bluuebunny/crossref_metadata_2025 huggingface dataset:
TOLERANCE TO THE EFFECT OF Δ1‐TETRAHYDROCANNABINOL ON CORTICOSTERONE LEVELS IN MOUSE PLASMA PRODUCED BY REPEATED ADMINISTRATION OF CANNABIS EXTRACT OR Δ1‐TETRAHYDROCANNABINOL
Authors: PERTWEE R.G.
Published: July 2012

Three injections of cannabis extract (500 mg/kg s.c. given over 3 or 5 days) diminished thymus gland weight but not the weights of spleen or liver in weanling female and adult male mice kept at room temperature.

Both cannabis extract (500 mg/kg s.c.) and Δ1‐tetrahydrocannabinol (Δ1‐THC; 10 and 20 mg/kg i.p.) elevated corticosterone levels in mouse plasma.

A pretreatment that consisted of three daily subcutaneous injections of 500 mg/kg of cannabis extract and that was shown to produce tolerance to the ‘cataleptic’ effect of Δ1‐THC (2 mg/kg i.v.) in mice, also produced tolerance to the effect of Δ1‐THC (10 mg/kg i.p.) on corticosterone levels in mouse plasma. However, this pretreatment did not reduce the rise in plasma corticosterone concentration produced by immobilization.

Tolerance to the effect of Δ1‐THC (10 mg/kg i.p.) on corticosterone levels in mouse plasma was also produced by the pretreatment of mice with a single injection of Δ1‐THC (10 mg/kg s.c). Three daily injections of Δ1‐THC (10 or 30 mg/kg s.c.) also produced tolerance.

In a thermoneutral environment (30–32° C) in which cannabis extract does not produce hypothermia, the drug no longer reduced thymus gland weight. However the effect of cannabis extract and of Δ1‐THC on corticosterone plasma levels was the same at room temperature as at 30–32° C. Tolerance to the latter effect of Δ1‐THC was also produced equally readily under the two conditions.

It is concluded that pretreatment with cannabis extract or Δ1‐THC can produce tolerance to the effect of Δ1‐THC on corticosterone levels in mouse plasma and does so without impairing the effect of immobilization stress on corticosterone release. In addition, both the rise in corticosterone plasma levels produced by cannabis or Δ1‐THC and the development of tolerance to this effect can still take place in the absence of hypothermia.
INVESTIGATIONS ON THE MODE OF ACTION OF ERGOTAMINE IN THE ISOLATED FEMORAL VEIN OF THE DOG
Authors: MÜLLER‐SCHWEINITZER E. , STÜRMER E.
Published: July 2012

Experiments on spiral strips cut from the femoral vein of dogs suspended in Krebs‐Henseleit solution were carried out.

Ergotamine caused stimulation in concentrations about 350 times lower than noradrenaline (ED50 of ergotamine = 2.2 × 10−9 m; ED50 of noradrenaline = 7.6 × 10−7 M), but the maximal responses to ergotamine were only about one third those to noradrenaline.

The pA2 value of ergotamine against noradrenaline was 8.8.

The effects of ergotamine can be blocked by prior administration of phentolamine. The pA2 value for phentolamine against ergotamine was 6.8 and the pA2 value for phentolamine against noradrenaline was 7.5.

It is concluded that the stimulant action of ergotamine on smooth vascular muscle probably is mediated mainly via α‐adrenoceptors.
VOLUNTARY LITHIUM INTAKE, ‘ANTIDOTAL THIRST’ AND CONCURRENT BEHAVIOUR OF RATS
Authors: LANGHAM R.J. , SYME G.J. , SYME L.A.
Published: July 2012

Voluntary intake of various pair combinations of fluids (100 mM, 10 mM LiCl, 10 mM NaCl, water) and body weight was measured daily in rats.

More lithium was consumed when water was available.

When offered a lithium‐sodium choice the rats did not consume significantly more saline than water on the previous trial. While saline consumption increased over the two days, lithium decreased slightly.

Following the lithium‐only trial, water and saline were provided. Marked polydipsia was observed on the first day and the rats drank more water than saline. On the second day there was a significant drop in saline intake while water consumption returned to baseline levels.

Behavioural measurements overall confirmed the depressant effect of lithium: decreased ambulation and rearing and increased time spent immobile/grooming.

These findings are discussed with reference to lithium toxicity, which may be a confounding variable in studies concerned with the effects of this salt on the behaviour of laboratory rodents. Behavioural irritability such as aggression reported in situations using long‐term lithium treatment may be reduced by provision for voluntary saline consumption.
CHOLINERGIC MECHANISMS IN CENTRAL THERMOREGULATION IN PIGEONS
Authors: CHAWLA NARESH , JOHRI M.B.L. , SAXENA P.N. , SINGHAL K.C.
Published: July 2012

In unanaesthetized pigeons the effect on cloacal temperature was studied of acetylcholine (ACh), carbachol, atropine and (+)‐tubocurarine injected into a cannulated lateral cerebral ventricle. The experiments were carried out at an ambient temperature of 19–25°C.

ACh or carbachol injected intraventricularly produced hyperthermia, and in larger doses hyperthermia followed by hypothermia. These were central effects because they were not obtained when these drugs were injected in the same doses intravenously.

Atropine injected intraventricularly produced hypothermia which was greater and longer lasting than the hypothermia produced with the same dose of atropine injected intravenously. After the intraventricular injection of atropine the hyperthermic effects of ACh and of carbachol were abolished.

(+)‐Tubocurarine injected intraventricularly produced a long‐lasting hyperthermia in doses which had no effect on temperature when injected intravenously. After the intraventricular injection of tubocurarine the hypothermic effects of ACh and of carbachol were abolished.

It is concluded that the effects of ACh and carbachol imitate the effects of ACh released from cholinergic neurones in the central pathway involved in temperature regulation. The hypothermic effect of atropine is attributed to unmasking the activity of continuously released ACh acting on nicotinic receptors, and the hyperthermic effect of tubocurarine to unmasking the activity of continuously released ACh acting on muscarinic receptors.
EFFECT OF MORPHINE ON ADRENERGIC TRANSMISSION IN THE MOUSE VAS DEFERENS. ASSESSMENT OF AGONIST AND ANTAGONIST POTENCIES OF NARCOTIC ANALGESICS
Authors: HUGHES J. , KOSTERLITZ H.W. , LESLIE FRANCES M.
Published: July 2012

Morphine inhibits the electrically evoked (0.1‐0.15 Hz, 1 ms) contractions of the longitudinal muscle of the mouse vas deferens but not of the rabbit, guinea‐pig, rat, cat, hamster or gerbil. This effect is stereospecific and is antagonized by naloxone or naltrexone.

