibre, reaching the maximum at about 18 days. The total receptive sites increased by about 30‐fold.

The significance of the findings is discussed and it is concluded thatN,O‐di andN,N,O‐tri‐[3H] acetyl α‐bungarotoxins are specific and irreversible labelling agents for the cholinergic receptors of skeletal muscle.
The structure of hydroxyethyl starch
Authors: BANKS W. , GREENWOOD C. T. , MUIR D. D.
Published: July 2012

It is suggested that the structure currently used to describe hydroxyethyl starch (a blood plasma volume expander) is a gross oversimplification.

A model having a much more complex substitution‐pattern is proposed, and an accurate, rapid test has been devised for distinguishing between the two models.

This test shows that the simple model has no basis in reality, and that the more complex substitution pattern is correct.

Studies involving the enzymic hydrolysis of hydroxyethyl starch are shown to provide qualitative support for the new model, and the significance of the findings is discussed.
Further observations on mesenteric vasoconstriction, survival and the clotting defect after endotoxin administration
Authors: COHEN M. M. , GREENWAY C. V. , INNES I. R. , LISTER G. E. , MURTHY V. S. , SCOTT G. D.
Published: July 2012

The initial response after endotoxin administration (3 mg/kg) in cats involved pulmonary vasoconstriction. This was not seen when endotoxin was given by slow infusion and it could be prevented after a bolus injection of endotoxin by pretreatment of the cats with aspirin (10 mg/kg). Intense mesenteric vasoconstriction occurred in all the cats.

The mesenteric vasoconstriction was a specific response of the mesenteric blood vessels. At the time the mesenteric bed constricted, the renal bed dilated, the hepatic arterial bed remained unchanged and the smooth muscle of the intestinal wall relaxed.

Arterial blood from cats with a fully developed mesenteric vasoconstriction after endotoxin administration was perfused through a normal intestine. No immediate vasoconstriction developed but the perfused intestine constricted slowly over 60 minutes. This suggests that mesenteric constriction was not due to circulating vasoconstrictor factors or the intestinal innervation, but involved a slow local mechanism within the intestine. It could not be prevented or reversed by a variety of pharmacological agents.

These observations suggest that endotoxin caused a unique type of mesenteric vasoconstriction in cats by a local mechanism which took up to 60 min to develop, was sufficiently potent to reduce mesenteric flow to <30% control, and was maintained until death of the cats. Blood from these animals did not clot when placed in a glass tube.

The mesenteric constriction and the clotting defect could be prevented by repeated administration of aminophylline and dextran solution before and after a bolus intravenous injection of endotoxin. Arterial pressure and mesenteric flow were maintained for at least 10 h in these experiments. Inadequate treatment intensified rather than reduced the intestinal mucosal damage.

Cats were treated with aspirin, endotoxin and the optimal regimen for prevention of the mesenteric constriction and allowed to recover from the anaesthetic agent. In this series, 63% survived indefinitely compared to 25% after aspirin and endotoxin treatment and 0% after endotoxin alone.

The possible mechanisms of action of aspirin and aminophylline‐dextran solution are discussed. Our failure to obtain 100% survival is probably due to pulmonary damage which develops 10–24 h after endotoxin administration. This delayed pulmonary action of endotoxin is not prevented by aspirin treatment and it seems unlikely that aspirin will be of any value in the treatment of the pulmonary lesion in man.
Role of 5‐hydroxytryptamine in ketamine‐induced hypothermia in the rat
Authors: FAHIM I. , ISMAIL M. , OSMAN O. H.
Published: July 2012

Intraperitoneal injection of graded doses of ketamine produced a dose‐dependent fall in body temperature of rats. Similarly, intracerebral injection of much smaller doses produced hypothermia.

Pretreatment of the rats with p‐chlorophenylalanine (PCPA) greatly attenuated the hypothermic response to ketamine whereas the intraperitoneal injection of 5‐hydroxytryptophan in PCPA‐treated rats restored the hypothermic effect of ketamine.

