bluuebunny/crossref_metadata_2025 huggingface dataset:
5‐HYDROXYTRYPTAMINE AND DOPAMINE TRANSPORT BY RAT AND HUMAN BLOOD PLATELETS
Authors: GORDON J.L. , OLVERMAN H.J.
Published: July 2012

Uptake of 5‐hydroxytryptamine (5‐HT) by rat platelets in plasma was very rapid and diffusion did not contribute significantly at substrate concentrations that did not saturate the active transport.

Under conditions which allowed measurement of initial rates of uptake, kinetic analysis revealed a high affinity uptake mechanism for 5‐HT (Km = 0.7 μM).

Uptake of dopamine was relatively slow and involved a lower affinity (Km = 70 μM) active transport process. Diffusion contributed significantly at concentrations that did not saturate the active transport.

5‐HT competitively inhibited uptake of dopamine, and vice versa; Ki values for both amines were similar to their respective Km values for uptake.

Chlorimipramine, desmethylimipramine and benztropine were tested as uptake inhibitors. Each was equipotent against 5‐HT and dopamine, although the absolute potency of the drugs varied greatly. Chlorimipramine was the most potent (Ki ≃ 100 nM), and kinetic analysis revealed that the inhibition was competitive against both 5‐HT and dopamine.

Similar results were obtained in studies with human platelets: Km values for 5‐HT and dopamine were about 1μM and 100 μM respectively. Activity profiles of inhibitors were also similar: each compound tested was equipotent against 5‐HT and dopamine, and the two amines each competitively inhibited uptake of the other.

We conclude that dopamine is actively transported by platelets via the 5‐HT uptake mechanism, but with a much lower affinity. There is no high‐affinity dopamine‐specific mechanism corresponding to that in the corpus striatum. Consequently although platelets may be valid models of transport in 5‐hydroxytryptaminergic neurones, they should not be regarded as models for the dopamine transport mechanism found in dopaminergic neurones.
RESPONSES OF THE PITUITARY‐ADRENAL SYSTEM OF THE PIG TO ENVIRONMENTAL CHANGES AND DRUGS
Authors: BLATCHFORD D. , HOLZBAUER MARGARETHE , INGRAM D.L. , SHARMAN D.F.
Published: July 2012

The reactivity of the pituitary‐adrenal axis of the young pig was tested for its suitability as a sensitive index for any discomfort that might be experienced under certain conditions of intensive husbandry.

In a thermoneutral environment, most undisturbed piglets showed only slight variations in the plasma concentrations of adrenocorticotrophic hormone (ACTH) and corticosteroids.

Stimuli such as exposure to ambient temperatures of +40°C or −5°C were required to cause large rises in the plasma concentrations of ACTH and corticosteroids.

Apparently milder stimuli, such as change of environment, slight frustration or changes in ambient temperatures between +5°C and +30°C only rarely caused a significant rise in plasma corticosteroids. Thus changes in plasma corticosteroid concentrations are not a sensitive index for the reaction of a piglet to its environment.

Increases in plasma ACTH concentrations occurred faster than those of the corticosteroids, were larger when expressed as a percentage of the basal values and occurred following relatively small disturbances such as omission of the reward in an operant behaviour test when corticosteroid changes were often not detectable. Thus rises in plasma ACTH might be a useful indication that a given situation is disturbing to a pig. The reaction of plasma ACTH concentrations to chronic irritations as they might occur in intensive husbandry remains to be investigated.

Azaperone (2 mg/kg i.m.), a drug which is used as a sedative in pigs, caused a rise of about 50% in plasma corticosteroid concentrations. It did not diminish the large steroid output seen when the animals were exposed to high and low ambient temperatures.
THE ACTIONS OF DIAZEPAM AND PHENYTOIN ON A LOW DOSE PENICILLIN EPILEPTIFORM FOCUS IN THE ANAESTHETISED RAT
Authors: GARTSIDE I.B.
Published: July 2012

A technique is described for the induction of an acute short‐lived epileptiform focus by the local injection of benzyl penicillin 25 units into the cerebral cortex of rats anaesthetized with urethane. The effects of anticonvulsants on this microfocus have been studied.