Normorphine is equiactive with morphine but its effects are more rapid in onset and decline.

In the mouse vas deferens, the resting outflow of tritium‐labelled catecholamines is unaffected by morphine. The electrically evoked outflow is depressed by morphine or normorphine in a dose‐dependent manner. The ID50 for inhibition of contraction and for depression of outflow is 0.5 μM.

The relative agonist potencies of compounds without antagonist component (codeine, pethidine, morphine, normorphine, heroin, levorphanol, Ba‐20227, etorphine) show good correlation with the relative agonist potencies determined in the guinea‐pig ileum and for analgesia in man.

For compounds with dual agonist and antagonist properties, the dose‐response curves for agonist activity are shallow. When the lowest concentrations giving a depression of the contraction of the mouse vas deferens are used, a good correlation is obtained with the guinea‐pig ileum.

The relative antagonist potencies of naloxone, nalorphine, levallorphan and cyclazocine agree well with those obtained in the guinea‐pig ileum; these, in turn, correlate well with the values obtained in the morphine‐dependent monkey.

The fact that the agonist effects of drugs with dual agonist and antagonist action show little or no dependence on concentration, makes the mouse vas deferens particularly suitable for the assay of antagonist activity.

As an assay preparation, the mouse vas deferens is less robust and consistent in its responses than the guinea‐pig ileum.
ROLE OF CYCLIC ADENOSINE 3‘,5’‐MONOPHOSPHATE IN THE ISOPRENALINE‐INDUCED RELAXATION OF THE OESTROGEN DOMINATED RABBIT UTERUS
Authors: NESHEIM BRITT—INGJERD , OSNES J.‐B. , ØYE I.
Published: July 2012

The role of cyclic adenosine 3′,5′‐monophosphate (cyclic AMP) in the relaxation produced by isoprenaline in muscle strips from the oestrogen dominated rabbit uterus has been investigated.

Isoprenaline 2 × 10−8 M produced an inhibition of the mechanical activity but no increase in cyclic AMP. Isoprenaline 2 × 10−6 M produced both inhibition of mechanical activity and increase in cyclic AMP.

The increase in cyclic AMP, but not the inhibition of mechanical activity, was blocked by propranolol 3.4 × 10−6 M.

Dibutyryl‐cyclic AMP produced a relaxation which mimicked that produced by isoprenaline, in that the longitudinal strips were more sensitive than the circular ones.

It is concluded that cyclic AMP may be a mediator of the β‐adrenergic effect in the oestrogen dominated rabbit myometrium. However, it seems not to be an obligatory link between stimulation of β‐adrenoceptors and relaxation. Other mechanisms may also exist.
THE EFFECTS OF MORPHINE ON THE RELEASE OF NORADRENALINE FROM THE CAT ISOLATED NICTITATING MEMBRANE AND THE GUINEA‐PIG ILEUM MYENTERIC PLEXUS‐LONGITUDINAL MUSCLE PREPARATION
Authors: HENDERSON G. , HUGHES J. , KOSTERLITZ H.W.
Published: July 2012

Electrical field stimulation of either the cat isolated nictitating membrane or the guinea‐pig ileum myenteric plexus‐longitudinal muscle preparation caused the release of noradrenaline into the bathing medium.

In the cat nictitating membrane, the output per pulse of noradrenaline was constant at frequencies of stimulation from 0.5 to 15 Hz. In the guinea‐pig myenteric plexus preparation the output per pulse of noradrenaline increased as the frequency of stimulation was increased from 2 to 16 Hz.

Phenoxybenzamine (29.3 μM) caused a marked increase in the noradrenaline output from both the cat nictitating membrane and guinea‐pig myenteric plexus preparations.

Morphine (0.13‐8 μM) inhibited the contractions of the cat nictitating membrane caused by electrical stimulation. This effect was greater at low (1 Hz) than at high (15 Hz) frequencies of stimulation. The site of action is at the nerve‐smooth muscle junction.

The action of narcotic analgesic drugs on the cat nictitating membrane showed stereospecificity. Naloxone (0.1 μM) reversed the inhibition caused by normorphine (3.2 μM).

Morphine (3 μM) reduced the noradrenaline output from the cat nictitating membrane stimulated at 1 Hz but not at 15 Hz. At 1 Hz, the inhibition of noradrenaline output by normorphine (5 μM) was reversed by naloxone (0.25 μM).

Morphine (1.5 μM) did not alter the noradrenaline output from the guinea‐pig myenteric plexus preparation stimulated at 2 or 16 Hz.
PROSTAGLANDINS IN PYOMETRIAL FLUID FROM THE COW, BITCH AND FERRET
Authors: HEAP R.B. , POYSER N.L.
Published: July 2012

Pyometra is a disorder of the uterus usually associated with bacterial infection plus obstruction.

Large quantities of fluid often collect in the uterus during this condition.

Pyometrial fluid obtained from three species was found to contain prostaglandin F2α, usually in large quantities.

Prostaglandin E2 was present in smaller quantities in five of the six samples.

These findings are discussed in relation to the known occurrence of prostaglandins in inflammatory fluid, and to the problem of infertility.
THE EFFECTS OF TETRAPHENYLBORON ON SPONTANEOUS TRANSMITTER RELEASE AT THE FROG NEUROMUSCULAR JUNCTION
Authors: MARSHALL I.G. , PARSONS R.L.
Published: July 2012

The effects of tetraphenylboron (TPB) on spontaneous transmitter release were studied in the frog sartorius muscle preparation.

TPB (0.001‐1 mM) produced a time‐dependent increase in miniature endplate potential (m.e.p.p.) activity that was not sustained. TPB (0.1 mM) produced similar effects on m.e.p.p. frequency in normal Ringer solutions, in the absence of Ca2+ or Cl− and in the presence of excess Ca2+ and of tetrodotoxin. The effect of TPB (0.01 mM) was reduced but not abolished in the absence of Ca2+.