Depletion of the brain monoamines by reserpine completely prevented the ketamine‐induced hypothermia. Treatment with sodium diethyldithiocarbamate (DEDTC), however, did not modify the hypothermic effect of ketamine.

Pretreatment of the rats with pargyline potentiated the ketamine‐induced hypothermia.

Depletion of brain monoamines by reserpine in combination with inhibition of noradrenaline biosynthesis (DEDTC) resulted in a long lasting fall in temperature which was not modified by ketamine.

When the ambient temperature was raised from 26° C to 32° C, ketamine‐induced hypothermia was much reduced and superimposed on a hyperthermia which occurred in all animals.

It is concluded that ketamine produces hypothermia in rats possibly through the release of 5‐hydroxytryptamine in the hypothalamus and that this effect is similar in some respects to that produced by morphine in non‐tolerant rats.
The contribution of prostaglandin production to contractions of the isolated uterus of the rat
Authors: VANE J. R. , WILLIAMS K. I.
Published: July 2012

Indomethacin and meclofenamate, both of which are potent inhibitors of prostaglandin synthetase, antagonized the contractor effects of oxytocin on the isolated uterus from the non‐pregnant rat. Contractions induced by acetylcholine or prostaglandin F2α were not antagonized.

Uteri from rats 17–22 days pregnant exhibited intermittent spontaneous contractions when used as isolated preparations. They also released prostaglandin‐like activity (mainly similar to F2α) into the bathing fluid. Both the prostaglandin release and the uterine activity were abolished by indomethacin. Activity could be restored by addition of low concentrations of prostaglandin E2 or F2α.

The release of prostaglandin F2α‐like activity by the uteri increased dramatically on the expected day of delivery (day 22).

The results add force to the hypothesis that the spontaneous activity of some isolated organs is due to an intramural prostaglandin generation, and that increased uterine prostaglandin production contributes to the expulsion of the foetus.
Effect of anti‐inflammatory drugs on the binding of calcium to cellular membranes in various human and guinea‐pig tissues
Authors: NORTHOVER B. J.
Published: July 2012

Cellular membranes were obtained by centrifugation of homogenates of various human and guinea‐pig tissues. These membranes took up added calcium (Ca) when incubated at 25° C for 10 min in histidine buffer at pH 7·4. The uptake of Ca was increased by the presence of adenosine triphosphate (ATP).

Evidence is presented that the membrane fragments which took up Ca under these conditions were derived from the endoplasmic reticulum.

The ATP‐dependent uptake of Ca by membranes derived from guinea‐pig aortic or gastric smooth muscle or from human umbilical arterial muscle was inhibited by indomethacin in a concentration‐dependent manner.

The ATP‐dependent uptake of Ca by membranes derived from heart, brain, skeletal muscle or liver of the guinea‐pig was not inhibited by indomethacin.

Endothelial cells were obtained from the lining of the human umbilical vein. Cellular membranes were prepared from the endothelial cells by homogenization and centrifugation. The endothelial membranes took up added Ca in the presence of added ATP and this uptake was inhibited by indomethacin and also by members of a group of pharmacologically‐related drugs.
The effects of (−)‐Δ9‐tetrahydrocannabinol on reserpine‐induced hypothermia in rats
Authors: ENGLERT L. F. , HO B. T. , TAYLOR DOROTHY
Published: July 2012

An intravenous injection into rats of 1 mg/kg (—)‐Δ9‐tetrahydrocannabinol Δ9‐THC) had no effect on rectal temperature and produced in the subcellular fractions of the brain a shift of 5‐hydroxytryptamine (5‐HT) from the particulate or ‘bound’ 5‐HT to the supernatant or ‘free’ fraction, whereas the noradrenaline (NA) decreased in both fractions.

Pretreatment of rats by an intravenous injection of 1 mg/kg Δ9‐THC three times a week for four weeks, prevented the hypothermia and the reduction in brain 5‐HT produced by an intraperitoneal injection of 15 mg/kg reserpine given 24 h after the last Δ9‐THC injection.

