bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of adrenaline on nerve terminals in the superior cervical ganglion of the rabbit
Authors: CHRIST D. D. , NISHI S.
Published: July 2012

Adrenaline decreases the release of transmitter from the presynaptic nerves in the superior cervical ganglion of the rabbit. The presynaptic mechanism of adrenaline action was investigated with micro‐electrode techniques.

Adrenaline (10−5M) did not change the threshold of the presynaptic nerve terminals to a current stimulus.

The effect of adrenaline on the excitatory postsynaptic potential (e.p.s.p.) was decreased when the calcium concentration of the perfusing solution was increased to 10 mm.

The effect of adrenaline on a train of e.p.s.ps (30–50 Hz) was analysed. Adrenaline decreased the readily available stores of transmitter, but only slightly changed the probability of release.

The probability of release was increased when the calcium concentration was increased to 5 mm.

It was concluded that adrenaline acts directly on excitation release coupling in the presynaptic terminals.
Influence of the duration of experimental fever on salicylate antipyresis in the rabbit
Authors: CRANSTON W. I. , LUFF R. H. , RAWLINS M. D. , WRIGHT V. ANN
Published: July 2012

Steady state fever has been produced in rabbits with a priming injection followed by a sustaining infusion of homologous plasma containing endogenous pyrogen (EP). This fever appears to last as long as the infusion continues.

Intravenous salicylate given 1 h after the start of the EP infusion produced only a small antipyretic effect. The same dose of salicylate given 4 h after the start of an EP infusion resulted in rapid and progressive defervescence. Intermediate antipyretic responses were obtained when salicylate was administered intravenously 2 and 3 h after the start of an EP infusion.

Less than 1% of the systemic dose, when injected into a lateral cerebral ventricle, produced a significantly smaller response at 1 h than at 4 h after the start of an EP infusion. At both these times the fall in temperature following the intraventricular salicylate injection was dose dependent, but the slope of the dose‐response line was significantly steeper at 4 h than at 1 hour.

It is suggested that salicylates produce their antipyretic effects by antagonizing the action of EP within the nervous system, and that the hypothalamic EP concentration falls during the course of an EP infusion.
Actions of noradrenaline, other sympathomimetic amines and antagonists on neurones in the brain stem of the cat
Authors: BOAKES R. J. , BRADLEY P. B. , BROOKES N. , CANDY J. M. , WOLSTENCROFT J. H.
Published: July 2012

The effects of (–)‐noradrenaline ((–)‐NA) and related compounds on brain stem neurones in decerebrate unanaesthetized cats have been investigated using the technique of iontophoretic application from micropipettes.

Four types of response to (–)‐NA have been described. These were short lasting inhibition, long lasting inhibition, excitation, and a biphasic response consisting of short lasting inhibition followed by excitation. A variable amount of desensitization of the excitatory response, but not of inhibitory responses, was observed.

Experiments in which small currents were used to pass (–)‐NA from pipettes with smaller tips did not lead to any appreciable change in the proportions of neurones excited or inhibited.

A variety of sympathomimetic agonists was tested. Short lasting inhibition was less sensitive than excitation to changes in molecular structure. Long lasting inhibition was more sensitive to molecular change and was not mimicked by some of the agonists which mimicked short lasting inhibition.

Although agonists without one ring hydroxyl had weaker effects than those with both, compounds in which both ring hydroxyl groups were absent (β‐hydroxyphenylethylamine, ephedrine and amphetamine) mimicked excitation strongly. It is possible that the compounds without both ring hydroxyl groups had some effect other than simple agonistic activity.

A dissociation was observed between responses to dopamine and (–)‐NA. p‐Tyramine mimicked dopamine, rather than (–)‐NA.

Neither the α‐agonist, phenylephrine nor the β‐agonist, isoprenaline mimicked neuronal responses to (–)‐NA. The α‐antagonists phentolamine and phenoxybenzamine and the β‐antagonists dichloroisoprenaline, propranolol and d(–)‐INPEA and combinations of propranolol with phentolamine or phenoxybenzamine were ineffective in blocking either excitation or inhibition. Thus, the central receptors appear to be different from peripheral α‐ and β‐receptors.

The most effective antagonist of excitation was (–)‐α‐methylnoradrenaline. Metaraminol and dihydroergotamine also had some antagonistic activity. None of the compounds tested blocked inhibition. The effects of (–)‐α‐methylnoradrenaline have been discussed in relation to the hypotensive action of α‐methyldopa.
Distribution kinetics and intestinal absorption of practolol in the rat
Authors: BARBER H. E. , BOURNE G. R.
Published: July 2012

After intravenous injection of practolol the blood concentration‐time curve is fitted by a bi‐exponential function. A two compartment open system model is therefore a minimal requirement in order to describe adequately the distribution of the drug in the body.

The parameters of the two compartment model for practolol were determined. The mean values for the ‘fast disposition’ half life and the ‘slow disposition’ half life were 0.5 min and 13.3 min, respectively.

The rate constants of distribution and elimination were similar in different animals. The volume of the central compartment was related to the weight of the animal.

The absorption of practolol from an intestinal site was measured by its appearance in the blood. The rate constant for this process was estimated to be 0.03 min−1.
Mechanism of the inhibitory action of indomethacin on smooth muscle
Authors: NORTHOVER B. J.
Published: July 2012

Strips of muscle from the wall of the guinea‐pig stomach contracted in response to electrical field stimulation (100 ms pulses, 0.2 Hz) or to histamine (1 μg/ml), and these responses were inhibited by indomethacin (2–20 mg/100 ml).