Phenytoin 20 mg/kg and diazepam 1 mg/kg intravenously significantly reduced the frequency of the normally occurring surface positive electrocorticogram (ECoG) plateaux and caused a greater decrease in the frequency of the epileptiform spikes normally associated with these plateaux.

A novel effect was seen in that both anticonvulsant drugs significantly reduced the amplitude of the epileptiform spike within the focus, as well as causing an even larger decrease in the amplitude of the propagated spike. The contribution of the anticonvulsant drug effect on the focal spike to its effect on propagated activity is discussed.
A STUDY OF THE SYMPATHOMIMETIC ACTION OF GUANETHIDINE ON THE ISOLATED ANOCOCCYGEUS MUSCLE OF THE RAT
Authors: FOSTER R.W. , SHAH D.S. , SMALL R.C.
Published: July 2012

Guanethidine, acting on the rat isolated anococcygeus, causes adrenergic neurone blockade (slowly terminated by washing), noradrenaline potentiation and, with higher concentrations, spasm (both rapidly terminated by washing).

The spasm is an indirect sympathomimetic action, for it is sensitive to phentolamine and reserpine and shows tachyphylaxis.

The concentration of cocaine equieffective with the spasmogenic concentration of guanethidine as an inhibitor of noradrenaline uptake caused much less spasm. Moreover, it did not enhance noradrenaline efflux from anococcygeus loaded with (−)‐[3H]‐nor adrenaline, as guanethidine did.

The spasm induced by guanethidine in excess of cocaine is due to guanethidine‐evoked noradrenaline release.
DIMINISHING HYPOTENSIVE EFFECT OF INCREASING DOSES OF PINDOLOL IN DOCA/SALINE HYPERTENSIVE RATS
Authors: BUCKINGHAM R.E. , HAMILTON T.C. , ROBSON D.
Published: July 2012

In DOCA‐saline hypertensive rats, pindolol (4, 20 or 50 mg/kg orally) produced a hypotensive effect which was inversely related to dose. Following adrenal demedullation, a hypotensive response to the highest dose of pindolol was unmasked and the magnitude of the responses to lower doses was increased. The results suggest that adrenal catecholamines moderate the hypotensive effects of high doses of pindolol.
ADRENAL ORIGIN OF PLASMA CATECHOLAMINES AFTER DECAPITATION: A STUDY IN NORMAL AND DIABETIC RATS
Authors: BERKOWITZ B.A. , HEAD R.J.
Published: July 2012

The concentrations of catecholamines and the activities of dopamines‐hydroxylase were measured in blood obtained from decapitated diabetic and aged‐matched control rats. The activity of dopamines‐hydroxylase in blood from diabetic rats was much greater (5 fold) than that seen for control rats. For both diabetic and control rats, decapitation was accompanied by an increase in levels of adrenaline and noradrenaline with no change in the activity of plasma dopamines‐hydroxylase. The results are consistent with a predominantly adrenal origin of catecholamines and extra‐adrenal origin of dopamine‐β‐hydroxylase. The high activity of dopamines‐hydroxylase in diabetes indicates either an increased activity of the sympathetic nervous system or changes in dopamines‐hydroxylase turnover.
THE ACTION OF BRADYKININ AND OXYTOCIN ON THE ISOLATED WHOLE UTERUS AND MYOMETRIUM OF THE RAT IN OESTRUS
Authors: WHALLEY E.T.
Published: July 2012

A technique is described for obtaining a myometrial preparation devoid of endometrium, from the uterus of the rat in oestrus.

Acetylcholine and prostaglandin F2α (PGF2α) produced concentration‐effect curves with the same maximal tensions and slope on the whole uterus and myometrial preparations. Concentration‐effect curves to bradykinin and oxytocin on the myometrial preparation were altered, resulting in a shift to the right and a decreased maximum response compared with those produced by the whole uterus.