As m.e.p.p. frequency fell from its peak level in TPB (0.04 mM) m.e.p.p. amplitude was reduced. The reduction of m.e.p.p. amplitude was not prevented by choline (30–300 μM).

When m.e.p.p. activity fell below the noise level in the presence of TPB (0.1 mM), lanthanum (0.5 mM) was ineffective in promoting measurable m.e.p.p. activity.

The effects of TPB were slowly reversible by washing.

The results indicate that TPB acts to reduce the nerve terminal stores of acetylcholine, probably by a combination of rapid release and concomitant inhibition of transmitter storage.
RENAL TUBULAR TRANSPORT OF PARACETAMOL AND ITS CONJUGATES IN THE DOG
Authors: DUGGIN G.G. , MUDGE G.H.
Published: July 2012

The renal tubular transport of paracetamol and its conjugates was investigated with renal clearance and stop flow studies in the dog. Paracetamol is sparingly bound to plasma proteins and therefore undergoes glomerular filtration. It is reabsorbed in the renal tubules by simple diffusion.

The conjugates of paracetamol, the sulphate and the glucuronide, both undergo glomerular filtration being weakly protein bound. At low concentrations in plasma both compounds are secreted by an active transport process. At higher concentrations both compounds are reabsorbed. Clearances are not dependent on urinary pH or flow rate. It is concluded that reabsorption is not a passive process but that there is an active bidirectional transport of the conjugates.

Net tubular secretion of the sulphate, but not the glucuronide, conjugate was inhibited by the administration of probenecid.
DECAMETHONIUM IN THE PERFUSED AND IMMERSED RAT DIAPHRAGM
Authors: HUMPHREY P.P.A.
Published: July 2012

The water content and mannitol space of rat diaphragms which were perfused through the inferior vena cava was increased compared with immersed diaphragms. The potassium content of both preparations, when expressed in terms of dry weight, was maintained at similar values to that found in vivo.

Despite the application of a constant concentration of decamethonium, a steady level of neuromuscular block was not obtained in either the perfused or immersed rat diaphragm. The immersed preparation differed from the perfused preparation in that recovery from paralysis occurred despite the continued presence of the drug.

The rate of uptake of labelled decamethonium (100 μM) at the end‐plate region was similar in the perfused and immersed diaphragm. The slopes of the regressions were 0.059 and 0.054 μ1 mg−1 min−1 (based on dry weight) respectively which were not significantly different. This implies that the rate of uptake of the drug at the end‐plate is slow and limited by the rate of entry into the fibre rather than by diffusion to the site of entry.
THE EFFECTS OF CYCLIC N‐2‐O‐DIBUTYRYL‐ADENOSINE 3′, 5′‐MONOPHOSPHATE, ADRENALINE AND AMINOPHYLLINE ON THE ISOMETRIC CONTRACTILITY OF THE ISOLATED HEMIDIAPHRAGM OF THE RAT
Authors: KENTERA D. , VARAGIĆ V.M.
Published: July 2012

N‐2‐O‐dibutyryl adenosine 3′,5′‐monophosphate (db cyclic AMP), adrenaline and aminophylline produce a potentiation of the tension developed (Td) and the maximum rate of rise of tension (dT/dt max) in the rat isolated diaphragm during indirect electrical stimulation. Aminophylline and db cyclic AMP also produce the same effect during direct stimulation.

Propranolol produced a depression of the action of adrenaline on Td and dT/dt max during indirect stimulation of the diaphragm. On the other hand, the potentiating actions of db cyclic AMP and of aminophylline on Td and dT/dt max during indirect stimulation were unaffected by propranolol.

The results support the idea that cyclic AMP may be involved not only in regulating the processes associated with synthesis, mobilization and storage of transmitter in the motor nerve terminal, but also in modifying some metabolic processes which regulate the function of the contractile elements.
ON THE ABILITY OF PROSTAGLANDIN E1 AND ARACHIDONIC ACID TO MODULATE EXPERIMENTALLY INDUCED OEDEMA IN THE RAT PAW
Authors: LEWIS A.J. , NELSON D.J. , SUGRUE M.F.
Published: July 2012

Prostaglandins E1 and E2 but not prostaglandin F2α, arachidonic acid or linolenic acid, produced slight oedema when injected into the rat hindpaw.

Prostaglandin E1 potentiated hindpaw oedema produced by carrageenan, kaolin, bradykinin and trypsin but not that produced by 5‐hydroxytryptamine (5‐HT), histamine, dextran B or compound 48/80. Carrageenan‐ and bradykinin‐induced paw oedemas were also potentiated by prostaglandin E2. Arachidonic acid potentiated responses to carrageenan and kaolin but not responses to bradykinin, trypsin, 5‐HT, histamine, dextran B or compound 48/80. Linolenic acid did not potentiate hindpaw oedema induced by carrageenan.

Potentiation of carrageenan‐induced oedema by prostaglandin E1 was not diminished by pretreatment with indomethacin, hydrocortisone or cyproheptadine. However, arachidonic acid potentiation of carrageenan oedema was reduced by pretreatment with non‐steroidal anti‐inflammatory drugs but not by anti‐inflammatory steroids or by paracetamol.

The enhancement of the response to carrageenan and kaolin by prostaglandins E1, E2 and arachidonic acid is discussed in terms of kinin mediation.
DESENSITIZATION IN THE INNERVATED AND IN THE CHRONICALLY DENERVATED SOLEUS MUSCLE OF THE MOUSE
Authors: HALL MOIRA T. , MALEQUE M.A. , WADSWORTH R.M.
Published: July 2012

A study was made of desensitization in chronically denervated and in normally innervated mouse soleus muscles.

Very high concentrations of acetylcholine produced small contractions of the innervated muscles; these were reduced in size when the addition was repeated 1 min after wash‐out.

Desensitization in innervated muscles was receptor specific: contractions in response to KCl and caffeine were not reduced following acetylcholine, nor did KCl produce desensitization.

In chronically denervated muscles non‐specific desensitization was observed if acetylcholine was added in the presence of low concentrations of acetylcholine or carbachol. Contractions to KCl but not to caffeine were reduced. KCl produced a similar kind of desensitization.