Glycerol‐extracted strips of stomach muscle developed tension when exposed to a mixture of ATP, CP, magnesium chloride and calcium chloride. The tension response was not altered by indomethacin (50 mg/100 ml).

Indomethacin failed to alter the content of ATP or of CP in strips of stomach muscle.

The calcium content of strips of stomach muscle increased in response to 30 min of electrical stimulation (100 ms pulses, 0.2 Hz). The uptake of calcium and the contraction of the strips were inhibited by indomethacin (2–20 mg/100 ml) to a similar extent.

Calcium uptake by electrically stimulated guinea‐pig aorta was inhibited by lower concentrations of indomethacin than were required by stomach muscle.
Effect of amphetamine on the transmission of repetitive impulses through the isolated superior cervical ganglion of the rat
Authors: DOWNING O. A.
Published: July 2012

The cervical sympathetic trunk of the isolated rat superior cervical ganglion was stimulated with short bursts of repetitive pulses. At room temperature with rates of stimulation of 4 Hz and above, the ganglionic action potentials were reduced in size.

Amphetamine (2·7 × 10−5m), which caused some depression of transmission during stimulation at 0·1 Hz, caused a partial reversal of the depression of transmission occurring with rates of stimulation above 4 Hz.

This action of amphetamine was mimicked by adrenaline (3 × 10−5m) and noradrenaline (9·6 × 10−5m) but not by isoprenaline (1·8 × 10−5m) and was unaffected by propranolol (1·4 × 10−5m) but was abolished by prior application of phenoxybenzamine (5·8 × 10−6m). Furthermore, this action of amphetamine was unaltered in ganglia taken from rats pretreated with reserpine (single dose of 6 mg/kg, 16 h before dissection).

Amphetamine had no effect on the surface potentials of the ganglion or on changes in these potentials produced by concentrations of carbachol (5·5 × 10−6m to 5·5 × 10−3m).

It is concluded that amphetamine has a direct action on α‐adrenoceptors situated at presynaptic sites.
Binding of bromosulphthalein sodium by human serum albumin using a continuous diafiltration technique
Authors: CRAWFORD J. S. , JONES R. L. , THOMPSON J. M. , WELLS W. D. E.
Published: July 2012

The recently introduced ultrafiltration‐cum‐dialysis technique termed continuous diafiltration has been used to obtain detailed binding isotherms of equilibrium solution concentration of bromosulphthalein (BSP) versus the number of molecules of BSP bound per molecule of human serum albumin for pure human serum albumin solutions (albumin concentrations: 1·59–3·39 g/100 ml) and for three dilutions of pooled human serum (albumin concentrations: 1·45–2·85 g/100 ml) in 310 ideal milliosmolar phosphate buffer at pH 7·4 and 22° C.

Qualitative analysis of the isotherms seems to indicate that there is a competition between the polymerization of the albumin to dimers and high oligomers and the binding of BSP by albumin.

The binding capacity of pure human serum albumin at total BSP (bound and free) concentrations below 2·3 mm is greater than that of the pooled serum at an equivalent albumin concentration, possibly indicating the blockage of binding sites by more strongly binding ligands.

The binding capacity of pure albumin at total BSP concentrations greater than 2·3 mm is less than that of pooled serum at an equivalent albumin concentration, suggesting the presence of other non‐ultrafilterable materials in the serum capable of binding BSP.
Relative activities on and uptake by human blood platelets of 5‐hydroxytryptamine and several analogues
Authors: BORN G. V. R. , JUENGJAROEN KANCHANA , MICHAL F.
Published: July 2012

The specificity of platelet receptor sites for 5‐HT uptake and for the rapid morphological change and aggregation was investigated with 5‐hydroxytryptamine (5‐HT) and seventeen analogues as well as with some antagonists of 5‐HT.

The analogues, with the exception of 5‐hydroxy‐N'N'‐dibutyltryptamine, caused the rapid morphological change in platelets. In concentrations below those needed to produce the agonistic action (viz. 0·05–2·0 μm), these analogues themselves inhibited competitively the shape change caused by 5‐HT.

The velocity of change in shape caused by 5‐HT was reduced in low Na media.

Ten analogues produced platelet aggregation; three of these, viz. 5‐methoxy‐α‐methyltryptamine, 5‐hydroxy‐α‐methyltryptamine and 5‐hydroxy‐N'N'‐diisopropyltryptamine), were approximately equipotent with 5‐HT. Six analogues did not induce platelet aggregation.

All the analogues which prevented the initial change in shape of platelets caused by 5‐HT also inhibited its aggregating effect, apparently competitively with low Ki values (0·02–1·6 μm).

As with the inhibition of shape change, the inhibition of aggregation shows relatively low structural specificity of the receptor site.

Methysergide was a potent inhibitor of shape change and aggregation (Ki˜0·03 μm); imipramine was much less inhibitory (Ki˜5–10μm).

Only one analogue (5‐hydroxy‐α‐methyltryptamine) was taken up like 5‐HT by platelets. All the other analogues inhibited the uptake of 5‐HT by platelets (Ki = 0·2–2·7 μm).

Methysergide was a weak inhibitor of 5‐HT uptake (Ki˜125 μm) whereas imipramine was very effective (Ki˜0·3 μm).

Our results show that the initial change in shape of platelets is required for and precedes aggregation. The structural specificity of the platelet receptor concerned with shape change and aggregation caused by 5‐HT appears low whereas the uptake mechanism is a highly specific one. The uptake probably proceeds through more than one step, the relationship between the steps is not yet clear.
Effects of infusions of catecholamines, angiotensin, vasopressin and histamine on hepatic blood volume in the anaesthetized cat
Authors: GREENWAY C. V. , LAUTT W. W.
Published: July 2012

Hepatic volume was recorded by a plethysmographic technique in cats anaesthetized with pentobarbitone; the hepatic artery and portal vein remained intact. Dose‐response curves were obtained for intravenous infusions of adrenaline, noradrenaline, angiotensin, vasopressin and histamine.