Pretreatment of rats by a single intravenous injection of 1 mg/kg Δ9‐THC prevented the hypothermia and reduction in brain 5‐HT produced by an intraperitoneal injection of reserpine given 1 h before. The reduction in brain NA was not prevented except at the 18 h time interval.

An injection of 1 mg/kg Δ9‐THC intravenously into rats 3 h after an intraperitoneal injection of reserpine accentuated the reserpine hypothermia as well as the reduction of 5‐HT but not of NA in the brain.

The reserpine hypothermia was not prevented by a single intravenous injection of 1 mg/kg Δ9‐THC when cinanserin, a 5‐HT inhibitor, was injected 30 min before the reserpine.
Effects of chlordane on conditioned avoidance response, brain seizure threshold and open‐field performance of prenatally‐treated mice
Authors: AL‐HACHIM G. M. , AL‐BAKER A.
Published: July 2012

Three groups of six pregnant albino mice at the third stage of gestation were given chlordane 1 or 2·5 mg/kg body weight or olive oil 10 ml/kg. They were dosed orally for seven consecutive days.

Ten young mice, regardless of sex, were randomly selected from the progeny of each group of treated mothers and tested for conditioned avoidance response, electroshock seizure threshold, and open‐field performance.

Offspring of chlordane‐treated mice made fewer conditioned avoidance responses than the controls on each day of training.

Electroshock seizure threshold was raised.

In the open‐field test, progeny of mothers receiving the larger dose were more active than controls. A dose × days interaction indicated a complex response of the chlordane‐treated mice to experience in the open‐field.

The significance of these findings is discussed.
The effects of dipyridamole on blood flow and oxygen handling in the acutely ischaemic and normal canine myocardium
Authors: MARSHALL R. J. , PARRATT J. R.
Published: July 2012

The effects of the intravenous administration of dipyridamole (0·25 mg/kg) were examined in a canine preparation that enabled simultaneous measurements to be made of blood flow in ischaemic and in essentially normal areas of the myocardium and also of oxygen handling (availability, consumption and extraction) in both these regions.

When administered to dogs anaesthetized with trichlorethylene 2–3 h after acute ligation of the descending branch of the left coronary artery, dipyridamole markedly increased blood flow in essentially normal regions (left circumflex flow) but failed to increase flow in the area supplied by the ligated vessel (measured by 133xenon clearance and by retrograde flow). In five of the six animals definite decreases in flow (stealing) were observed in the ischaemic region. These flow changes were related to the decreased trans‐ventricular perfusion pressure (diastolic peripheral coronary pressure minus left ventricular end‐diastolic pressure) and were accompanied by electrocardiographic evidence of increasingly severe myocardial ischaemia. The results support the suggestion that only increasing the perfusion gradient will usefully improve blood flow (and hence oxygen availability) to the acutely ischaemic myocardium.

Despite these effects on ischaemic muscle blood flow, the oxygen tension of the blood draining the infarcting muscle was markedly elevated. The conclusion is drawn that dipyridamole decreases the efficiency of the myocardial circulation by opening up vessels that do not take part in tissue exchange.
The actions of bombesin on gastric secretion of the dog and the rat
Authors: BERTACCINI G. , ERSPAMER V. , IMPICCIATORE M.
Published: July 2012

Bombesin stimulated acid secretion from the denervated fundic pouch of the dog. Whereas the concentration of hydrochloric acid in bombesin‐produced juice was always higher than in control juice this did not occur for pepsin, the concentration of which remained below the basal values. The threshold dose of bombesin was 5–30 ng/kg by the subcutaneous route and 0·05–0·2 (μg/kg)/h by intravenous infusion. At low doses bombesin was more active than caerulein, even on a molar basis, and at high dose levels was as active as caerulein. In contrast to gastrin and caerulein, bombesin elicited a moderate secretory response also following rapid intravenous injection.