Indomethacin produced greater antagonism of the responses of the whole uterus to bradykinin and oxytocin than to acetylcholine and PGF2at, whereas responses of the myometrium to all four agonists were similarly depressed.

Responses of the myometrial preparation to a range of concentrations of bradykinin and oxytocin were significantly enhanced by prior sensitization of the myometrium to PGF2flt. This significant enhancing effect of PGF2flt was only seen with the threshold dose of acetylcholine.

It appears that the mechanism of action of bradykinin and oxytocin on the rat uterus involves both a direct action and an indirect action. The indirect action possibly involves release of prostaglandins) from the endometrium.
A NEW BIOASSAY FOR GLUCAGON
Authors: GAGNON G. , REGOLI D. , RIOUX F.
Published: July 2012

The relaxant action of glucagon has been studied in strips of rabbit renal arteries partially contracted by a low concentration (1 ng/ml) of noradrenaline.

The preparation was relaxed in a dose‐dependent manner by concentrations of glucagon varying between 25 ng/ml and 420 ng/ml.

The relaxant effect of glucagon (0.1 μg/ml ≅ ED60) on this preparation was not affected by propranolol (5.0 μg/ml), cimetidine (10 μg/ml), diphenhydramine (10 μg/ml), indomethacin (5.0 μg/ml), phentolamine (1.2 μg/ml), atropine (10 μg/ml) and 8‐Leu‐ATII (1.0 ng/ml) but was slightly potentiated by Des‐Arg9 Leu‐OMe8‐Bk (25 μg/ml) and indomethacin (50 μg/ml).

The dose‐response curve to glucagon remained parallel in the presence of papaverine (2.5 μg/ml) but was shifted to the left by a factor of 2.5 to 2.8. Theophylline (250 μg/ml) also potentiated the vascular relaxation induced by glucagon.

Insulin (10 μg/ml) did not influence the relaxant effect of glucagon.

The removal of the N‐terminal amino acid (His) of glucagon reduced by 89% the biological activity of this fragment on the vascular preparation. The removal of the C‐terminal amino acids Met‐27, Asn‐28 and Thr‐29 of glucagon resulted in a fragment which was inactive either as an agonist or as an antagonist when tested at concentrations as high as 925 ng/ml.

It is concluded that the relaxation of partially contracted strips of rabbit renal arteries by glucagon constitutes a simple, sensitive, relatively specific and reliable bioassay which may be useful for the determination of glucagon in biological materials and for structure‐activity relationship studies with this hormone.
METABOLISM AND DISTRIBUTION OF EXOGENOUS HISTAMINE IN CATS
Authors: IMRIE P.R. , MARLEY E. , THOMAS D.V.
Published: July 2012

The metabolism and disposition in blood and tissues of exogenous [14C]‐histamine was examined in cats.

The principal metabolites in blood of histamine instilled into the small intestine (directly or by transfer from the stomach) and colon were imidazoleacetic acid and t‐methylimidazoleacetic acid, being present in approximately equal amounts although in individual cats one or other acid could predominate. Only small amounts of histamine entered the circulation although in two of four cats given the largest dose (82 μmol/kg) large amounts were recovered. The amount of 14C radioactivity absorbed varied directly with the dose instilled. The chief metabolite in kidney and urine, whether histamine was instilled into the intestine or infused parenterally, was t‐methylimidazoleacetic acid. Histamine was not absorbed from the stomach and its metabolism there was negligible.

