bluuebunny/crossref_metadata_2025 huggingface dataset:
Influence of pH on aggregation and protein binding of barbituric acid and amylobarbitone
Authors: MIKIKITS W. , SKINNER A. , SPECTOR R. G. , WATTS D. C.
Published: July 2012

Cryoscopic methods indicated that barbituric acid exists in aqueous solution as a monomer. Amylobarbitone is a monomer at pH 8, but appears to be polymerized at pH 2. The size of the oligomers increases with drug concentration.

Using a non‐equilibrium dialysis technique supportive evidence for the monomeric form of barbituric acid and the polymerization of amylobarbitone was obtained. The degree of polymerization appeared to increase with fall in pH. Binding constants for these barbiturates with bovine serum albumin were derived, but in acid media no binding was observed.
On the neuromuscular paralysis produced by procaine
Authors: HIRST G. D. S. , WOOD D. R.
Published: July 2012

The effects of procaine on neuromuscular transmission in the rat phrenic nerve diaphragm preparation have been examined using intracellular recording techniques.

The paralysis produced by procaine resembled that produced by tubocurarine and it is concluded that this effect of procaine results from a change in post‐junctional sensitivity to transmitter; at low rates of stimulation procaine did not depress the transmitter release.

During high frequency stimulation of the phrenic nerve a distinct form of prejunctional failure was observed. It is suggested that this depression results from a combination of local anaesthesia and anoxia and that it would explain reports of a reduction in the amount of transmitter released when assayed in a conventional manner.
Changes in the time course of transmitter action produced by procaine
Authors: HIRST G. D. S. , WOOD D. R.
Published: July 2012

In addition to reducing the sensitivity of the end‐plate to transmitter, procaine produced changes in the time course of the end‐plate potential. The time to peak potential was reduced by procaine, whether recording from fibres paralysed by tubocurarine or from fibres paralysed by high magnesium concentration. The rate of decay of potential was also markedly reduced. Similar observations were made recording spontaneous miniature end‐plate potentials.

Procaine did not produce any marked change in the electrical constants of muscle fibres.

In the presence of procaine the accumulation of charge at the end‐plate was prolonged; the rate of decay of charge was reduced. It is suggested that the prolonged end‐plate potentials arise from a prolongation of the end‐plate current.
Factors influencing the inhibitory action of anti‐inflammatory drugs on carrageenin induced oedema
Authors: GREEN ANN Y. , GREEN D. , MURRAY PATRICIA A. , WILSON A. B.
Published: July 2012

In a series of experiments carried out over 2½ years, the inflammatory response of the rat hind paw to injected carrageenin was relatively constant, but the anti‐inflammatory activity of phenylbutazone was subject to wide variation.

Phenylbutazone, aspirin and indomethacin were all well absorbed after oral administration, and the resultant plasma drug concentrations were closely similar to those produced when the drugs were administered intraperitoneally.

The anti‐inflammatory effect of the drugs on carrageenin oedema was variable and poorly correlated with log dose and plasma concentration.

There was a pronounced and linearly correlated increase in the anti‐inflammatory activity of phenylbutazone with increasing ambient temperature in the range 5–30° C.

Variations in relative humidity at constant temperature (20° C) did not influence the anti‐oedema potency of phenylbutazone.

For the precise evaluation of anti‐inflammatory activity in carrageenin oedema tests, it is concluded that accurate control of temperature is essential.
Effects of pethidine and nalorphine on the mechanical and electrical activities of mammalian isolated ventricular muscle
Authors: GRUNDY H. F. , TRITTHART H.
Published: July 2012

. The strength of the isometric mechanical contraction of electrically‐driven ventricular muscle has been recorded simultaneously with the resting and action potentials; the effects of pethidine and of nalorphine on these parameters have been studied.

. When lower concentrations of pethidine (0·22–6·5 μg/ml) were perfused, isometric peak tension was decreased in parallel with the maximum upstroke velocity of the action potential; these actions are considered to result from membrane stabilization. At higher concentrations (11·8–109 μg/ml) pethidine usually produced, in addition, a progressive decrease in the resting and action potentials associated with marked irregularities in, or even abolition of, the mechanical response. It is suggested that these effects of the higher doses might be due to a depression of ATPase activity in the myocardial membrane.

. Compared with pethidine, nalorphine had similar, but weaker, actions.
Blockade of the reticulospinal inhibitory pathway by nitrous oxide and tetrodotoxin
Authors: FRANK G. B. , OHTA M.
Published: July 2012

. The effects of nitrous oxide and tetrodotoxin were investigated on the reticulospinal inhibitory pathway in the acutely decerebrated cat.

. Both agents abolished the reticular inhibition of the segmental reflex potentials before they blocked either the segmental reflex potentials or the reticular facilitation of the reflex potentials.

. These results confirmed the hypothesis that preferential block of the reticulospinal inhibitory pathway might be an important neural mechanism of the excitement stage of anaesthesia.
On the role of central nervous system catecholamines and 5‐hydroxytryptamine in the nialamide‐induced behavioural syndrome
Authors: MODIGH K. , SVENSSON T. H.
Published: July 2012

. Intraperitoneal administration of nialamide, 200 mg/kg, to mice elicited a pronounced increase in motor activity and rectal temperature concomitant with a gradual increase in the concentrations of 5‐hydroxytryptamine (5‐HT), noradrenaline (NA) and dopamine in the brain.

. In mice treated with l‐tryptophan, 300 mg/kg, 1 h before nialamide, the increase in motor activity appeared earlier than after nialamide alone, and the hyperthermia was more pronounced. The increase in 5‐HT concentrations in the brain was more pronounced in these animals, whereas the concentrations of NA and dopamine were of the same magnitude as after nialamide alone.