Adrenaline and noradrenaline decreased hepatic blood volume and did not differ significantly in potency. Up to 40% of the hepatic blood volume was expelled by doses within the range secreted by the adrenal medullae.

Isoprenaline, infused into the hepatic artery, had no significant effect on hepatic blood volume in doses which caused maximal vasodilatation of the hepatic arterial bed. Relaxation of hepatic capacitance vessels mediated by β‐adrenoceptors did not occur.

Angiotensin infusions in doses previously shown to cause intestinal and splenic vasoconstriction, decreased hepatic blood volume and on a molar or microgramme basis, angiotensin was the most potent of the agents tested. Doses within the probable physiological range of endogenous production decreased hepatic blood volume by up to 20%. The responses were not significantly different when the hepatic nerves were intact or sectioned.

Vasopressin infusions produced only small decreases in hepatic blood volume. Doses within the range secreted by the posterior pituitary which constrict the intestinal and splenic resistance vessels, did not decrease hepatic blood volume by more than 10%.

Histamine produced no change in hepatic blood volume in doses which readily produce outflow block in dogs. Either the specific hepatic venous smooth muscle involved in outflow block is absent in the cat or it has no histamine receptors.

After the rapid change in hepatic blood volume at the onset of the infusion, hepatic volume remained steady for the duration of each infusion. There was no evidence that these agents caused net transsinusoidal fluid movements.
Selective inhibition of angiotensin pressor responses in the pithed rat by tetraethylthiuram disulphide (disulfiram) and sodium diethyldithiocarbamate (DDC)
Authors: DAY M. D. , HALL J. M. , OWEN D. A. A.
Published: July 2012

Pressor responses to sympathetic outflow stimulation, noradrenaline and angiotensin have been recorded in pithed rats.

Disulfiram (50 mg/kg) and sodium diethyldithiocarbamate (DDC) (5–100 mg/kg) both caused an initial increase in the pressor response to all three procedures followed by a selective inhibition of the angiotensin responses.

Penicillamine (1–100 mg/kg) and ascorbic acid (1–500 mg/kg) increased the pressor responses to all three procedures without any subsequent blocking action.

Reserpine (5 mg/kg daily for 3 days) abolished responses to sympathetic outflow stimulation but did not impair angiotensin or noradrenaline responses.

In reserpinized rats, the initial enhancement of angiotensin responses after disulfiram and sodium diethyldithiocarbamate was absent or reduced and the onset of the subsequent block was accelerated.

Possible mechanisms for the angiotensin‐blocking action of disulfiram and sodium diethyldithiocarbamate are discussed.
Effect of sympathomimetic drugs in eliciting hypertensive responses to reserpine in the rat, after pretreatment with monoamineoxidase inhibitors
Authors: CASHIN C. H.
Published: July 2012

The effects of some rapidly metabolized sympathomimetic amines, such as β‐phenylethylamine and p‐tyramine, in eliciting hypertensive responses to reserpine in the anaesthetized rat, have been studied.

Retardation of metabolism, by pretreatment with the monoamineoxidase inhibitors iproniazid or phenelzine, causes β‐phenylethylamine (which in untreated rats has no effect) to induce hypertensive responses to reserpine. Tyramine and other hydroxy substituted phenylethylamines are much less active in this respect, probably because of relatively poor lipid solubility.

Hypertensive responses to reserpine are due to catecholamine release, which is believed to be from stores made accessible to indirectly acting sympathomimetic amines with high lipid solubility by an action of reserpine on cell membranes.
Nature of the calcium dependent potassium leak induced by (+)‐propranolol, and its possible relevance to the drug's antiarrhythmic effect
Authors: GLYNN I. M. , WARNER ANNE E.
Published: July 2012

Manninen (1970) recently reported that in the presence of calcium ions, (+)‐propranolol causes a massive loss of potassium ions from human red cells, together with a marked inward ‘counter‐transport’ of potassium ions from the medium.

This paper shows, theoretically, that counter‐transport of the kind he observed may be accounted for by the setting up of a diffusion potential across the cell membrane and does not imply that, under the influence of propranolol, potassium ions cross the membrane by some process other than free diffusion.

The physiological and pharmacological significance of this interpretation of Manninen's findings is briefly discussed.
Metabolism of amylobarbitone in patients with chronic liver disease
Authors: MAWER G. E. , MILLER N. E. , TURNBERG L. A.
Published: July 2012

A single dose of amylobarbitone (3·23 mg/kg) was given by intravenous injection to each of ten healthy controls and two groups of five patients with chronic liver disease. A curve of serum amylobarbitone concentration against time was prepared for each subject and the proportion of the serum amylobarbitone bound to protein determined. The urinary excretion of the metabolite hydroxyamylobarbitone, ethyl (3 hydroxyisoamyl) barbituric acid was measured.

The degree of protein binding of serum amylobarbitone was reduced in the five patients (group I) with abnormally low concentrations of albumin in serum (<3·5 g/100 ml) but was normal in the five patients (group II) with normal serum albumin concentrations (>3·5 g/100 ml).

The equation for a double exponential decay was fitted to the concentration/time curves for amylobarbitone free in the serum water. The mean intercepts and rate constants were used to calculate the dimensions of mathematical models based on a two compartment open system.