In contrast, when histamine was infused into blood leaving the intestine (portal vein) the main metabolite in blood and tissues was t‐methylimidazoleacetic acid being found in approximately 5‐fold the concentration of imidazoleacetic acid. The small amount of histamine which eluded inactivation/uptake by liver, lungs, heart during the infusion was halved on circulation through the intestine. When histamine was infused into blood supplying the intestine, (cranial mesenteric artery) t‐methylimidazoleacetic acid while still the major metabolite in blood was now only 1.4 times the concentration of imidazoleacetic acid. Additionally, the blood concentration of histamine during the infusion exceeded that of the metabolites.

t‐Methylimidazoleacetic acid was also the principal metabolite in blood and tissues following histamine infusion into a cannula carrying a replacement venous blood supply to the liver of abdominally eviscerated cats. Imidazoleacetic acid and t‐methylhistamine were present in equal concentrations and in one‐quarter to one‐third that of the methylated acid. The latter was also the principal metabolite following intra‐arterial histamine infusion to abdominally eviscerated cats without a hepatic blood supply, although initially tmethylhistamine predominated: a large peak of histamine was present during the infusion period. When additionally the renal vessels were ligated, tmethylhistamine predominated throughout the experiment.

In conclusion, intraduodenally instilled histamine was metabolized equally by diamine oxidase and imidazole N‐methyltransferase (followed by deamination by monoamine oxidase). In contrast, imidazole N‐methyltransferase was the principal inactivator of parenterally infused histamine, deamination of tmethylhistamine by monoamine oxidase becoming progressively less efficient with the cumulative exclusion of the intestines, liver and kidney from the circulation.
In vitro EFFECTS OF NON‐STEROIDAL ANTI‐INFLAMMATORY DRUGS ON HUMAN POLYMORPHONUCLEAR CELLS AND LYMPHOCYTE MIGRATION
Authors: BROWN K.A. , COLLINS A.J.
Published: July 2012

The action of the non‐steroidal anti‐inflammatory drugs (NSAID), sodium salicylate, aspirin, phenylbutazone and indomethacin was investigated on the migration of human polymorphonuclear cells (PMNs) and lymphocytes, using the system of migration of leucocytes from glass capillary tubes.

All NSAID produced a dose‐dependent inhibition of cell migration, and were more effective on the migration of the PMN than on lymphocytes.

Drugs optimally suppressed PMN migration after 20 to 24 h incubation, and lymphocytes after

to 6 h.

Prolonged incubation of cells with several concentrations of NSAID demonstrated an ‘escape’ from inhibition in PMNs prepared from one subject.
ASPIRIN, PROTEIN TRANSACETYLATION AND INHIBITION OF PROSTAGLANDIN SYNTHETASE IN THE KIDNEY
Authors: CATERSON ROBYN J. , DUGGIN GEOFFREY G. , HORVATH JOHN , MOHANDAS JANARDANAN , TILLER DAVID
Published: July 2012

The effect of aspirin on the kidney has been investigated in mice and rabbits. [Acetyl‐14C]‐aspirin was administered intraperitoneally in doses ranging from subtherapeutic to toxic. The degree of acetylation of protein was determined by the radioactivity remaining on protein precipitates of renal cortex and medulla after sequential washing designed to remove non‐covalently bound material. Controls were established, by the use of [carboxyl‐14C]‐aspirin.

The acetyl‐14C residue was bound to renal proteins in a linear manner in increasing amounts with increasing dosage up to 100 mg/kg. The [carboxyl‐14C]‐aspirin was not bound and thus the salicylate portion of the molecule was not bound covalently to the renal protein. The time course of the acetylation was rapid, consistent with the rate of aspirin absorption. The disappearance of acetylated protein was slow, with a Tl/2 of 112.5 h in the renal cortex, and 129.5 h in the renal medulla.

Differential centrifugation, Sephadex chromatography and gel electrophoresis were carried out on tissue homogenates to determine the site of acetylation. The acetylation was greatest in the microsomal fraction, although all protein fractions showed some degree of acetylation.

The prostaglandin synthetase activity of a particulate preparation from rabbit kidney was determined by a spectrophotometric assay of malondialdehyde formation. Aspirin (10 mg/kg, i.v.) significantly inhibited prostaglandin synthetase in the renal cortex and medulla.