. Treatment with p‐chlorophenylalanine methylester‐HCl (PCPA), 400 mg/kg, 24 h before nialamide partially antagonized the increase in motor activity and the accumulation of NA and dopamine was not significantly different from that observed after nialamide alone.

. Treatment with PCPA, 800 mg/kg, 72, 48 and 24 h before nialamide, completely antagonized the increase in motor activity and rectal temperature. The accumulation of brain 5‐HT was greatly depressed in these animals. The concentrations of dopamine 1, 3 and 6 h and the concentration of NA 6 h after the nialamide injection were significantly lower in the mice given PCPA 800 mg/kg × 3, than in the mice given nialamide alone.

. Administration of dl‐5‐hydroxytryptophan, 30 mg/kg, 1 h after the nialamide injection, to mice pretreated with PCPA, 800 mg/kg × 3, restored the increase in motor activity and rectal temperature.

. l‐Tryptophan, 300 mg/kg, given 1 h before nialamide to mice pretreated with PCPA, 800 mg/kg × 3, elicited a moderate increase in motor activity and a slight increase in the accumulation of 5‐HT in the brain when compared to that after PCPA, 800 mg/kg × 3, and nialamide.

. Administration of α‐methyltyrosine methylester, 200 mg/kg, 2 h before nialamide partially antagonized the increase in motor activity and completely antagonized the increase in rectal temperature elicited by nialamide alone. The accumulation of brain NA and dopamine was inhibited in these animals.

. It is concluded that the excitation in mice, elicited by nialamide, is mediated largely via brain 5‐HT, but that also the brain catecholamines seem to contribute to this effect.
Influence of age and of testosterone on the response of male rats to parachlorophenylalanine
Authors: BOND VALERIE J. , SHILLITO ELIZABETH E. , VOGT MARTHE
Published: July 2012

. Castrated male rats and male rats that had been castrated as well as adrenalectomized, showed hypersexual behaviour 24 h after treatment with parachlorophenylalanine (PCPA), as did intact rats.

. A dose of PCPA 100 mg/kg was sufficient to induce mounting behaviour; this dose lowered the cerebral 5‐hydroxytryptamine (5‐HT) to about 50% in 24 h and further to 40% in 72 hours.

. Groups of juvenile male rats treated chronically with PCPA 100 mg/kg or 50 mg/kg, or with testosterone propionate 1·25 mg, showed hair loss after three weeks of treatment (6 injections), because of increased social interaction.

. Groups of intact male rats 9–11 weeks old given testosterone propionate 1·25 mg subcutaneously, showed mounting behaviour 3–5 h after the injection which was indistinguishable from the behaviour seen 24 h after treatment with PCPA 100 mg/kg. The 5‐HT content of the brain was not altered by testosterone.

. The number of rats which showed mounting after PCPA treatment did not change with age, but the younger rats made more mounts in the observation time than rats more than three months old.

. The age of castration (3 weeks or 4 months) did not influence the results.
Analysis of the mechanism of action of some ganglion‐blocking drugs in the rabbit superior cervical ganglion
Authors: LEES G. M. , NISHI S.
Published: July 2012

. Mechanisms of action of hexamethonium, mecamylamine and (+)‐tubocurarine on the rabbit superior cervical ganglion were investigated by intracellular recording techniques.

. In concentrations up to 1 mm, none of these drugs affected the resting membrane potential nor altered the excitability of the postganglionic neurone to direct or antidromic stimulation.

. Post‐tetanic potentiation of the excitatory postsynaptic potential (e.p.s.p.) was inhibited by mecamylamine (10–100 μm) but not affected by either hexamethonium (5–100 μm) or (+)‐tubocurarine (10–50 μm).

. The decline in amplitude of successive e.p.s.ps in a train (40 Hz) was not influenced by hexamethonium or (+)‐tubocurarine but was greatly exaggerated in the presence of mecamylamine; desensitization of the receptors for acetylcholine was excluded as a possible explanation for this latter finding.

. Mecamylamine depressed the quantal content of e.p.s.ps in a train, with the exception of the first e.p.s.p. which had an increased quantal content.

. Reduction in quantal content was attributed to a substantial fall in the size of the store of quanta of transmitter immediately available for release and to a reduction in the rate of mobilization of acetylcholine into that store; mecamylamine also caused a simultaneous increase in the fractional release.

. Hexamethonium and (+)‐tubocurarine had no effect on transmitter release.

. The time‐course of presynaptic effects of mecamylamine was similar to the duration of its postsynaptic blocking action.

. It is concluded that inhibition of ganglionic transmission by mecamylamine is due to both presynaptic and postsynaptic inhibitory actions; in contrast, hexamethonium and (+)‐tubocurarine reduce transmission solely by their postsynaptic actions.
Inhibitory and stimulatory effects of secretin on gastric secretion in conscious rats
Authors: JOHANSSON IRENE , LUNDELL L. , SVENSSON S. E.
Published: July 2012

. The effect of pure secretin on gastrin‐induced secretion has been studied in conscious rats with Pavlov or Heidenhain pouches.

. Rapid intravenous injection of secretin did not inhibit a plateau secretion of acid in the Heidenhain pouch, but infusion of the same amount of secretin over two hours inhibited secretion in both Heidenhain and Pavlov pouches.

. A rapid intravenous injection of secretin before the onset of gastrin infusion enhanced the acid secretory response to gastrin in both types of pouches.

. Secretin stimulated pepsin secretion.
Effect of etorphine, morphine and diprenorphine on neurones of the cerebral cortex and spinal cord of the rat
Authors: BISCOE T. J. , DUGGAN A. W. , LODGE D.
Published: July 2012

. The actions of etorphine, morphine and diprenorphine were investigated on neurones of the cerebral cortex and spinal cord of rats anaesthetized with pentobarbitone.