The acid secretion provoked by bombesin was almost completely inhibited by atropine and reduced by approximately 50% by hexamethonium.

Bombesin did not stimulate acid secretion in the lumen‐perfused preparation of the rat stomach when administered by subcutaneous injection (up to 10 μg/kg) or by intravenous infusion (up to 10 (μg/kg)/hour). An irregular increase in acid output was observed only following rapid intravenous injection and this was of doubtful significance.

The mechanism of the secretagogue action of bombesin on the dog stomach is discussed.
CHANGES IN MONOAMINE CONCENTRATIONS IN MOUSE BRAIN ASSOCIATED WITH ETHANOL DEPENDENCE AND WITHDRAWAL
Authors: GRIFFITHS P.J. , LITTLETON J.M. , ORTIZ A.
Published: July 2012

Chronic administration of ethanol to mice by inhalation induced tolerance to ethanol and produced an increase in the concentration of brain monoamines.

Withdrawal of ethanol from dependent mice caused behavioural changes associated with a further transient rise in brain monoamine concentrations which then declined to control levels.

Inhibition of the withdrawal syndrome by the administration of ethanol postponed the changes in monoamines associated with withdrawal.

Administration of inhibitors of catecholamine synthesis before withdrawal of ethanol modified the withdrawal syndrome.
THE MECHANISM OF RENIN RELEASE FROM THE ISCHAEMIC KIDNEY
Authors: LABAL S.E. , POLA J.L. , SEEBER A. MARTINEZ , TAQUINI A.C.
Published: July 2012

The re‐establishment of blood flow to an ischaemic kidney produced an elevation of blood pressure in the rat. This response did not occur in animals with a pithed spinal cord or in rats with low blood pressure produced by haemorrhage. When the blood pressure was raised in rats with pithed spinal cords, by the intravenous infusion of noradrenaline, the response was restored. Occlusion of the subclavian arteries did not prevent the response. It is considered that the increase in blood pressure, produced by renin release, after re‐establishment of the blood flow in an ischaemic kidney is a ‘washout’ phenomenon independent of the integrity of the nervous system.
REVERSAL LEARNING ENHANCED BY LYSERGIC ACID DIETHYLAMIDE (LSD): CONCOMITANT RISE IN BRAIN 5‐HYDROXYTRYPTAMINE LEVELS
Authors: KING A.R. , MARTIN I.L. , MELVILLE K. ARABELLA
Published: July 2012

Small doses of lysergic acid diethylamide (LSD) (12.5–50 μg/kg) consistently facilitated learning of a brightness discrimination reversal.

2‐Bromo‐lysergic acid diethylamide (BOL‐148), a structural analogue of LSD, with similar peripheral anti‐5‐hydroxytrypamine activity but no psychotomimetic properties, had no effect in this learning situation at a similar dose (25 μg/kg).

LSD, but not BOL‐148, caused a small but significant increase in brain 5‐hydroxytryptamine levels, but had no effect on the levels of catecholamines in the brain at 25 μg/kg.
ANTI‐INFLAMMATORY PROPERTY OF 401 (MCD‐PEPTIDE), A PEPTIDE FROM THE VENOM OF THE BEE Apis mellifera (L.)
Authors: HANSON JENNIFER M. , MORLEY J. , SORIA‐HERRERA C.
Published: July 2012

Peptide 401, a potent mast cell degranulating factor from bee venom, substantially inhibited the oedema provoked by subplantar injection of carrageenin or intra‐articular injection of turpentine in the rat. The ED50 of 401 was c. 0.1 mg/kg. The anti‐inflammatory effect was assessed by measurement of the increased 125I‐albumin content of an injected site in comparison with an uninjected contralateral site.

Peptide 401 also suppressed the increased vascular permeability due to intradermal injection of various smooth muscle spasmogens (histamine, bradykinin, 5‐hydroxytryptamine (5‐HT), and prostaglandins).

Other comparable mast cell degranulating agents (48/80 and melittin) showed little evidence of anti‐inflammatory activity when tested at comparable dosage on turpentine arthritis and carrageenin oedema.