After washing out moderate or supramaximal concentrations from the chronically denervated muscle no desensitization was observed. However, 1 min after washout of very high concentrations the muscle was non‐specifically desensitized.

It is concluded that relatively high concentrations of acetylcholine are required to produce specific desensitization in the soleus muscle. Chronically denervated muscles, being supersensitive, show non‐specific loss of sensitivity with concentrations of acetylcholine too low to produce specific desensitization.
PARALLEL BIOASSAY OF BOMBESIN AND LITORIN, A BOMBESIN‐LIKE PEPTIDE FROM THE SKIN OF Litoria aurea
Authors: ENDEAN R. , ERSPAMER V. , ERSPAMER G. FALCONIERI , IMPROTA G. , MELCHIORRI P. , NEGRI L. , SOPRANZI N.
Published: July 2012

The spectrum of biological activity exhibited by litorin, a bombesin‐like nonapeptide found in extracts of the skin of the Australian leptodactylid frog Litoria aurea was compared with that exhibited by the tetradecapeptide bombesin.

Litorin proved to be more potent than bombesin on isolated smooth muscle preparations and on the urinary bladder in situ. However, it was less potent on dog systemic blood pressure and kidney vasculature, activation of the renin‐angiotensin system being slight or lacking.

Gastrin release and acid secretion produced by litorin was more rapid in onset but less intense and less sustained than that elicited by bombesin. The same could be observed for pancreatic secretion.

Gall bladder contraction stimulated by litorin was probably caused by a double action of the peptide, directly on the bladder smooth muscle, and indirectly by cholecystokinin release.

In its effects on the myo‐electric activity of the dog duodenum (inhibition of spikes and increase in frequency of pacesetter potentials leading to the appearance of a sequence of slow and small potentials) litorin possessed approximately 50 to 70% of the activity of bombesin.
ANTAGONISM OF γ‐AMINOBUTYRIC ACID AND GLYCINE BY CONVULSANTS IN THE CUNEATE NUCLEUS OF CAT
Authors: HILL R.G. , SIMMONDS M.A. , STRAUGHAN D.W.
Published: July 2012

Some convulsant substances have been applied to single neurones in the cat cuneate nucleus by microiontophoresis. Numerical values were derived for the effectiveness and selectivity of the substances as antagonists of γ‐aminobutyric acid (GABA) and glycine.

(+)‐Bicuculline methochloride was the most effective GABA antagonist and it also excited many neurones. It antagonized GABA in 93% of experiments but also antagonized glycine in 41% of experiments. In most experiments the antagonism of GABA was greater than the antagonism of glycine resulting in an overall selective antagonism of GABA that was statistically significant. Nevertheless, in only about one quarter of the individual experiments was the GABA antagonism substantial and the selectivity clearcut.

(+)‐Bicuculline and picrotoxin were less easily applied to neurones by microiontophoresis and were found to antagonize GABA in 30% and 35% of experiments, respectively. They also antagonized glycine in 25% and 30% of experiments, respectively. Overall, neither substance could be shown to be selective, statistically, although in the few individual experiments where the GABA antagonism was substantial the antagonism was clearly selective.

(+)‐Tubocurarine antagonized GABA in 59% and glycine in 32% of experiments and it also excited many neurones. Penicillin antagonized GABA in 33% of experiments without antagonizing glycine. Neither antagonist caused any substantial antagonisms of GABA and neither showed significant selectivity overall. (—)‐Bicuculline methochloride, leptazol and bemegride antagonized GABA or glycine in less than 10% of experiments, although (—)‐bicuculline methochloride excited most neurones.

Strychnine antagonized glycine in every experiment while antagonizing GABA in only 5% of experiments. In each individual experiment the antagonism of glycine was substantial and clearly selective, resulting in a statistically significant selectivity overall.

It is concluded that the selective glycine antagonist strychnine is considerably better than the presently available GABA antagonists for distinguishing between responses to GABA and glycine, when the antagonists are applied by microiontophoresis.
STEREOSELECTIVE BINDING IN CARDIAC TISSUE OF THE ENANTIOMERS OF BENZETIMIDE, AN ANTIMUSCARINIC DRUG
Authors: GRAY J.A. , LÜLLMANN H. , MITCHELSON F. , REIL G.‐H.
Published: July 2012

Benzetimide, possessing two stable enantiomers, dexetimide and levetimide, has been investigated in guinea‐pig atria with respect to its atropine‐like action and its tissue distribution.

The antagonistic potency of dexetimide was found to be over 6000 times higher than that of levetimide, the pA2 values being 9.82 and 6.0 respectively.

The tissue accumulation was investigated for both isomers in the concentration range from 1.5 × 10−9 m to 10−6 M yielding tissue to medium ratios (T/M) of between approximately 50 and 10. The highest values were found for the lowest concentrations. At any concentration investigated, dexetimide exhibited a higher uptake than the levoisomer.

The rate of uptake and washout of dexetimide was extremely slow, that of levetimide being considerably faster at equimolar concentrations. The same pattern held true for the onset and decline of the antagonistic action.

The high accumulation was found to be almost entirely due to unspecific binding. Even in the case of dexetimide the relative size of the receptor compartment could not be determined. The unspecific binding sites displayed a certain stereoselectivity but to a much lesser extent than the specific receptor binding sites.
IDENTIFICATION OF SEPARATE RECEPTORS FOR ADENOSINE AND ADENOSINE 5′‐TRIPHOSPHATE IN CAUSING RELAXATIONS OF THE ISOLATED TAENIA OF THE GUINEA‐PIG CAECUM
Authors: SPEDDING M. , WEETMAN D.F.
Published: July 2012

The mechanisms by which adenosine 5′‐triphosphate (ATP), adenosine 5′‐diphosphate (ADP), adenosine 5′‐monophosphate (AMP) and adenosine relax the taenia caecum preparation of the guinea‐pig have been studied. ATP and ADP produced similar effects which were qualitatively different from those of AMP and adenosine.

2‐2′Pyridylisatogen tosylate (PIT: 50 μm for 30 min) blocked the effects of ATP and ADP, but exhibited weak activity against AMP and failed to antagonize the effects of adenosine. The action of PIT was unaffected by the inclusion of dipyridamole (2 μm) in the bathing fluid.