. In the cerebral cortex, intravenous etorphine increased the latency of the primary evoked response to a peripheral nerve stimulus and suppressed the rhythmical after‐discharge. Diprenorphine reversed this effect. These actions were demonstrated on both field potentials and unit firing.

. Morphine had no effect on the primary response but the frequency of after‐discharge bursts was reduced and there was an increase in firing between bursts.

. In the cerebral cortex, electrophoretically applied etorphine reduced after‐discharges when applied for long periods but had no effect on the depressant actions of glycine and γ‐aminobutyric acid (GABA) nor on the excitant action of acetylcholine and l‐glutamate. Similarly there was no alteration by etorphine of the effects of glycine, GABA and l‐glutamate on spinal cord neurones.

. It is concluded that etorphine may act pre‐synaptically in the cerebral cortex.
The nature of adrenergic mechanisms involved in anaphylatoxin activity in the guinea‐pig
Authors: HICKS R. , SACKEYFIO A. C.
Published: July 2012

. Evidence is presented to elucidate the nature of the adrenergic mechanisms involved in responses of the guinea‐pig to anaphylatoxin (AT).

. Investigation by means of adrenalectomy, adrenergic neurone blockade, α‐ and β‐ adrenoceptor blockade and exclusion of autonomic reflexes, revealed that the adrenergic mechanisms provoked included catecholamine release from the adrenal medulla, sympathetic reflex activity, stimulation of adrenergic neurones and α‐ and β‐adrenoceptor activity.

. The cardiovascular effects of AT, mediated by histamine release, were largely attributable to adrenal medullary and adrenergic neuronal mechanisms. These mechanisms also exerted a restraint on the predominantly histamine mediated bronchoconstrictor effect of AT.

. The cardiovascular effects of AT activity, not attributable to histamine release, were also probably associated with catecholamine release. However, the bronchoconstrictor component of this AT activity was not significantly affected by guanethidine, and it would, therefore, appear that neuronal bronchodilator mechanisms did not exert a restraint upon this aspect of AT activity.

. These findings are generally compatible with previous work showing that adrenergic mechanisms operate during AT‐induced responses. In contrast to previous reports, however, the adrenergic activity was predominantly associated with the effects of released histamine.
Histamine formation from 14C‐l‐histidine in man
Authors: BERG B. , GRANERUS G. , JOHANSSON MAJ‐BRITT , WESTLING H. , WHITE T.
Published: July 2012

. 14C‐l‐histidine was given i.v. to one normal subject and two patients with chronic myelocytic leukaemia. Urinary excretion of histamine and two of its metabolites methylhistamine and methylimidazoleacetic acid, total as well as 14C‐labelled, was measured, as well as blood 14C‐histamine. In addition the total urinary and pulmonary elimination of 14C was followed.

. Total 14C elimination was high during the first days, then declined slowly except for a plateau at the 10th–14th day in the two patients. There was a measurable elimination even after some months.

. 14C‐histamine appeared in the blood of the leukaemic patient, whereas in the normal subjects the values were hardly measurable.

. The leukaemic patients excreted much more of the two 14C‐labelled histamine metabolites than the normal subject. The difference in excretion of the 14C‐labelled metabolites was largest around the 12th day after the infusion of 14C‐l‐histidine.

. The results indicate that the leukaemic patients formed at least 20 times more histamine daily than the normal subject.
Effect on reproductive organs of three clomiphene analogues
Authors: BASU J.
Published: July 2012

. The oestrogenic properties of four triphenylethylene compounds were compared. They can be listed as follows in order of their oestrogenic potency: 1‐[p‐(β‐diethylaminoethoxy)‐phenyl]‐2‐nitro‐1,2‐diphenylethylene (E.I.P.W. 111) > clomiphene > 1‐[p‐(β‐dimethylaminoethoxy)‐phenyl]‐2‐nitro‐1,2‐diphenylethylene (E.I.P.W. 113)>1‐[p‐(β‐diethylaminoethoxy)‐phenyl]‐1,2‐diphenylethylene (E.I.P.W. 103). The oestrogenic potency of compound E.I.P.W. 111 was found to be about 1/10th of that of oestradiol.

. Compound E.I.P.W. 111 is partially antioestrogenic but not progesteronic in nature. It has no androgenic effect.
The cardiovascular actions of WR‐149,024 (1,18‐diamino‐7,13‐diaza‐9,10‐dithiaoctadecane tetrahydrochloride)
Authors: CALDWELL R. W. , HEIFFER M. H. , HERMAN E. H.
Published: July 2012

. The general cardiovascular properties of WR‐149,024 (a straight chain sulphur‐containing aliphatic amine) in dogs and cats are reported.

. Intravenous administration of this compound produced an immediate hypotension and bradycardia in intact anaesthetized dogs. These effects were independent of the parasympathetic nervous system since they were also present in atropinized and bilaterally vagotomized dogs.

. Ascending aortic blood flow increased after administration of WR‐149,024 despite a reduction in blood pressure, contractile force and heart rate. It appears that the initial hypotension is due to a decrease in total peripheral vascular resistance since WR‐149,024 produced relatively little change in force of contraction or heart rate in the isolated, blood‐perfused heart preparation.

. WR‐149,024 reversed the pressor effects of adrenaline within 10 min of injection while at the same time the vasopressor response to angiotensin or the vasodepressor response to isoprenaline was not altered. α‐Adrenoceptor blockade was still evident up to five days after dosing.

. WR‐149,024 did not block phenylephrine inhibition of intestinal motility. These findings suggest that WR‐149,024 initiates a relatively specific and prolonged α‐adrenoceptor blockade.
Effect of chronic drug treatment on intestinal membrane transport of 14C‐l‐DOPA
Authors: RIVERA‐CALIMLIM LEONOR
Published: July 2012

. By the use of the everted jejunal sac it was shown that chronic oral treatment of rats with various drugs can either increase or decrease the mucosal transport of 14C‐l‐DOPA or alter its serosal/tissue ratio.