The five patients (group I) who had abnormally low concentrations of albumin in serum showed impairment of amylobarbitone metabolism; the rate constant β(h−1) for the second exponential decay of serum amylobarbitone concentration was reduced (P<0·01), the urinary excretion of hydroxyamylobarbitone was reduced (P<0·001) and the mean serum water clearance (Ce ml/min) representing amylobarbitone elimination by metabolism was reduced.

The five patients (group II) who had normal concentrations of albumin in serum showed no impairment of amylobarbitone metabolism. Within the total patient group there were strong and significant positive correlations between the serum albumin concentration and each of the indices of the rate of amylobarbitone metabolism.

Both patient groups showed an increase in the first dispositional rate constant α(h−1) and in the clearance (Ct ml/min) representing transfer between central and peripheral compartments. The physiological basis for this observation is uncertain.

The clinical response to the single intravenous dose of amylobarbitone was not significantly greater (P=0·11) in the patient group (I) with slow amylobarbitone metabolism than in the patient group (II) with a normal rate of amylobarbitone metabolism.
Pharmacology of o‐chlorobenzylidene malononitrile (CS)
Authors: BRIMBLECOMBE R. W. , GREEN D. M. , MUIR A. W.
Published: July 2012

The effects of o‐chlorobenzylidene malononitrile (CS) have been studied on several isolated organs and tissues, anaesthetized animals and cat encéphale isolé preparations.

On the isolated guinea‐pig ileum an initial dose of CS produced a small, non‐maintained contraction. Subsequent doses had reduced effects. There was no effect on peristalsis when the substance was given intraluminally.

No significant effects of CS were detected on the rat phrenic nerve‐diaphragm preparation, the isolated perfused rabbit heart or on the contractor response of the indirectly stimulated cat tibialis muscle.

In the cat encéphale isolé preparation 1 mg/kg (i.v.) produced a brief period of electrocortical alerting but no abnormal activity in the electrocorticogram. Doses in excess of 10 mg/kg produced cortical depression.

Intravascular injection into the chloralose anaesthetized cat resulted typically in a pressor response accompanied by a brief period of apnoea. The threshold dose for the pressor response varied with the route of administration, but generally lay between 2·5 and 12·5 μg/kg; the threshold dose for apnoea was slightly higher. Small variations in this pattern of response were seen with different species and other anaesthetics.

When administered by stomach tube to chloralose anaesthetized cats, CS produced no measurable effects at doses of up to 100 mg/kg.

No changes in blood pressure or respiration were detected in anaesthetized cats given pure CS aerosol for 1 h in concentrations of between 345 mg/m3 and 1·39 g/m3 via a tracheal cannula or through the upper respiratory tract. Pure CS solution given by slow intravenous infusion at a similar dose and over a similar period produced significant effects on blood pressure and respiration.

Pyrotechnically generated (grenade) CS produced variable effects when given by inhalation in concentrations of between 460 and 1,040 mg/m3 for 1 hour. Respiratory depression, possibly reflex in nature, regularly occurred when the material was given via the upper respiratory tract, and respiratory stimulation occurred when it was given via a tracheal cannula.

Some cats were pre‐exposed to a dose of 500 (mg/min)/m3 on 4 successive days and on the fifth day anaesthetized and exposed to high concentrations of grenade CS. Three out of six cats died during or after this final exposure compared to one out of six among animals not so pre‐exposed. The general pattern of response to the final exposure to CS in the two groups was similar.
The physiological disposition of 14C‐methsuximide in the rat
Authors: NICHOLLS P. J. , ORTON T. C.
Published: July 2012

. 14C‐Methsuximide (N‐methyl‐14C‐2‐methyl‐2‐phenylsuccinimide) was rapidly absorbed from the small intestine of the rat (t½ 17·4 min).

. The drug was rapidly and fairly evenly distributed throughout the body with peak blood and tissue levels occurring 1 h after oral administration. At all times, adrenals, body fat, kidneys and liver had higher levels of 14C‐methsuximide than other tissues and the drug freely traversed the blood‐brain barrier. However, radioactivity disappeared rapidly from most tissues after the initial phase of the distribution.

. During 24 h, 26% of the orally administered radioactivity was recovered in urine and 29% appeared in expired air as 14CO2. The excretion of 14CO2 indicated N‐demethylation of 14C‐methsuximide to 2‐methyl‐2‐phenylsuccinimide. 2·7% of an administered dose of methsuximide was excreted unchanged in 24 h urine and 2·7% appeared as 2‐methyl‐2‐phenylsuccinimide. 2‐Methyl‐2‐phenylsuccinimide was also detected as a urinary metabolite of methsuximide in man.

. 2‐Methyl‐2‐phenylsuccinimide possesses anticonvulsant activity and it is suggested that this metabolite contributes to the overall anticonvulsant activity and toxicity of methsuximide.

. Rat urine also contained a radioactive substance with similar chromatographic properties to one of the products of alkaline hydrolysis of methsuximide. This compound may arise from the spontaneous decomposition of the parent drug in vivo.
Relative importance of the enzymic hydrolysis of suxamethonium in plasma and tissues: studies in Rhesus monkeys
Authors: PECK ANTHONY W.
Published: July 2012

. Suxamethonium was given by intravenous infusion to anaesthetized Rhesus monkeys and the infusion rate required to produce after 10 min a 50% reduction in twitch tension of the indirectly stimulated gastrocnemius or tibialis anterior muscle (IR50) was calculated from results obtained with paired infusions of two concentrations, repeated at intervals. The IR50 values in three monkeys were (388, 958 and 1,010 nmol/kg)/minute.