Aspirin and renal proteins undergo a transacetylation reaction resulting in stable acetylated protein, with acetylation being greatest in the microsomal fraction. Aspirin has been shown to inhibit prostaglandin synthetase and this could lead to functional impairment of the tissue.
EFFECTS OF CALCIUM ON ACID SECRETION FROM THE RAT ISOLATED GASTRIC MUCOSA DURING STIMULATION WITH HISTAMINE, PENTAGASTRIN, METHACHOLINE AND DIBUTYRYL CYCLIC ADENOSINE‐3′,5′‐MONOPHOSPHATE
Authors: MAIN I.H.M. , PEARCE J.B.
Published: July 2012

An isolated gastric mucosal preparation from immature rats is described. The mucosal surface was superfused and acid secretion was recorded continuously by monitoring H+‐ion concentration.

Repeated stimulation with submaximal concentrations of histamine or dibutyryl cyclic adenosine 3′,5′‐monophosphate (db cyclic AMP) produced consistent responses. Secretion induced by pentagas‐trin and methacholine demonstrated varying degrees of tachyphylaxis. All responses were readily reversed on washing out the secretagogue.

Reduction of Ca2+ from 3.6 mm increased responses to histamine, pentagastrin and methacholine while increase of Ca2+ to 7.2 mm decreased responses. Db cyclic AMP‐induced secretion was not influenced by external Ca2+.

When Mg2+ was raised from 1.2 mm responses to histamine and pentagastrin increased. Replacement of Ca2+ with Mg2+ produced a transient increase followed by a decrease in responses.

The similarity of the effects of Ca2+ on pentagastrin, methacholine and histamine indicates that neither pentagastrin nor methacholine act via Ca2+‐dependent histamine release.
ANTAGONISM BY CLONIDINE OF NEURONAL DEPRESSANT RESPONSES TO ADENOSINE, ADENOSINE‐5′‐MONOPHOSPHATE AND ADENOSINE TRIPHOSPHATE
Authors: STONE TREVOR W. , TAYLOR DAVID A.
Published: July 2012

Adenosine and its nucleotides adenosine‐5′‐monophosphate (AMP) and adenosine triphosphate (ATP) have been applied by microiontophoresis to neurones in the cerebral cortex of rats anaesthetized with urethane. The firing rate of most neurones was depressed, though two cells were encountered which showed biphasic responses to ATP consisting of an initial excitation succeeded by depression.

The application of clonidine with iontophoretic currents of less than 25 nA resulted in blockade of the depressant responses to the purines, without affecting responses to noradrenaline, 5‐hydroxytryptamine or γ‐aminobutyric acid (GABA). At much higher doses of clonidine, direct depression of cell firing occurred and occasional interaction with noradrenaline was noted.

In the case of the biphasic responses to ATP, clonidine seemed to block only the depressant phase. Reduction of the excitatory component paralleled changes of background firing.

It is concluded that, in common with some other 2‐substituted imidazoline derivatives, clonidine possesses the ability to block responses to purine compounds.
DEPRESSION OF EVOKED POTENTIALS IN BRAIN SLICES BY ADENOSINE COMPOUNDS
Authors: SCHOLFIELD C.N.
Published: July 2012

A study has been made of the action of adenosine on surface slices of guinea‐pig olfactory cortex in vitro.

With extracellular recordings from the pial surface and stimulation of the presynaptic input, the lateral olfactory tract (LOT) generated a monosynaptic negative wave representing dendritic excitatory potentials. This negative wave was depressed by bath application of 1 μm adenosine with increasing effect up to 1 mm. Adenosine 5′‐triphosphate (ATP), adenosine 5′‐monophosphate (AMP) and cyclic adenosine 3′,5′‐monophosphate (cyclic AMP) had similar depressant actions. Adenine and guanosine were very weak depressants.

Theophylline concentrations in the range 10 μm to 3 mm progressively antagonized the action of adenosine.