. 14C‐l‐DOPA transport was significantly increased in rats that were chronically treated with l‐DOPA and diminished in those that were treated with chlorpromazine and phenobarbitone.

. Chronic treatment with amantadine and neomycin did not affect 14C‐l‐DOPA intestinal transport, although direct addition of amantadine to the medium, significantly increased 14C‐l‐DOPA transport in everted sacs of non‐treated rats. Addition of neomycin directly to the medium did not affect 14C‐l‐DOPA transport.

. The possible mechanisms of these findings and their clinical significance are discussed.
Effects of gamma‐hydroxybutyrate on chick behaviour, electrocortical activity and crossed extensor reflexes
Authors: OSUIDE GABRIEL
Published: July 2012

Convulsant and anticonvulsant effects of gamma‐hydroxybutyrate (GHB) have been studied in chicks.

When administered alone, GHB produced weak myoclonic seizures accompanied by electrocortical synchrony and spikes.

GHB was found to protect chicks against leptazol‐ and picrotoxin‐induced seizures. A slight potentiation of strychnine‐induced seizures was evident.
Central cholinergic and adrenergic mechanisms in the release of antidiuretic hormone
Authors: BHARGAVA K. P. , KULSHRESTHA V. K. , SRIVASTAVA Y. P.
Published: July 2012

Studies on the urine outflow, blood ADH concentration and electrolyte excretion were carried out in α‐chloralose anaesthetized hydrated dogs; the agonists and antagonists of specific cholinoceptors and adrenoceptors were injected by the intracerebroventricular technique, to delineate the role of the C.N.S. receptors in the control of ADH secretion.

Central injection of acetylcholine elicited a dose‐dependent antidiuretic response which was associated with an increase in the blood ADH titre. Central atropinization partially blocked the antidiuretic response. The remaining antidiuretic response was reversed to a diuretic one by further pretreatment with phenoxybenzamine. The diuretic response thus obtained could be blocked by propranolol.

The α‐adrenoceptor agonists, phenylephrine and noradrenaline, induced dose‐dependent antidiuretic responses with a concomitant rise in blood ADH concentration. Their effect could be blocked by pretreatment centrally with phenoxybenzamine. Low doses of adrenaline induced a diuretic response and a decrease in blood ADH concentration, higher doses elicited a dose‐dependent antidiuretic response and increase in the titre of ADH in blood. Central phenoxybenzamine pretreatment reversed the antidiuretic effect of high doses of adrenaline to a diuretic effect which could be blocked by propranolol.

Isoprenaline elicited a dose‐dependent diuretic response and a decrease in blood ADH titre and propranolol competitively blocked the effect of isoprenaline.

It is concluded that central muscarinic cholinoceptors and the α‐adrenoceptors are concerned in the release of ADH, whereas the β‐adrenoceptors are concerned with inhibition of ADH release.
The actions of prostaglandins E1 and F2α on the perfused vessels of the isolated rabbit ear
Authors: TAI SUHAILA A. AL , GRAHAM J. D. P.
Published: July 2012

In the isolated rabbit ear vascular bed, perfused with Krebs solution, prostaglandins E1 and F2α produce dose‐dependent, phentolamine‐sensitive constrictions.

These are absent if the animal is pre‐treated with reserpine or if the ear is denervated in advance.

If noradrenaline or vasopressin is added to the Krebs solution, vascular resistance is high and PGE1 and PGF2α produce vasodilatation which is unaffected by hyoscine or propranolol.

Perfusion with theophylline, with added ATP, ADP or 3′5′‐AMP, or pre‐treatment of the animal with stilboestrol antagonizes the dilator response to PGE1 in the presence of noradrenaline, which may be reversed. Most of the responses to PGF2α are reversed. These treatments elevate the level of 3′5′‐AMP in tissues.

It is postulated that prostaglandins exert a regulatory action on 3′5′‐AMP levels through inhibition of adenyl cyclase and/or phosphodiesterase and that the resulting rising or falling level of 3′5′‐AMP determines the nature of the response by the smooth muscle to the released noradrenaline.
The effect of 2,4‐dinitrophenol on electrical and mechanical activity, metabolism and ion movements in guinea‐pig ventricular muscle
Authors: McDONALD T. F. , MacLEOD D. P.
Published: July 2012

DNP (2,4‐dinitrophenol) reduced the duration of the action potential of guinea‐pig ventricular muscle at a greater rate than did anoxia. The effect was dose‐dependent and was modified by the concentration of glucose in the medium. DNP (0·1 mm) reduced the amplitude of the action potential of muscles incubated with 5 mm glucose; on raising the glucose concentration to 50 mm the effect was reversed.

A large dose‐dependent loss of K+ occurred within 15 min of incubation with DNP and was attributed to increased efflux. K+ loss was not related to Na+ gain during the first 60 min of incubation; during the first 30 min DNP‐treated muscle did not gain any Na+. Although the shortening of the action potential by DNP during aerobic incubation was similar to that of muscles incubated under anaerobic conditions in glucose‐free medium, the anaerobic incubation was not associated with increased 42K efflux.

It was concluded that the reduction in duration of the action potential was not necessarily the result of an increased K+ efflux. The effect of DNP on 42K efflux is considered to result from a direct effect on the cell membrane; the effect on electrical activity may be a combination of the increase in K+ efflux and a reduction in the inward current due to Na+ and Ca++ previously assumed to be dependent on the glycolytic production of ATP.