. In one experiment the cholinesterase activity in plasma was increased to 125 and then to 182% of the initial value by infusions of purified human cholinesterase (usual enzyme). This increased the IR50 by 34 and then by 60%, respectively.

. Inhibition by iso‐OMPA of cholinesterase activity in plasma and tissues (four monkeys) by more than 90% lowered the mean IR50 value to (69 ± 11 (s.e. m.) nmol/kg)/minute. Restoration of cholinesterase activity in the plasma of these animals by infusion of purified human cholinesterase raised the IR50's to values within the normal range.

. It is concluded that in the Rhesus monkey most of the infused suxamethonium is hydrolyzed by the cholinesterase in plasma before reaching the motor endplates. This agrees with observations in man with usual cholinesterase and contrasts with experiments in the cat where the hydrolysis of suxamethonium by cholinesterase in tissues was found to be more important than the hydrolysis by cholinesterase in plasma.
The effects of isoprenaline and phenylephrine on oxygen consumption in isolated smooth muscle
Authors: WESTON A. H.
Published: July 2012

. Simultaneous measurements of oxygen consumption and mechanical activity have been made in isolated preparations of guinea‐pig taenia coli, rabbit abdominal aorta and the longitudinal muscle of rabbit duodenum.

. Mean resting oxygen consumption was greater in mechanically‐active preparations (taenia coli and duodenum) than in the aorta which showed no spontaneous activity.

. The relaxation produced by isoprenaline in guinea‐pig taenia coli and rabbit duodenum was accompanied by a dose‐dependent fall in oxygen consumption.

. The relaxation produced by phenylephrine in guinea‐pig taenia coli was accompanied by a dose‐dependent fall in oxygen consumption whereas, in the rabbit duodenum, the transient fall in tension was not accompanied by any significant change in oxygen consumption.

. The increase in tension produced by phenylephrine in rabbit abdominal aorta was accompanied by an increase in oxygen consumption.

. Changes in mechanical activity and oxygen consumption produced by isoprenaline and phenylephrine were antagonized by propranolol and phentolamine respectively.

. It is concluded that the variations in oxygen consumption associated with spontaneous or drug‐induced mechanical changes are simple reflections of altered mechanical activity. The possibility of additional direct metabolic actions of isoprenaline and phenylephrine is discussed.
The effects on cardiac muscle and nerve of a fluorinated decahydroquinoline derivative, L7810, rapidly absorbed after oral administration
Authors: BAGWELL E. E. , POLSTER P. , WILLIAMS E. M. VAUGHAN
Published: July 2012

. L7810 (4‐carbamoyloxy‐1‐(4‐(4‐fluorophenyl)‐4‐oxobutyl) decahydroquinoline, has a local anaesthetic action on frog nerve 1·75 times that of procaine.

. L7810 protected anaesthetized guinea‐pigs against ouabain‐induced ventricular fibrillation and increased the lethal dose of ouabain.

. L7810 reduced the rate of rise of intracellularly recorded action potentials in rabbit isolated atria; the resting potential was not affected, but the duration of the action potential was prolonged.

. Unlike most drugs with local anaesthetic properties L7810 did not depress contractions in isolated atria but increased them.

. L7810 reduced the spontaneous frequency, maximum follow frequency and conduction velocity of rabbit isolated atria.

. L7810 had no blocking action on the chronotropic or positive inotropic actions of isoprenaline on isolated atrial muscle.

. In anaesthetized dogs L7810 caused a small dose‐related bradycardia, and a large dose‐related decrease in peripheral vascular resistance. There was no blockade of the effects of isoprenaline on heart rate or peripheral blood flow.
Interaction between picrotoxin and 5‐hydroxytryptamine in the superior cervical ganglion of the cat
Authors: de GROAT W. C. , LALLEY P. M.
Published: July 2012

. Electrophysiological techniques were utilized to study the actions of 5‐hydroxytryptamine (5‐HT) and picrotoxin on the superior cervical ganglion of the cat.

. The intra‐arterial administration of 5‐HT to the ganglion elicited both depressant and excitatory actions. In low doses (0·01–0·5 μg) the amine produced a depression of ganglionic transmission. In larger doses (2–50 μg) it produced an excitation of ganglion cells (early discharge) and an initial enhancement of transmission, which was followed by depression. Picrotoxin (25–500 μg, i.a.) blocked the initial excitatory effects of 5‐HT but did not block the depression. Picrotoxin did not antagonize the excitatory actions of injected cholinomimetic agents or potassium chloride.

. In ganglia conditioned by repetitive stimulation of the preganglionic nerve (30 Hz for 30 s) 5‐HT also elicited a late‐occurring and very prolonged discharge on certain postganglionic nerves (‘spinal’) but not on others (external carotid). The late discharge was only partially depressed by picrotoxin.

. Recordings from the surface of the superior cervical ganglion revealed that 5‐HT produced three types of ganglionic potentials: (1) an initial transient depolarization which coincided with the early discharge, (2) a late‐occurring, prolonged depolarization which coincided with the late discharge, and (3) a hyperpolarization which in some experiments accompanied the depression of transmission. The late depolarization and hyperpolarization were not observed in every experiment. Picrotoxin (25–500 μg) blocked the initial depolarization, but did not block the late depolarization or the hyperpolarization.

. It is concluded the 5‐HT can produce three distinct responses in the superior cervical ganglion: a depressant effect and two types of excitation. It seems likely that depression and excitation occur via the activation of different receptors, since picrotoxin selectively blocks the latter. The finding that picrotoxin is a 5‐HT antagonist in peripheral ganglia raises the possibility that picrotoxin might also influence tryptaminergic mechanisms in the central nervous system.
The distribution of vasopressin and oxytocin in the hypothalamoneurohypophysial system of the guinea‐pig
Authors: BISSET G. W. , ERRINGTON M. L. , RICHARDS C. D.
Published: July 2012

. The ratio of the content of vasopressin to that of oxytocin (V/O ratio) was estimated in the supraoptic nucleus (SON), paraventricular nucleus (PVN) and posterior pituitary gland (PIT) of guinea‐pigs.