Dibutyryl cyclic AMP (100 μm) and agents which increase intracellular cyclic AMP were not depressants, suggesting that the action of adenosine was not cyclic AMP‐mediated.

Intracellular recordings confirmed the depressant effect of adenosine on excitatory potentials generated by LOT stimulation and also showed that postsynaptic action potentials and the membrane of the soma were unaffected by adenosine.

Since presynaptic action potentials were also unaffected by adenosine, these experiments suggest that adenosine reduces excitatory transmission at LOT synapses and fortifies the idea that adenosine has a ‘neurohumoral’ action.
EFFECTS OF DROPERIDOL ON ACTIVITY OF CAROTID BODY CHEMORECEPTORS IN CAT
Authors: AMINOFF M.J. , JAFFE R.A. , SAMPSON S.R. , VIDRUK E.H.
Published: July 2012

The effect of droperidol on the spontaneous activity of carotid body chemoreceptors and on their response to various stimuli was studied in 21 anaesthetized, paralyzed and artificially ventilated cats. Carotid body blood flow was controlled with a perfusion pump, and drugs were injected into the perfusion circuit.

In low doses, droperidol transiently increased the rate of spontaneous chemoreceptor activity, but in higher doses it depressed chemoreceptor activity after an initial stimulation.

Droperidol reduced or abolished the normal increase in chemoreceptor activity produced by stagnant asphyxia. This effect did not depend solely on the ability of droperidol to suppress spontaneously occurring impulses. Chemoreceptor responses to sodium cyanide, and to dopamine were also inhibited.

Dopamine antagonists other than droperidol were also studied for their effect on chemoreceptor activity. Chlorpromazine depressed spontaneous chemoreceptor activity and also reduced the chemoreceptor responses to sodium cyanide and dopamine, as did pimozide. The effects of these dopamine antagonists were much briefer and less marked than those of droperidol.

Although the influence that we have shown droperidol to have on peripheral chemoreceptor activity has an uncertain basis, it may have important implications in human and veterinary medicine.
POTENTIATION BY SUBSTANCE P OF CONTRACTIONS OF THE ISOLATED VAS DEFERENS OF THE MOUSE ELICITED BY ELECTRIC FIELD STIMULATION AND BY DRUGS
Authors: BLACKWELL M. , JAMES T.A. , STARR M.S.
Published: July 2012

Isolated vasa deferentia from the mouse were opened longitudinally and suspended in Krebs solution at 37°C in an organ bath. Contractions of the muscle were elicited by electric field stimulation, noradrenaline (10−6m) and acetylcholine (10−6m). Continued transmural stimulation evoked a biphasic response comprising a rapid twitch followed about 10s later by a smaller, sustained rise in muscle tone.

The amplitudes of nerve‐mediated and drug‐induced responses were considerably potentiated by substance P (SP) in the dose range 10−12 to 10−7m. Higher concentrations of SP were directly spasmogenic. The sensitizing property of SP was dose‐dependent and was usually well maintained, but always disappeared quickly on washing the preparation. In some experiments SP facilitated the twitch, but not the subsequent phase of the electrically‐induced contraction or the response to externally applied noradrenaline.

Phentolamine (10−6m) failed to block this effect of SP, but itself potentiated the nerve‐mediated twitch, and completely abolished the sustained secondary contraction.

Desmethylimipramine (10−6m) enhanced the delayed contraction but not the immediate contraction.

The uptake of tritiated noradrenaline (3 × 10−7m) by vasa was inhibited by desmethylimipramine (10−6m) and increased by nialamide (3 × 10−5m), but was not modified by SP (10−6m).

Nerve‐mediated release of accumulated radioactivity was accelerated by phentolamine, but not by SP or desmethylimipramine.