Electrogenic Na+ pumping may contribute to the maintenance of resting potential in K+‐depleted, DNP‐treated cardiac muscle.
The effect of dehydroemetine on isolated guinea‐pig atria
Authors: DUROTOYE A. O. , SALAKO L. A.
Published: July 2012

The mechanism of the inhibitory effect of dehydroemetine on the heart was investigated using spontaneously contracting isolated guinea‐pig atria.

In normal Locke solution, dehydroemetine caused a reduction in the rate and amplitude of contraction of the atria. The effect was antagonized by adrenaline and augmented by acetylcholine.

Increasing the potassium concentration of the bathing medium increased the inhibitory effect of dehydroemetine on the atria, while decreasing the potassium concentration antagonized the effect of dehydroemetine.

The character of the inhibitory effect of dehydroemetine on the atria altered when the sodium concentration of the bathing solution was lowered to 75·6 mmol. In the normal sodium medium arrest of beat by dehydroemetine was gradual; in the low sodium medium, it was abrupt.

In the low, as in the normal sodium medium, the inhibitory effect of dehydroemetine was more marked the higher the potassium concentration of the bathing medium.

In both standard Locke solution and Locke solution containing 75·6 mmol sodium, the effect of dehydroemetine closely mimicked that obtained by adding excess potassium to the solution.

On the basis of the foregoing it was suggested that dehydroemetine acts by increasing the permeability of the myocardial cell membrane to potassium thereby leading to the accumulation of potassium in the extracellular space.
Studies of the interaction of 5‐hydroxytryptamine and the perivascular innervation of the guinea‐pig caecum
Authors: DRAKONTIDES ANNA B. , GERSHON MICHAEL D.
Published: July 2012

The action and interaction of noradrenaline (NA), 5‐hydroxytryptamine (5‐HT) and the sympathetic innervation was studied in the isolated taenia of the guinea‐pig caecum.

Addition of 5‐HT led to a contraction of the taenia while addition of NA or perivascular nerve stimulation resulted in relaxation. Responses to 5‐HT or perivascular nerve stimulation were abolished by tetrodotoxin. Tetrodotoxin did not affect responses to applied NA. Hexamethonium and hyoscine converted the 5‐HT response to a relaxation and augmented the relaxation which followed low frequency perivascular nerve stimulation. Hexamethonium and hyoscine did not affect the dose‐response relationship for NA.

Fatigue of mechanical responses of the taenia to perivascular nerve stimulation was accelerated when nerves were stimulated in the presence of 5‐HT or α‐methyl‐p‐tyrosine (α‐MPT). These two agents were additive in this action.

Reserpine, 6‐hydroxydopamine and α‐MPT all reduced the NA content of the taenia. However, only after 6‐hydroxydopamine could adrenergic activity be related to NA content.

Segments of taenia were incubated with either tritiated NA or 5‐HT. An increased rate of release of radioactivity followed perivascular nerve stimulation after incubation with either substance. This release did not occur when tissue was taken from animals given reserpine or 6‐hydroxydopamine.

It is concluded that 5‐HT activates neural elements exclusively while NA has a direct effect on smooth muscle. 5‐HT can apparently be taken up by adrenergic axons, and appears to enter the releasable neurotransmitter pool. Since none of the actions characteristic of 5‐HT are seen when it is released by adrenergic axons as a false neurotransmitter, the released amine probably fails to reach neuronal receptors for 5‐HT.
Effect of glucocorticoids on histamine metabolism in mice
Authors: REILLY MARGARET A. , SCHAYER R. W.
Published: July 2012

Histamine formation and catabolism were studied in vivo in standardized experiments; for the former, animals pretreated with inhibitors of histamine catabolism were killed 10 min after intravenous injection of 14C‐L‐histidine; for the latter, no inhibitors were used and animals were killed 2·5 min after intravenous injection of 14C‐histamine. In vitro assays of histidine decarboxylase activity were also made.

Pretreatment of adrenalectomized mice with cortisol for one day caused a major alteration in histamine formation; stomach and intestine were abnormally high in the 14C‐histamine: total 14C ratio, while most other tested tissues were lower. Brain and thymus were unaffected. Cortisol treatment caused a marked increase in urinary excretion of both 14C‐histamine and total 14C.

Following injection of a rapidly absorbed corticoid, significant effects on urine and stomach were demonstrable at 30 min and 4 h, respectively.

In cortisol‐treated adrenalectomized mice histidine decarboxylase activity, relative to controls, was decreased in lung but virtually unaffected in kidney, heart, muscle and liver. In stomach, activity was increased but the statistical significance was low.

In mice injected with 14C‐histamine, cortisol pretreatment caused a small drop in tissue levels of 14C‐histamine, 14C‐methylhistamine and total 14C, but increased levels in urine. In all cases, however, the ratio of the two amines to total 14C was not significantly different from controls.

From the foregoing experiments it was concluded that the results in (2) could be largely attributed to entry into urine of 14C‐histamine and total 14C, thus reducing the availability of these substances in blood for extraction by tissues. In stomach, the cortisol‐induced increase in histamine formation may involve some process other than increased histidine decarboxylase activity.

The activation of histidine decarboxylase in liver and lung of intact mice by Freund's adjuvant, or by endotoxin, was reduced by corticoid treatment.

In a single short experiment on the effect of cortisol on histamine formation in adrenalectomized rats, results from stomach, lung and heart, the only tissues assayed, were similar to those from the mouse experiment.
A comparison of the pharmacological and biochemical properties of substrate‐selective monoamine oxidase inhibitors
Authors: CHRISTMAS A. J. , COULSON C. J. , MAXWELL D. R. , RIDDELL D.
Published: July 2012

M&B 9302, E‐250, NSD 2023, and Lilly 51641, substrate‐selective inhibitors of monoamine oxidase (MAO), and two non‐selective inhibitors of MAO (tranylcypromine and phenelzine) have been compared in the rat for activity in (i) inhibiting rat brain monoamine oxidase in vitro and in vivo using tyramine, 5‐hydroxytryptamine (5‐HT) and benzylamine as substrates; (ii) increasing brain levels of noradrenaline (NA) and 5‐HT and (iii) antagonizing tetrabenazine‐induced sedation.