. Extracts were assayed for antidiuretic activity to estimate vasopressin and for milk‐ejecting activity to estimate oxytocin. In assays for milk‐ejecting activity, trypsin was used to inactivate vasopressin in the extracts.

. The mean V/O ratios in the SON, PVN and PIT were 28, 85 and 70 respectively in male guinea‐pigs, 6·8, 7·4 and 6·9 in non‐lactating females, and 5·1, 3·3 and 6·6 in lactating females.

. The distribution of the hormones within the hypothalamus is discussed in relation to their independent release in response to electrical stimulation of the SON and PVN.
Cyclopentolate in treatment of sarin miosis
Authors: MOYLAN‐JONES R. J. , THOMAS D. PRICE
Published: July 2012

. Six young male volunteers were exposed to sarin vapour (isopropyl methyl phosphonofluoridate) at a concentration of 0·5 mg/m3 for 30 min (concentration time (Ct) 15 (mg min)/m3).

. The resulting clinical syndrome was treated by instilling 0·06 ml of a 1% solution of cyclopentolate into the conjunctival sac.

. Visual acuity, retinoscopy, objective and subjective refraction and pupil sizes were noted before the trial, after exposure to sarin and after treatment with cyclopentolate.

. No appreciable difference was demonstrated between the control objective retinoscopy values and those obtained after cyclopentolate treatment of the clinical syndrome induced by sarin. Reduced near visual acuity was observed in some subjects treated with cyclopentolate as compared with acuity after exposure to sarin alone, considered to be due to the partial cycloplegia produced by treatment. Visual acuity after exposure to sarin alone was improved in some instances by the miosis produced.

. It is suggested that unless full dark adaptation is a consideration, treatment of the ophthalmic condition resulting from exposure to this dosage of sarin should be reserved for those experiencing distressing ocular symptoms.
Actions of morphine on the segmental reflex of the decerebrate‐spinal cat
Authors: KRIVOY W. , KROEGER D. , ZIMMERMANN E.
Published: July 2012

The actions of morphine were studied on the segmental reflex of the decerebrate‐spinal cat. Morphine decreased arterial blood pressure.

Morphine inhibited mono‐ and polysynaptic reflexes. The influence of morphine on monosynaptic reflexes was more obvious at stimulation of the dorsal root at a frequency of 12·5 Hz than at 05 or 2·5 Hz.

The total amount of activity recorded from the ventral root after morphine depended on whether or not the evoked reflex was maximal or submaximal.

These actions of morphine were antagonized by naloxone.
Some initial animal and human pharmacological studies with benapryzine (BRL 1288)
Authors: BROWN D. M. , HUGHES B. O. , MARSDEN C. D. , MEADOWS J. C. , SPICER B.
Published: July 2012

The pA2 anti‐acetylcholine activity in vitro for benapryzine was 6·55 compared with 902 for benzhexol.

In vivo, the anti‐acetylcholine activity of benapryzine relative to benzhexol was 0·038 as assessed by the mydriatic response of mice after subcutaneous administration. The relative activity assessed by the inhibition of pilocarpine‐induced salivation was 0·13 after oral administration and 0056 following subcutaneous administration of the drugs.

Benapryzine had the same order of activity as benzhexol in inhibiting oxotremorine‐induced tremors in mice.

Benapryzine had anticonvulsant properties but no analgesic activity, whilst in high doses it antagonized the extrapyramidal symptoms induced by perphenazine in rats.

In patients benapryzine was effective in reducing the symptoms of Parkinson's disease without overt anti‐cholinergic effects or central hallucinogenic actions.

Benapryzine abolished the excess tremor and reduced the rigidity and akinesia induced by physostigmine in Parkinsonian subjects.
Acute systemic anaphylaxis in the calf
Authors: EYRE P. , LEWIS A. J. , WELLS P. W.
Published: July 2012

Acute systemic anaphylaxis in calves was characterized by marked systemic hypotension hypertension in the pulmonary arteries and abdominal vena cava, and transient apnoea. Calves responded with a second reaction to antigen, but a third anaphylactic response could not be evoked.

Suppression of systemic anaphylaxis could not be effected with mepyramine, whereas methysergide or diethylcarbamazine each suppressed anaphylaxis by 50%. Disodium cromoglycate alone did not inhibit anaphylaxis: however, when disodium cromoglycate was combined with diethylcarbamazine almost total suppression (85%) was achieved. Sodium meclofenamate also was a powerful inhibitor of anaphylaxis (80%). It is tentatively suggested that slow reacting substance (SRS‐A) may be an important mediator of bovine anaphylaxis.

Bilateral vagotomy did not modify the circulatory responses to injected histamine, 5‐hydroxytryptamine (5‐HT) or antigen, whereas the effects of these agents on ventilation (apnoea) were abolished by vagotomy.

Plasma histamine concentration was increased during anaphylaxis, whereas plasma 5‐HT was not. Whole blood histamine concentration fell sharply and remained depressed during 20 min of anaphylactic shock. Reduced whole blood histamine levels probably reflect the severe leucopoenia in the calves.

Histamine concentrations in six tissues taken from calves subjected to anaphylaxis were not different from those in control calves mast cells were of similar numbers to controls, but showed some swelling, granular spilling and metachromasia.