There was a significant correlation between the sensitivity of individual preparations to ATP or ADP and the blocking potency of PIT.

The presence of adenosine in the bathing fluid (2 mm for > 30 min) desensitized the taenia to subsequent applications of adenosine. The effects of ATP were increased by this procedure.

The results indicate that ATP and adenosine relax the taenia by different mechanisms.
AN IRREVERSIBLE EFFECT OF LITHIUM ADMINISTRATION TO PATIENTS
Authors: LINGSCH C. , MARTIN K.
Published: July 2012

Lithium administration to patients leads to a pronounced inhibition (about 90%) of the choline transport system in erythrocytes. The transport system does not recover when ghosts are prepared from the erythrocytes, thereby removing intracellular as well as extracellular lithium.

When a patient is taken off lithium, the choline transport in erythrocytes recovers only very slowly over a period of three months, i.e. at about the same rate at which the erythrocytes that had been exposed to lithium are replaced by new cells.

It is concluded that therapeutic concentrations of lithium produce an irreversible inhibition of the choline transport system in human erythrocytes.
THE PHARMACOLOGY OF ANAPHYLAXIS IN THE CHICKEN INTESTINE
Authors: CHAND N. , EYRE P.
Published: July 2012

The Schultz‐Dale phenomenon has been demonstrated in several circular smooth muscle strips of oesophagus, crop, duodenum, jejunum and ileum taken from young and adult domestic fowl sensitized actively to crystalline bovine albumin or horse plasma.

The ileal strips contract to acetylcholine, histamine, 5‐hydroxytryptamine (5‐HT), prostaglandins E1, E2, F2α, bradykinin and bovine slow reacting substance of anaphylaxis (SRS‐A). Marked seasonal and individual variations in the responsiveness of gut tissues to these exogenous agonists were noted.

Antagonism of contractions to histamine by mepyramine suggests the existence of H1‐histamine receptors in chicken ileum. Blockade of 5‐HT‐induced contractions by methysergide shows the preponderance of ‘D’‐musculotropic tryptamine receptors.

Failure of selective receptor antagonists of acetylcholine, histamine and 5‐HT to modify the Schultz‐Dale reaction suggests the nonparticipation of aminergic mechanisms in this reaction.

Partial to complete blockade of the Schultz‐Dale reaction by a prostaglandin receptor antagonist (polyphloretin phosphate, PPP); prostaglandin synthetase inhibitors (sodium meclofenamate and phenylbutazone); inhibitors of synthesis and release of histamine and SRS‐A (PR‐D‐92‐EA, M&B 22948, diethylcarbamazine citrate, and PPP) and an inhibitor of proteinases (aprotinin) strongly suggests the involvement of vasoactive lipids and polypeptides in the anaphylactic response of chicken ileum to specific antigen.
CIRCULATORY EFFECTS OF ORAL AND SUBCUTANEOUS ADMINISTRATION IN NORMAL SUBJECTS OF A NEW BRONCHODILATOR, IBUTEROL, A PRO‐DRUG TO TERBUTALINE
Authors: HÖGLUND ELIN , WESTLING H. , WHITE T.
Published: July 2012

The di‐isobutyryl ester of terbutaline, ibuterol, was given subcutaneously and orally to healthy volunteers and its effects on heart rate, arterial blood pressure, and ECG were compared with those of terbutaline itself. The effects of the two substances were qualitatively identical, but quantitatively different.

By mouth, ibuterol acted more rapidly, and was 2–3 times more active. After intramuscular injection, ibuterol caused less increase in local blood flow than terbutaline.

Ibuterol can be regarded as a pro‐drug, which in itself has little activity, but which can be made active in the body.
HYPOTENSION IN RABBITS INFECTED WITH Trypanosoma brucei
Authors: BOREHAM P.F.L. , WRIGHT I.G.
Published: July 2012

Blood pressures and heart rates of 12 anaesthetized rabbits chronically infected with T. brucei were measured (average infection time 39 days (range 25–67)). The systolic BP was 31.4 ± 5.7 mmHg, the diastolic BP 25.0 ± 7.2 mmHg, and the heart rate 120.5 ± 24.2 beats/minute. Two rabbits were already hypotensive 10 days after infection. In 12 anaesthetized control rabbits, the systolic BP was 66.2 ±7.3 mmHg (mean ± s.e.), the diastolic BP 60.2 ± 7.3 mmHg, and the heart rate 116.3 ±15.9 beats/minute.

The intravenous injection of 3 × 108 disintegrated trypanosomes into infected rabbits lowered the blood pressure by 41.4 ± 22.0%. Pretreatment of two rabbits with aprotinin prior to administration of parasites prevented the fall in blood pressure.

Injection of 3 × 108 live trypanosomes complexed with hyperimmune sera produced a fall of 68.3 ± 38.4% in the systolic BP of normal rabbits. Disintegrated or live trypanosomes, or hyperimmune sera alone had no effect. Pretreatment of animals with aprotinin prior to administration of the immune complex abolished the fall in BP.

The results suggest that the profound hypotension in chronic trypanosomiasis is caused by complex formation of trypanosomes with antibody. Since it can be prevented by pretreatment with aprotinin, it is likely that activation of plasma kallikrein with a subsequent release of plasma kinins contributes to this effect.
PHARMACOLOGICAL PROPERTIES OF N‐(3′,4′‐DIMETHOXYCINNAMOYL) ANTHRANILIC ACID (N‐5′), A NEW ANTI‐ATOPIC AGENT
Authors: AZUMA H. , BANNO K. , YOSHIMURA T.
Published: July 2012

N‐(3′,4′‐dimethoxycinnamoyl) anthranilic acid (N‐5′) exhibited a dose‐dependent, potent inhibition of the passive cutaneous anaphylaxis (PCA) mediated by homocytotropic antibodies (HTA), which was hardly affected by anti‐inflammatory agents such as phenylbutazone, indomethacin and prednisolone at any dose used. The HTA‐induced PCA was significantly inhibited by combined treatment with diphenhydramine and cyproheptadine.