Concentrations of M&B 9302 and Lilly 51641 required to produce 50% inhibition of 5‐HT oxidation by brain mitochondrial MAO were 1·4 × 10−8M and 2·5 × 10−7M respectively. Higher concentrations were required to inhibit tyramine oxidation whilst benzylamine oxidation was inhibited only at concentrations above 10−5M.

E‐250 showed the reverse substrate‐selectivity in inhibiting the oxidation of benzylamine at concentrations below that required to inhibit the oxidation of 5‐HT. NSD 2023 showed little substrate selectivity in vitro.

Qualitatively similar results were obtained in vivo, except that NSD 2023 showed more marked substrate‐selectivity.

All the inhibitors except E‐250 produced a dose‐related rise in brain 5‐HT levels. Only phenelzine and Lilly 51641 showed a linear relationship between NA levels and dose.

All the drugs antagonized, in dose‐related fashion, the effects of tetrabenazine in reducing locomotor activity. E‐250 and NSD 2023 failed to restore locomotor activity to control levels whilst in high doses the other inhibitors, when given before tetrabenazine, produced a considerable increase in locomotor activity.

Antagonism of tetrabenazine sedation appears to be correlated with (a) inhibition of the enzyme species that oxidize 5‐HT and NA but not with inhibition of the enzyme species that oxidize benzylamine; (b) the rise in brain 5‐HT levels rather than NA levels.
A structure‐activity study of sympathomimetic amines on the beta‐adrenoceptors of guinea‐pig trachea
Authors: CHAHL LORIS A.
Published: July 2012

The relative activities of a large number of sympathomimetic amines were estimated on the β‐adrenoceptors of the guinea‐pig tracheal chain preparation. Concentrations which produced half‐maximal responses were measured for each drug and the maximum responses were also noted and expressed as a percentage of that produced by isoprenaline.

The relative activities of the amines generally decrease with loss of hydroxyl groups from the structure, and amines with less than two hydroxyl groups produce little or no observable response.

The affinity constants of the partial agonists and antagonists were measured. The hydroxyl group on the β carbon atom of the side chain, N‐alkyl groups and an α carbon methyl group increase affinity, whereas the p‐phenolic group decreases affinity. The m‐phenolic group does not seem to affect affinity.

By comparing the effects of groups on affinity with their effects on activity, it was deduced that N‐alkyl groups, m‐ and p‐phenolic groups and probably also the β carbon hydroxyl group increase efficacy. Alpha carbon methylation appears to reduce efficacy.
Amphetamine and conditioned ‘anxiety’
Authors: CAPPELL HOWARD , GINSBERG RONALD , WEBSTER C. D.
Published: July 2012

Rats pressed a bar for milk reward at a steady rate, but this baseline responding was suppressed in the presence of an auditory stimulus associated with electric shock (conditioned suppression). The effects of (+)‐amphetamine sulphate on this conditioned suppression were studied in two experiments.

(+)‐Amphetamine sulphate (0·5, 1·0 or 2·0 mg/kg) reduced the baseline rate of responding and also reduced the conditioned suppression, i.e. responding in the presence of the auditory stimulus was partially restored. Both these effects were dose related.

In a further experiment the effects of 1·0 mg/kg on two levels of conditioned suppression were studied. Regardless of its degree, (+)‐amphetamine attenuated suppression.

The results were compared to previous research which found that amphetamine increased baseline responding and exaggerated conditioned suppression. It was concluded that the conditioned suppression procedure should be used with caution as an animal model of anxiety in psychopharmacological investigations.
An analysis of central adrenoceptors for control of cardiovascular function
Authors: BHARGAVA K. P. , MISHRA N. , TANGRI K. K.
Published: July 2012

In dogs anaesthetized with pentobarbitone sodium, bradycardia with hypotension occurred on intracerebroventricular (i.c.v.) injection of noradrenaline (50–200 μg) or phenylephrine (100–400 μg), but tachycardia with hypotension occurred on i.c.v. injection of isoprenaline (100–200 μg).

These cardiovascular responses were central effects, and from the results obtained after bilateral vagotomy, removal of both stellate ganglia and transection of the upper cervical cord, it was evident that the efferent nervous pathway for all these effects was the sympathetic nervous system.

An i.c.v. injection of the α‐adrenoceptor blocking agent phenoxybenzamine (10 mg) blocked the bradycardia and hypotension produced by noradrenaline or phenylephrine, and an i.c.v. injection of a β‐adrenoceptor blocking agent, either propranolol (2 mg) or N‐isopropyl‐p‐nitrophenyl‐ethanolamine (INPEA) (10 mg), blocked the tachycardia and hypotension produced by isoprenaline.

The cardiovascular effects produced by i.c.v. injection of the three sympathomimetic amines could be reproduced in cross‐circulation experiments in the recipient dog when the amines were injected into its head circulation, and the effects of noradrenaline and phenylephrine, but not those of isoprenaline, were abolished by the α‐adrenoceptor blocking agent yohimbine (1 mg/kg) injected intravenously into the donor dog.

It is concluded that the central α‐adrenoceptors are concerned with bradycardia and the central β‐adrenoceptors with tachycardia, but that both receptors are concerned with hypotension.
Effects of perivascular nerve stimulation on the contraction and automaticity of the blood‐perfused canine papillary muscle
Authors: ENDOH M. , HASHIMOTO K. , KIMURA T.
Published: July 2012

Effects of ventricular perivascular nerve stimulation (p.n.s.) on the ventricular contractility and idioventricular rate were investigated with the blood‐perfused papillary muscle of the canine right ventricle.