Histamine, 5‐HT, bradykinin and antigen caused increased pulmonary artery perfusion pressure and ventilation resistance in isolated lungs from sensitized calves. However, there was no difference in histamine and 5‐HT concentration in perfusates obtained during antigen infusion of sensitized and control lungs.

Systemic anaphylaxis of calves may result from the interaction of histamine, 5‐HT and SRS‐A. The present data implicate (by indirect measurement) SRS‐A as an important mediator of anaphylaxis in this species.
Attenuation of amphetamine‐induced motor stimulation and stereotypy by 6‐hydroxydopamine in the rat
Authors: FIBIGER H. C. , FIBIGER H. P. , ZIS A. P.
Published: July 2012

In accord with previous reports, intraventricular administration of 6‐hydroxydopamine (250 μg) to rats did not influence spontaneous locomotor activity. Neither was the stereotyped behaviour seen after high doses of (+)‐amphetamine (5 mg/kg) changed by this treatment. Increases in motor activity induced by (+)‐amphetamine (0·5 and 1·0 mg/kg) were significantly reduced after 6‐hydroxydopamine.

When 6‐hydroxydopamine (250 μg) was administered to tranylcypromine (5 mg/kg) pretreated animals, spontaneous activity was significantly reduced. The stimulant effects of (+)‐amphetamine (0·5 and 10 mg/kg) were completely abolished and amphetamine stereotypy (5·0 mg/kg) was absent or reduced after this treatment.

Bilateral injections of 6‐hydroxydopamine (10 μg) into the substantia nigra abolished the more pronounced features of amphetamine stereotypy. However, although significantly reduced, amphetamine‐induced locomotor stimulation was observed in these animals. Spontaneous activity was also reduced.

These observations suggest that dopaminergic nigro‐striatal neurones mediate some of the stimulant effects of amphetamine as well as being of critical importance in amphetamine‐induced stereotypy. However, other catechol‐aminergic neurones also appear to be involved in amphetamine motor stimulation. The results are consistent with the view that amphetamine exerts its behavioural effects indirectly through its action on brain catecholamines.
Passage of intravenously administered tubocurarine into the liquor space in man and dog
Authors: DEVASANKARAIAH G. , HARANATH P. S. R. K. , KRISHNAMURTY A.
Published: July 2012

In anaesthetized patients under controlled respiration, samples of lumbar cerebrospinal fluid were withdrawn 15 and 60 min after an intravenous injection of 30 mg tubocurarine. When tested on the frog rectus muscle preparation contracted by acetylcholine, they exerted curare‐like activity which corresponded to between 0·05 and 0·33 μg/ml tubocurarine.

In dogs anaesthetized with pentobarbitone sodium and artificially ventilated, two procedures were adopted to find out if tubocurarine passes into the liquor space after an intravenous injection of 0·3 or 3 mg/kg and during its intravenous infusion at a rate of 10 (μg/kg)/minute. Either samples of cisternal cerebrospinal fluid (c.s.f.) were collected, or different regions of the liquor space were perfused with artificial c.s.f. and the effluent was collected. The samples of c.s.f. and the effluent were assayed for curare‐like activity on the frog rectus muscle.

After the intravenous injection of tubocurarine samples of cisternal effluent collected during perfusion from lateral ventricle to cisterna exerted curare‐like activity. It corresponded to 20 ng/min tubocurarine in the sample collected during the first 15 min after the injection of 0·3 mg/kg and to 40–60 ng/min in the samples collected up to 2 h after the injection of 3 mg/kg.

During intravenous infusion of tubocurarine the cisternal c.s.f. as well as the effluent from the perfused regions of the liquor space exhibited curare‐like activity. Expressed in equivalents of tubocurarine, the activity in the cisternal c.s.f. ranged from between 0·1 and 0·75 μg/ml. On perfusion from lateral ventricle to aqueduct or cisterna, the activity ranged from between 3 and 25 ng/min in the aqueductal and from between 4 and 40 ng/min in the cisternal effluent. On perfusion from the lumbar‐spinal subarachnoid space to cisterna it ranged from between 6 and 55 ng/min in the cisternal effluent.
Effect of long‐term treatment with high doses of guanethidine on sperm transport and fertility of rats
Authors: HEPP R. , KREYE V. A. W.
Published: July 2012

Male rats treated with guanethidine 25 mg/kg daily for eight weeks had no demonstrable ejaculatory function immediately after cessation of treatment. Four weeks later, ejaculatory function had returned in two‐thirds of the males, and after eight weeks, all males were able to deposit sperm in the vagina. However, fertility had returned at that time in only two of the nine males. On the basis of these findings it might be expected that fertility would return in the other males after a more prolonged observation period.

At autopsy, 66 days after cessation of treatment, the vasa deferentia were congested and filled with viscous material, and along their course dilated regions and pseudocysts containing sperm debris and spermatozoa were found.

The isolated ducts of the guanethidine‐treated males showed a markedly increased response to noradrenaline if compared with ducts from control rats. Response to tyramine was similar in both treated and untreated rats. In view of the increased response to noradrenaline it may be concluded that the noradrenaline stores, which are sensitive to tyramine, were still reduced 66 days after guanethidine treatment had been stopped.
Myogenic peristalsis in isolated preparations of chicken oesophagus
Authors: BARTLET A. L.
Published: July 2012

Nicotine, 20 μg/ml, briefly and partially blocked the longitudinal contractions of a chick vagus nerve‐oesophagus preparation to nerve stimulation, but potentiated them in the presence of hyoscine, 10 μg/ml.