The anti‐inflammatory effects were not abolished by pretreatment with mepyramine and methysergide, which abolished the increased vascular permeability produced by local injection of 401.

The anti‐inflammatory action of 401 was not affected by regional denervation or pretreatment with phenoxybenzamine, and was reduced but not abolished by adrenalectomy.

Measurement of skin temperature, fractional extraction of 86Rb and blood flow in perfused mesentery gave no evidence that the anti‐inflammatory action of 401 was due to reduced tissue perfusion.

It is concluded that 401 may exert its anti‐inflammatory action directly by making the vascular endothelium anergic to phlogistic stimuli.
PHENYTOIN INHIBITION OF PARATHYROID HORMONE INDUCED BONE RESORPTION in vitro
Authors: HARRIS M. , JENKINS M.V. , WILLS M.R.
Published: July 2012

A study is reported of the effects of phenytoin and phenobarbitone on bone calcium mobilization by parathyroid hormone in vitro.

In a therapeutic concentration (15 μg/ml), phenytoin significantly inhibited parathyroid hormone‐induced calcium release from bone.

The inhibitory effect of phenytoin on bone calcium mobilization could play a role in the maintenance of hypocalcaemia in epileptic patients on long‐term anticonvulsant drug therapy.
EFFECTS OF THE MUSCARINIC AGONIST McN‐A‐343 ON THE RELEASE BY SYMPATHETIC NERVE STIMULATION OF [3H]‐NORADRENALINE FROM RABBIT ISOLATED EAR ARTERIES AND GUINEA‐PIG ATRIA
Authors: ALLEN G.S. , RAND M.J. , STORY D.F.
Published: July 2012

McN‐A‐343 (4‐(m‐chlorophenylcarbamoyloxy)‐2‐butynyltrimethylammonium chloride) in concentrations of 10−5 and 10−4 m inhibits the stimulation‐induced efflux of radioactivity from segments of rabbit ear artery that have previously been incubated with (–)‐[3H]‐noradrenaline, and also decreases the contractile response.

The inhibitory effects of McN‐A‐343 (10−5 m) on the efflux of radioactivity and the contractions induced by low frequencies of stimulation (2 and 5 Hz) are reversed by atropine, but atropine does not modify these effects with high frequencies of stimulation (20 and 50 Hz).

McN‐A‐343 (10−4 m) enhances the stimulation‐induced efflux of radioactivity from guinea‐pig atria that have previously been incubated with (–)‐[3H]‐noradrenaline, and prolongs the positive inotropic response. These effects are not modified by atropine.

It is concluded that McN‐A‐343 has different effects on adrenergic transmitter release in the two tissues. In the artery, it acts as an agonist on muscarinic receptors of adrenergic terminals to inhibit transmitter release at low frequencies of stimulation. In the atria it enhances transmitter efflux from the tissue, largely by inhibiting re‐uptake.
APOMORPHINE‐INDUCED AND PILOCARPINE‐INDUCED HYPOTHERMIA IN MICE: DRUG INTERACTIONS AND CHANGES IN DRUG SENSITIVITY AFTER CAUDATE NUCLEUS LESIONS
Authors: GLICK S.D. , MARSANICO R.G.
Published: July 2012

Apomorphine and pilocarpine each produced dose‐dependent hypothermic effects in mice. However, the dose‐response curve for pilocarpine was steeper than that for apomorphine.

Bilateral lesions of the caudate nucleus produced a permanent decrease in sensitivity to apomorphine but had no effect on sensitivity to pilocarpine.

Apomorphine and pilocarpine had synergistic effects; i.e. the hypothermic effect was greater following a combination of the drugs than following either drug alone.

The effect of apomorphine was antagonized by either haloperidol or scopolamine; only scopolamine antagonized the effect of pilocarpine.

These results suggest that a mechanism involving dopaminergic neurones in the caudate nucleus has a modulatory role in temperature regulation.