Doses of N‐5′ which potently inhibited HTA‐induced PCA inhibited only slightly the heterologous PCA produced by anti‐bovine serum albumin (BSA) rabbit serum. This heterologous PCA was clearly inhibited by phenylbutazone, indomethacin and prednisolone. Diphenhydramine and cyproheptadine, singly or combined inhibited the heterologous PCA only slightly.

The increased vascular permeability caused by histamine and 5‐hydroxytryptamine was significantly inhibited by diphenhydramine or cyproheptadine, but not by N‐5′ and the anti‐inflammatory agents used.

N‐5′ 150 mg/kg orally inhibited rat paw oedema induced by carrageenin by about 26% while phenylbutazone, indomethacin and prednisolone produced significant inhibition.

N‐5′ at concentrations of 100 and 1000 μm significantly inhibited (by about 52% and 95%, respectively) the histamine release from rat peritoneal cells induced by HTA; 10 μm N‐5′ had little effect. Histamine release was inhibited by phenylbutazone or indomethacin at 1000 μm but not at 100 μm. Prednisolone had no effect on histamine release at any of the concentrations used.

These findings suggest that the inhibition of the HTA‐induced PCA by N‐5′ may be due to inhibition of histamine release and is clearly different from the actions of anti‐inflammatory agents such as phenylbutazone, indomethacin and prednisolone.
EFFECT OF AMINOPHYLLINE ON TRYPTOPHAN AND OTHER AROMATIC AMINO ACIDS IN PLASMA, BRAIN AND OTHER TISSUES AND ON BRAIN 5‐HYDROXYTRYPTAMINE METABOLISM
Authors: CURZON G. , FERNANDO J.C.R.
Published: July 2012

Aminophylline and other methylxanthines increase brain tryptophan and hence 5‐hydroxytryptamine turnover. The mechanism of this effect of aminophylline was investigated.

At lower doses (≯ 100 mg/kg i.p.) the brain tryptophan increase could be explained by the lipolytic action of the drug, i.e. increased plasma unesterified fatty acid freeing plasma tryptophan from protein binding so that it became available to the brain.

Plasma unesterified fatty acid did not increase when aminophylline (100 mg/kg i.p.) was given to nicotinamide‐treated rats but as both plasma total and free tryptophan rose, a tryptophan increase in the brain still occurred.

The rise in brain tryptophan concentration following the injection of a higher dose of the drug (150 mg/kg i.p.) could no longer be explained by a rise of plasma free tryptophan as the ratio of brain tryptophan to plasma free tryptophan rose considerably. Plasma total tryptophan fell and the plasma insulin concentration rose.

The increase of brain tryptophan concentration after injection of 150 mg/kg aminophylline appeared specific for this amino acid as brain tyrosine and phenylalanine did not increase. However as their plasma concentrations fell the brain/plasma ratio for all three amino acids rose.

The higher dose of aminophylline increased the muscle concentration of tryptophan but that of tyrosine fell and that of phenylalanine remained unaltered. The liver concentrations were not affected.

The aminophylline‐induced increases of the ratio of brain tryptophan to plasma free tryptophan no longer occurred when the drug was given to animals injected with the β‐adrenoceptor blocking agent propranolol or the diabetogenic agent streptozotocin.

The changes in brain tryptophan upon aminophylline injection may be explained by (a) increased availability of plasma tryptophan to the brain due to increased lipolysis and (b) increased effectiveness of uptake of tryptophan by the brain due to increased insulin secretion.
EFFECT OF IONIZING RADIATION ON PROSTAGLANDIN‐LIKE ACTIVITY IN TISSUES
Authors: EISEN V. , WALKER D.I.
Published: July 2012

One to 7 days after whole body exposure of mice to a single dose of 700 R of x‐rays, little or no change was detected in prostaglandin‐like activity in the brain, blood and seminal vesicles. Slight increases in intestinal and renal tissue were not significant. In the lung, mean activity rose from 62 ng/g to a transient peak of 145 ng/g wet weight on the fourth day (P > 0.05). In the spleen, mean levels rose steadily from 13.2 ng/g to 259 ng/g on the fourth day (P < 0.01), and were still 184.4 ng/g on the seventh day.

Prostaglandin‐like activity was measured 4 days after single doses of 200–700 R. In the lung, a significant rise was produced by 600 and 700 R, and in the spleen by 200–700 R.

Thin layer chromatography showed that part of the prostaglandin‐like activity in spleen extracts had an RF similar to that of [3H]‐prostaglandin E1, and part to that of [3H]‐prostaglandin F2α.

Splenic tissue from mice exposed to 700 R four days earlier, inactivated prostaglandin E1 less potently than did tissue from non‐irradiated mice.
IS THE CONTRACTILE RESPONSE TO EXOGENOUS ACETYLCHOLINE DUE TO A PRESYNAPTIC EFFECT?
Authors: LEE C.Y. , TSAI M.C.
Published: July 2012

Whether the contractile response induced by exogenous acetylcholine (ACh) chiefly involved the pre‐or post‐synaptic junctional site of the motor endplate was studied by using the cat gastrocnemius nerve muscle preparation poisoned with β‐bungarotoxin (β‐BuTX), a toxin isolated from the venom of Bungarus multicinctus which acts presynaptically.

After neuromuscular transmission was completely blocked by β‐BuTX, the dose‐response curve of the contractile response induced by close intra‐arterial injection of ACh, was compared with that of the control. No appreciable difference was observed.

In contrast, the response to ACh was completely abolished when neuromuscular transmission was blocked by α‐bungarotoxin, a toxin isolated from the same venom which acts postsynaptically.

It is concluded that postjunctional site of the motor end‐plate is chiefly involved in the contractile response produced by exogenous ACh.
THE EFFECT OF NON‐STEROIDAL ANTI‐INFLAMMATORY DRUGS ON ADENOSINE TRIPHOSPHATE CONTENT AND HISTAMINE RELEASE FROM RAT PERITONEAL CELL SUSPENSIONS RICH IN MAST CELLS
Authors: CHAMPION G.D. , DAY R.O. , RAY J.E. , WADE D.N.
Published: July 2012

Non‐steroidal anti‐inflammatory drugs (NSAID) suppressed compound 48/80‐induced histamine release from rat peritoneal cells in vitro in a dose‐dependent manner.

NSAID suppressed the adenosine triphosphate (ATP) content of rat peritoneal cells in vitro and this correlated strongly with the suppression of compound 48/80‐induced histamine release.