Strychnine, 20 μg/ml, antagonized the longitudinal contractions of the chick oesophagus to nerve stimulation, though not to acetylcholine or 5‐hydroxytryptamine. Hyoscine, 10 μg/ml, enhanced the nerve‐blocking action of strychnine.

These observations suggest that in the vagus nerve of the chicken, hyoscine either blocks certain types of fibre selectively or interacts with pharmacological receptors for strychnine and nicotine.

Tetrodotoxin, 1 μg/ml, propranolol, 40 μg/ml, cocaine, 200 μg/ml, or strychnine, 100 μg/ml, which render autonomic nerves inexcitable, potentiated the spontaneous movements of isolated preparations of chicken oesophagus at normal intra‐luminal pressure; they also potentiated peristaltic response to increased intra‐luminal pressure.

These observations suggest that the preparations contain intramural nerves that inhibit the musculature.

Peristalsis in the chicken oesophagus was unaffected by nicotine, 20 μg/ml, tubocurarine, 20 μg/ml, hyoscine, 10 μg/ml, phentolamine, 1 μg/ml, propranolol, 0·5 μg/ml, mepyramine, 1 μg/ml, methysergide, 0·1 μg/ml, and morphine, 20 μg/ml. It was produced in preparations of chicken oesophagus after removal of the mucous membrane. Papaverine, 20 μg/ml, inhibited the peristalsis and had a spasmolytic action in the musculature.

These observations suggest that the peristalsis in isolated preparations of chicken oesophagus is dependent solely upon myogenic contractility.
Barbiturate‐induced transmitter release at a frog neuromuscular junction
Authors: THOMSON T. D. , TURKANIS S. A.
Published: July 2012

The influence of barbiturates on neuromuscular transmission at end‐plates of frog sartorius muscles was investigated electrophysiologically on preparations bathed in Ringer solution containing a low concentration of calcium and a high concentration of magnesium.

Effects of a convulsant barbiturate, 5‐(2‐cyclohexylideneëthyl)‐5‐ethyl barbituric acid (CHEB), were compared with those of phenobarbitone.

CHEB and phenobarbitone increased the mean quantum content of the end‐plate potentials and decreased the mean amplitude of the miniature end‐plate potentials.

Both barbiturates enhanced the duration of the nerve‐terminal action potential and had little or no effect on the effective resistance of the skeletal muscle membrane.
Characterization of α‐adrenoceptors in the myocardium
Authors: BENFEY B. G.
Published: July 2012

In the driven rabbit left atrium α‐adrenoceptors mediate the inotropic effect of phenylephrine and the prolongation of functional refractory period by sympathomimetic amines.

These receptors are highly sensitive to blockade by phentolamine and phenoxybenzamine.

Prolongation of functional refractory period is greater with the secondary amines, phenylephrine, adrenaline and epinine, than with the primary amines, norphenylephrine, noradrenaline and dopamine.
Effect of cocaine on the affinity of α‐adrenoceptors for noradrenaline
Authors: INNES I. R. , MAILHOT R.
Published: July 2012

Doses of cocaine which cause specific or unspecific supersensitivity in cat spleen did not alter the blocking effect of phenoxybenzamine on the responses of isolated cat spleen strips to noradrenaline.

The same doses of cocaine did not increase the protection of α‐adrenoceptors given by noradrenaline during a standard exposure to phenoxybenzamine.

It is concluded that cocaine does not change the affinity of the α‐adrenoceptor for noradrenaline, and therefore changes in affinity are not responsible for the potentiating action of cocaine.
The role of the substantia nigra in the locomotor stimulant action of amphetamine
Authors: COSTALL B. , NAYLOR R. J.
Published: July 2012

The electrolytic brain lesion technique was used to evaluate the role of the substantia nigra in the mediation of the locomotor stimulant effect of (+)‐amphetamine in the rat The effect upon the results of variations in strain and basal activity levels of the rats was assessed.

In the immediate postoperative phase the lesioned animals developed spontaneous stereotyped behaviour patterns which were more intense in rats of initially high basal activity. Activity was depressed at this stage and only that of the low activity animals was stimulated by amphetamine.

After the 2nd postoperative day rats with lesions of the substantia nigra developed hyperactivity, but this was only maintained in rats initially of low basal activity. During this stage the locomotor stimulant effect of amphetamine (1·0 mg/kg) was apparent and after the 9th postoperative day animals generally displayed an increased sensitivity to the drug effect.

The involvement of the substantia nigra with the control of locomotor activity is indicated but its integrity would not appear essential for the mediation of the locomotor stimulant effects of amphetamine.
Anti‐inflammatory and some other pharmacological effects of 3,4‐trans‐2,2‐dimethyl‐3‐phenyl‐4‐[p‐(β‐pyrrolidinoethoxy)‐phenyl]‐7‐methoxy‐chroman (Centchroman)
Authors: DHAWAN B. N. , SRIMAL R. C.
Published: July 2012

Anti‐inflammatory, analgesic, antipyretic and other pharmacological activities of a new chroman derivative, Centchroman, have been described.

Centchroman was found to possess significant anti‐inflammatory action in the carrageenin‐induced oedema test in mice and rats. It inhibited granuloma formation in the cotton pellet test. The anti‐arthritic activity was also evident in formaldehyde‐induced arthritis and adjuvant‐induced arthritis in rats.

Centchroman had a lower ulcerogenic index than phenylbutazone.

The mechanism of the anti‐inflammatory action of Centchroman seemed to be independent of endogenous adrenocortical hormones or of its weak oestrogenic activity.

Centchroman antagonized phenylquinone writhing and bradykinin‐induced bronchospasm but was devoid of any antipyretic activity.