Perivascular nerve stimulation of supramaximal voltage and 1 msec pulse‐duration caused a definite positive inotropic response at a frequency of 1 Hz, which gradually reached a maximum at 15 to 20 Hz when the papillary muscle was electrically driven at 120 beats/min at a constant temperature of 38–39° C. The frequency—response curve was sigmoid.

The spontaneous regular idioventricular rate of 46 ± 4 beats/min was accelerated to at most 60 ± 4 beats/min (n = 11) by p.n.s. The stimulus frequency—response relations between chronotropic and inotropic responses to p.n.s. were almost the same.

Tetrodotoxin blocked completely the responses to p.n.s. while it had little or no effect on the inotropic response to exogenous noradrenaline.

Positive inotropic responses to p.n.s. were diminished by β‐adrenoceptor blocking agents (alprenolol, propranolol and pindolol) and were enhanced during infusion of cocaine.

In reserpine‐ or guanethidine‐pretreated muscles, p.n.s. as well as field stimulation produced negative inotropic responses, which were enhanced by physostigmine and were blocked by atropine.

Hexamethonium enhanced slightly the positive inotropic responses to p.n.s. as well as field stimulation.

It was concluded that the perivascular nerves of the coronary artery of the canine ventricle are mainly composed of postganglionic adrenergic fibres but there are also pre‐ and postganglionic cholinergic nerve fibres.
Effects of several muscarinic agonists on cardiac performance and the release of noradrenaline from sympathetic nerves of the perfused rabbit heart
Authors: FOZARD J. R. , MUSCHOLL E.
Published: July 2012

The effects of several muscarinic agonists on atrial tension development, ventricular rate and noradrenaline release from terminal sympathetic fibres evoked by electrical nerve stimulation (SNS) and 1,1‐dimethyl‐4‐phenylpiperazinium (DMPP) were measured in isolated perfused rabbit hearts.

Hexamethonium, in a concentration which almost abolished the release of noradrenaline by DMPP, had no effect on the release produced by SNS, confirming that the stimulation was postganglionic.

The order of potency for inhibition of atrial tension development was N‐methyl‐1,2,5,6, tetrahydro‐nicotinic acid prop‐2‐yne ester (MH‐1)>oxotremorine > acetylcholine > methacholine > carbachol > furtrethonium > pilocarpine>4‐(m‐chlorophenylcarbamoyloxy)‐2‐butynyltrimethylammonium chloride (McN‐A‐343)>N‐benzyl‐3‐pyrrolidyl acetate methobromide (AHR 602). All effects were abolished by atropine (1·4 × 10−6M).

Each compound was more potent relative to acetylcholine in inhibiting ventricular rate than atrial tension. With the exception of carbachol, the order of potency was the same.

Both AHR 602 and McN‐A‐343 facilitated the release of noradrenaline by SNS and inhibited that by DMPP. The effects were atropine‐resistant and hence non‐muscarinic.

The muscarinic compounds (except AHR 602 and McN‐A‐343) each produce atropine‐sensitive inhibition of noradrenaline release evoked both by SNS and DMPP although it is likely that furtrethonium and pilocarpine have additional non‐muscarinic inhibitory activity against DMPP. The order of potency on both parameters and the potencies relative to acetylcholine were in good agreement with those for inhibition of atrial tension.

The results suggest that similar muscarinic receptors mediate inhibition of atrial tension development, ventricular rate and neuronal noradrenaline release caused by SNS and DMPP.

In terms of the two muscarinic sites known to be present in the superior cervical ganglion, the receptors of the terminal fibres mediating inhibition of noradrenaline release are more likely to correspond to those mediating hyper‐polarization than to those mediating depolarization, for which AHR 602 and McN‐A‐343 show specificity.
Apparent differences between the effects of hyoscine in vivo and in vitro on the responses of chicken oesophagus to nerve stimulation
Authors: BARTLET A. L.
Published: July 2012

In chickens anaesthetized with sodium pentobarbitone, stimulation of a vagus nerve produced contractions in the muscles in the pre‐crop oesophagus which were only partly antagonized by hyoscine.

The effect of hyoscine in an isolated preparation of chicken oesophagus responding to nerve stimulation was shown previously to be similar to that now found in the in vivo preparation.
The effects of indomethacin on calcium, sodium, potassium and magnesium fluxes in various tissues of the guinea‐pig
Authors: NORTHOVER B. J.
Published: July 2012

Isolated tissues of the guinea‐pig were bathed with Krebs solution at 37° C and subjected to 100 ms pulses of electrical stimulation for 30 min at a frequency of 0·1 or 1·0 Hz. The tissues were then dried, ashed, and the ash analysed for calcium, sodium, potassium and magnesium.

Gastric smooth muscle, cardiac and skeletal muscles and brain all showed a gain of sodium and calcium and a loss of potassium in response to electrical stimulation, but there was no significant change in the magnesium content of any of these tissues.

Indomethacin (0·5 mm) reduced the calcium content of unstimulated gastric smooth muscle and reduced the gain of calcium and sodium in response to electrical stimulation, but slightly increased the net loss of potassium in response to electrical stimulation.

Gastric smooth muscle which had gained calcium as a result of electrical stimulation, gradually lost it again when stimulation ceased. Indomethacin (0·5 mm) hastened the net loss of calcium from previously stimulated muscle.

Indomethacin (0·5 mm) failed to alter the calcium, sodium, potassium and magnesium contents of unstimulated cardiac muscle, skeletal muscle and brain. In these tissues indomethacin (0·5 mm) also failed to prevent the changes in the content of these minerals which occurred in response to electrical stimulation.
A study of clofazimine in the rat
Authors: CURREY H. L. F. , FOWLER P. D.
Published: July 2012

Clofazimine, an anti‐mycobacterial agent used in the treatment of leprosy, has been reported to be particularly effective in the treatment of acute erythema nodosum leprosum reactions.