The correlation demonstrated suggests that the mechanism of action of NSAID in the rat peritoneal cells is via depletion of cellular ATP.
EFFECT OF p‐BROMOPHENACYL BROMIDE, AN INHIBITOR OF PHOSPHOLIPASE A2, ON ARACHIDONIC ACID RELEASE AND PROSTAGLANDIN SYNTHESIS BY THE GUINEA‐PIG UTERUS in vitro
Authors: MITCHELL SHEILA , POYSER N.L. , WILSON N.H.
Published: July 2012

The synthesis of prostaglandins F2α and E2 by guinea‐pig uterine homogenates was inhibited by p‐bromophenacyl bromide (PBPAB), an inhibitor of phospholipase A2.

Metabolism of prostaglandin F2α by uterine homogenates was undetectable; this was not affected by PBPAB.

There was no significant difference between the amounts of arachidonic acid released from uterine homogenates on days 7 and 15 of the oestrous cycle. Small amounts of dihomo‐γ‐linolenic acid were detected in the homogenates.

The release of arachidonic acid from uterine homogenates was greatly inhibited by PBPAB.

Addition of exogenous arachidonic acid to uterine homogenates did not overcome the inhibition of uterine prostaglandin F2α synthesis produced by PBPAB.

It is concluded that PBPAB inhibits both the release of arachidonic acid from the guinea‐pig uterus and its subsequent conversion into prostaglandins.
EFFECT OF HARMALINE ON SODIUM TRANSPORT IN Rana esculenta SKIN
Authors: EHRENFELD J. , GARCIA‐ROMEU F.
Published: July 2012

Harmaline, together with certain hallucinogenic alkaloids of the same group (harmine, 2 methyl harmine) stimulates sodium transport across the in vitro skin of Rana esculenta when it is added to the external medium at a low concentration (0.1 mm). This effect is due to an increase of the sodium influx, and is reversed by washing. It is suggested that harmaline intervenes at the sodium penetration sites at the external face of the transport compartment.

At a higher concentration (5 mm) added to the internal medium harmaline inhibits sodium net absorption. The inhibition is due mainly to an increase of the efflux, while the influx may be either inhibited or increased. Under these conditions the influx becomes insensitive to amiloride. It is suggested that the inhibition of sodium transport is the result of harmaline interfering with a transport ATPase, and also that harmaline induces new sites for the passage of sodium.
INTERACTION OF COCAINE WITH CHLORDIAZEPOXIDE ASSESSED BY MOTOR ACTIVITY IN MICE
Authors: D'MELLO G. , STOLERMAN I.P.
Published: July 2012

Effects of a range of doses of cocaine and chlordiazepoxide given separately and as mixtures were determined on the spontaneous locomotor activity of mice.

Cocaine increased locomotor activity (walking) during 3 or 5 min trials in a dose‐related manner.

Chlordiazepoxide had little effect on the total amount of locomotor activity except for depression at very high doses. A lower dose of chlordiazepoxide increased activity at the beginning of the trials only.

Mixtures containing certain doses of cocaine and chlordiazepoxide increased locomotor activity to a much greater extent than cocaine alone. This high level of activity was manifested throughout 5 min trials.

This action of cocaine is similar to that of amphetamine.
STEREOSPECIFICITY OF 2,4‐DIAMINOBUTYRIC ACID WITH RESPECT TO INHIBITION OF 4‐AMINOBUTYRIC ACID UPTAKE AND BINDING
Authors: JOHNSTON G.A.R. , TWITCHIN B.
Published: July 2012

S(+)‐2,4‐Diaminobutyric acid is at least 20 times more potent than the R(—)‐stereoisomer as an inhibitor of the sodium‐dependent uptake of 4‐aminobutyric acid (GABA) in rat brain slices. Both isomers, however, are equipotent as inhibitors of sodium‐independent binding of GABA to membranes from rat brain. The latter finding may be relevant to the reported neurotoxicity in rats of both isomers of 2,4‐diaminobutyric acid after intracisternal injection.
EVIDENCE FOR DOPAMINE DEAMINATION BY BOTH TYPE A AND TYPE B MONOAMINE OXIDASE IN RAT BRAIN in vivo AND FOR THE DEGREE OF INHIBITION OF ENZYME NECESSARY FOR INCREASED FUNCTIONAL ACTIVITY OF DOPAMINE AND 5‐HYDROXYTRYPTAMINE
Authors: GREEN A.R. , MITCHELL B.D. , TORDOFF ANN F.C. , YOUDIM M.B.H.
Published: July 2012

1 Tranylcypromine (20 mg/kg) administration to rats totally inhibited brain monoamine oxidase (MAO) oxidation of 5‐hydroxytryptamine (5‐HT), phenylethylamine and dopamine as measured in vitro. When l‐3,4‐dihydroxyphenylalanine (l‐DOPA) (50 mg/kg) was given 30 min after the tranylcypromine, brain dopamine and noradrenaline concentrations rose markedly and the rats displayed characteristic behavioural changes and locomotor activity.

2 Clorgyline (5 mg/kg) administration inhibited 5‐HT oxidation by almost 100% but phenylethylamine by only 29% while (‐)‐deprenil (5 mg/kg) injection almost totally inhibited phenylethylamine oxidation and inhibited 5‐HT metabolism by only 31%. Administration of l‐DOPA after pretreatment with either drug did not alter brain dopamine or noradrenaline concentrations and the animals did not display any behavioural changes.

3 Administration of clorgyline plus (‐)‐deprenil (5 mg/kg of each) almost totally inhibited oxidation of both phenylethylamine and 5‐HT; there was a large rise of brain dopamine and noradrenaline concentrations and the animals displayed the behavioural changes observed when tranylcypromine and l‐DOPA had been given.

4 The effects of tranylcypromine (20 mg/kg) on brain 5‐HT, dopamine and noradrenaline concentrations up to 48 h after injection were recorded. Brain 5‐HT concentrations were considerably elevated for 18 h after injection and then fell steadily. In contrast, brain dopamine concentrations rose slightly and remained at this level for 48 h while noradrenaline levels doubled and also remained at this level for 48 hours.