The present experiments were designed to study in the rat this apparent anti‐inflammatory activity.

In doses relatively non‐toxic to the animals clofazimine inhibited both rat adjuvant arthritis and the inflammatory paw swelling following an adjuvant injection.

Clofamizine failed to inhibit both the primary antibody response to sheep erythrocytes and the tuberculin skin response.

It is concluded that clofazimine exhibits definite anti‐inflammatory (but not immunosuppressive) activity, and that it should be tested in patients with rheumatoid arthritis.
Pharmacological actions of a new β‐adrenoceptor agonist, MJ‐9184–1, in anaesthetized cats
Authors: GWEE M. C. E. , NOTT M. W. , RAPER C. , RODGER I. W.
Published: July 2012

The effects of (–)‐isoprenaline and the new β‐adrenoceptor agonist, MJ‐9184–1, on the lungs, on the cardiovascular system, and on slow contracting skeletal muscle have been compared in cats under chloralose anaesthesia.

Both amines reduced the increases in airways resistance produced by 5‐HT, depressed incomplete tetanic contractions of the soleus muscle, lowered the blood pressure and produced an increase in heart rate. In comparison with (‐)‐isoprenaline, MJ‐9184–1 had a long duration of action.

The effects of MJ‐9184–1 and (–)‐isoprenaline were antagonized by the β‐adrenoceptor antagonist, propranolol.

MJ‐9184–1 was approximately half as potent as (–)‐isoprenaline in its effects on pulmonary resistance and soleus muscle contractility, and one seventh as potent in producing chronotropic effects in the heart.

These results suggest that MJ‐9184–1 possesses some specificity as a β2 receptor stimulant.
The effect of sodium γ‐hydroxybutyrate on the metabolism of dopamine in the brain
Authors: HUTCHINS D. A. , RAYEVSKY K. S. , SHARMAN D. F.
Published: July 2012

Sodium gamma hydroxybutyrate (GHB‐Na), when given to rats and mice, caused a sleep‐like state and a fall in body temperature of about 10° C.

GHB‐Na produced a dose‐dependent increase in the concentration of dopamine (DA) in the brains of mice kept at an environmental temperature of 18–20° C or 30–32° C.

The concentrations of 3,4‐dihydroxyphenylacetic acid (DOPAC) and 4‐hydroxy‐3‐methoxyphenylacetic acid (HVA), the metabolites of DA, were increased in the striatal tissues of rats and mice, after the administration of GHB‐Na. However there was a delay of 60 min before the concentration of HVA increased whereas there appeared to be little delay before the concentration of DOPAC increased.

When GHB‐Na was administered to reserpine‐treated animals, no increase occurred in the concentration of dopamine in the brains of mice or rats, or of DOPAC in the rat brain.

Reserpine did not prevent the induction of the sleep‐like state by GHB‐Na.

The results presented suggest that the effect of GHB‐Na in increasing the concentration of DA requires unimpaired storage mechanisms for the amine.
Effects of some centrally acting drugs on acetylcholine synthesis by rat cerebral cortex slices
Authors: SHARKAWI M.
Published: July 2012

Brain cortex slices from rats injected i.p. with urethane (1 g/kg), chloral hydrate (350 mg/kg) or physostigmine (0·75 mg/kg) were examined for acetylcholine (ACh) content, cholinesterase (total enzyme) activity and formation of 14C‐ACh from carbon 14‐uniformly labelled glucose (U‐14C‐d‐glucose) in the presence of 0·01 mm physostigmine.

Slices from rats treated with urethane, chloral hydrate, or physostigmine contained significantly higher concentrations of ACh than slices from untreated animals.

Only slices from physostigmine‐treated rats had a significantly lower cholinesterase activity.

Slices from urethane‐ or chloral hydrate‐treated animals formed significantly less 14C‐ACh than slices from untreated or physostigmine‐treated rats when incubated in 4 mm K+ medium. In an ACh‐releasing medium (31 mm K+) slices from rats treated with urethane or chloral hydrate and slices from untreated rats formed similar amounts of 14C‐ACh.

Slices from rats treated with atropine (25 mg/kg) or pentylenetetrazol (75 mg/kg) had a similar ability to form 14C‐ACh as slices from untreated animals when incubated in either 4 or 31 mm K+ medium.

These findings suggest that the intraneuronal ACh concentration is a limiting factor in the regulation of ACh synthesis.
The mechanism of the facilitatory action of edrophonium in cat skeletal muscle
Authors: BLABER L. C.
Published: July 2012

The effects of edrophonium have been observed in the transversely cut tenuissimus muscle of the cat.

Concentrations of edrophonium 10−7M to 10−5M increased the amplitude of the end‐plate potential (e.p.p.) but produced no greater increase in time course than previously observed in curarized muscle.

When the e.p.p. and gross nerve action potential were recorded simultaneously, antidromic discharges were observed in the motor nerve concomitantly with repetitive e.p.ps in the presence of edrophonium.

Edrophonium produced no effect on the input resistance or equilibrium potential of the end‐plate.

The fractional release of transmitter was significantly increased by edrophonium but there was no increase in the quantal release of transmitter in the transversely cut muscle preparation.

In curarized muscle edrophonium also increased the quantal release, the size of the available store of transmitter and the rate of refilling of the available store.

It is concluded that edrophonium facilitates transmission to skeletal muscle by inducing a repetitive antidromic discharge in the nerve, following orthodromic stimulation. The antidromic discharge propagates by axon reflex to other nerve terminals of the same motor unit producing repetitive e.p.ps. It is also suggested that edrophonium antagonizes tubocurarine by acting as a partial agonist at the motor nerve terminal.