5 When l‐tryptophan (50 mg/kg) was given at various times after tranylcypromine the characteristic hyperactivity syndrome appeared at 12 h but not 18 h after tranylcypromine and a further rise in brain 5‐HT was only observed at 12 hours. When l‐DOPA (50 mg/kg) was given at various times after tranylcypromine a further large rise in brain dopamine and noradrenaline occurred at 12 h but not at 18 h and all the behavioural changes were observed only at 12 hours.

6 Measurement of MAO activity at the above times after tranylcypromine showed that the half‐life of recovery of the enzyme activity with 5‐HT and dopamine as substrates was 4.5 days and 8.5 days with phenylethylamine as substrate. Inhibition of MAO oxidation of dopamine and 5‐HT was approximately 85%, 18 h after tranylcypromine injection.

7 It is concluded from both the studies with clorgyline and deprenil and the recovery of MAO activity after tranylcypromine, that dopamine is metabolized by both Type A and Type B MAO in vivo and that it is only when both forms are almost totally inhibited that there is an increase in dopamine and 5‐HT functional activity, as judged by the appearance of the hyperactivity syndromes.
A POTENT NEW β2‐ADRENOCEPTOR BLOCKING AGENT
Authors: IMBS J.L. , MIESCH F. , SCHWARTZ J. , VELLY J. , LECLERC G. , MANN A. , WERMUTH C.G.
Published: July 2012

1 (t‐Butyl‐amino‐3‐ol‐2‐propyl) oximino‐9 fluorene is a new β2‐adrenoceptor blocking agent with a pA2 of 9.23 ± 0.25 on isolated trachea.

2 It provokes hypertension in normotensive rats and does not prevent arterial hypertension in SHR rats, although it does prevent the renin secretion normally induced by isoprenaline infusion.
THE EFFECT OF ZINC ON ANAPHYLAXIS in vivo IN THE GUINEA‐PIG
Authors: CHO C.H. , DAI S. , OGLE C.W.
Published: July 2012

The protective effects of pretreatment with zinc sulphate aerosols against bronchoconstriction induced by egg albumen or histamine aerosols were assessed in sensitized or non‐sensitized guinea‐pigs respectively. Pretreatment with an adequate concentration of zinc sulphate aerosol significantly prolonged the time of onset of bronchoconstriction in sensitized guinea‐pigs challenged with egg albumen, but did not appreciably alter the onset time of histamine‐induced bronchoconstriction in non‐sensitized animals. These findings suggest that zinc aerosols may be of prophylactic value against bronchoconstriction of allergic origin.
CHARACTERIZATION OF (±)‐METHADONE UPTAKE BY RAT LUNG
Authors: CHI C.H. , DIXIT B.N.
Published: July 2012

By use of a sensitive and specific fluorescence assay procedure it was shown that after subcutaneous administration to rats, (±)‐methadone was concentrated in the lung. Lung to serum ratios ranging from 25 to 60 were obtained indicating that the rat lung tissue was capable of extracting (±)‐methadone against a concentration gradient.

This phenomenon was investigated in vitro with rat lung slices incubated in Krebs‐Ringer phosphate buffer (pH 7.4). The uptake was expressed in terms of tissue to medium concentration ratios (T/M ratio).

The principal observations were: (i) Studies on the time‐course of the uptake showed that the T/M ratios of (±)‐methadone increased rapidly during the first 60 min of incubation and then more slowly, with a plateau occurring at 180 min; (ii) The T/M ratio of (±)‐methadone progressively increased from 9.5 to 17 as the pH of the incubation medium was varied from 6.2 to 7.8; (iii) When the concentration of (±)‐methadone in the incubation medium was varied from 0.005 to 0.5 mM, the T/M ratio decreased rapidly suggesting self‐saturation of the transport process. Beyond the medium concentration of 0.5 mM, the T/M ratio declined very slowly.

These results suggested that at low concentrations, (±)‐methadone was transported predominantly by a self‐saturable process while at higher concentrations it was transported by a process of simple diffusion.

At low concentrations (0.01 mM) the uptake of (+)‐methadone was higher than that of (‐)‐isomer indicating stereo‐specificity of the uptake process. The uptake of (±)‐methadone at low concentration (0.01 mM) was significantly inhibited by low temperature, lack of O2, lack of glucose, lack of Na+ in the incubation medium, and by exposure of the tissue to high temperature (≅100°C). The uptake was also inhibited by relatively high concentration of iodoacetate (1.0 mM) and of naloxone (1.0 mM).

Kinetic analysis of data showed that the diffusion constant for (±)‐methadone was 5.0 (h−1) and the Vmax of the active transport process was 6.5 μmol g−1 h−1.
THE INFLUENCE OF GASTRIC EMPTYING ON PLASMA CONCENTRATIONS OF THE ANALGESIC, MEPTAZINOL
Authors: FRANKLIN R.A.
Published: July 2012

The influence of gastric emptying on the rate of absorption and peak plasma concentrations of meptazinol was studied in monkeys by comparison of the plasma concentrations of the drug achieved after intragastric and intraduodenal administration of the compound. Absorption was much more rapid and plasma concentrations were very much higher after intraduodenal than after intragastric dosage.

Determination of the ‘normal’ gastric emptying time in rats and monkeys showed that this was much longer in the monkey than in the rat. In addition, meptazinol was shown to have a pronounced retarding action on gastric emptying in the monkey, an effect which was not apparent in the rat.

The significance of these observations in relation to the species difference in oral potency of the drug is discussed.
CATECHOL‐SUBSTITUTED PHENOXY‐PROPANOLAMINES: ADRENOCEPTOR ACTIVITY IN THE ANAESTHETIZED CAT
Authors: DOWD H. , KEH G.S. , RAPER C.
Published: July 2012

The pharmacological actions of racemic noradrenaline, adrenaline, isoprenaline and N‐t‐butylnoradrenaline have been compared with those of their corresponding derivatives containing an oxymethylene (OXY) link between the ring and ethanolamine side chain.

The compounds were tested in the anaesthetized cat for their ability to produce positive chronotropic effects, bronchodilator actions, changes in perfusion pressure in the perfused hind limb and decreases in soleus muscle contractions.

In comparison with the parent compounds, the OXY‐derivatives of adrenaline and noradrenaline had very weak α‐adrenoceptor stimulant effects.