These findings suggest that SP sensitizes the muscle cells to depolarizing stimuli but that it has no facilitatory effect on sympathetic neural elements.
A COMPARISON OF NICOTINE AND STRUCTURALLY RELATED COMPOUNDS AS DISCRIMINATIVE STIMULI
Authors: CHANCE WILLIAM T. , KALLMAN MARY D. , ROSECRANS JOHN A. , SPENCER R. MASON
Published: July 2012

Of seven nicotine‐like compounds tested as discriminative stimuli in the rat, only 3‐pyridyl‐meth‐ylpyrollidine (3‐PMP) generalized to the stimulus effects of nicotine.

3‐PMP caused equivalent nicotine‐like responding at a dose (800 μg/kg) approximately 4 times that used for the original nicotine discrimination (200 μg/kg). The ED50 for 3‐PMP was about 5 times that for nicotine.

Testing of the compounds as possible antagonists of the nicotine‐elicited cue were negative.

The nicotine‐like cue produced by an 800 μg/kg injection of 3‐PMP was effectively blocked by mecamylamine but not by hexamethonium or atropine. Thus, 3‐PMP appears to produce generalization to the nicotine cue via action on central nicotinic‐cholinoceptors as has been previously reported for the nicotine discriminative stimulus.

Mecamylamine blocked the stimulus‐effects of 3‐PMP (800 μg/kg) and of nicotine (200 μg/kg) with an ED50 of 0.32 and 0.20 mg/kg respectively.
COMPARISON OF THE RESPONSES OF SINGLE CORTICAL NEURONES TO TYRAMINE AND NORADRENALINE: EFFECTS OF DESIPRAMINE
Authors: BEVAN P. , PUN R.Y.K. , SZABADI E.
Published: July 2012

The technique of microelectrophoresis was used in order to compare the actions of tyramine and noradrenaline on single neurones in the cerebral cortex of the rat.

Tyramine could both excite and depress cortical neurones. Each tyramine‐sensitive cell was also sensitive to noradrenaline. There was a high correlation between the directions of responses to tyramine and noradrenaline, most cells excited by tyramine being excited by noradrenaline, and most cells depressed by tyramine being depressed by noradrenaline.

In the case of both excitatory and depressant responses, tyramine appeared to be less potent than noradrenaline.

Tyramine evoked ‘slower’ responses than noradrenaline, both the latencies to onset and the recovery times being longer for responses to tyramine than for responses to noradrenaline.

When the rates of release of tyramine and noradrenaline from micropipettes were measured in vitro, no significant difference could be observed between the transport numbers of the two drugs. Thus the difference in potency between the two drugs, and the difference in the time courses of responses to the two drugs, are presumably of biological origin.

Desipramine could discriminate between neuronal responses to tyramine and noradrenaline: responses to tyramine were antagonized, while responses to noradrenaline were either potentiated or unaffected. Responses to DL‐homocysteic acid were not affected by desipramine.

The results are consistent with the hypothesis that tyramine is an indirectly acting sympathomimetic amine in the brain, and desipramine acts by blocking the uptake of both tyramine and noradrenaline into presynaptic noradrenergic nerve terminals.
THE EFFECTS OF UPTAKE, ON α‐ADRENOCEPTOR ANTAGONIST POTENCY IN DOG SAPHENOUS VEIN
Authors: HUMPHREY P. P. A.
Published: July 2012

The effects of α‐adrenoceptor antagonists on contractile responses to noradrenaline and methoxamine were examined in isolated saphenous vein strips of the dog.

Phentolamine, labetalol and thymoxamine antagonized responses to methoxamine to a greater extent than responses to noradrenaline.

Cocaine (3.0 × 10−5 mol/1) increased the potency of noradrenaline by about eight fold, but had little or no effect on the potency of methoxamine.

In the presence of cocaine (3.0 × 10−5 mol/1) the potency of the antagonists against noradrenaline was increased such that the pA2 values were then similar to those obtained against methoxamine.

It is concluded that the lower potency of phentolamine, labetalol and thymoxamine as antagonists of noradrenaline than of methoxamine is due to the presence of an avid saturable uptake! process in the saphenous vein.
A COMPARISON OF THE ANTIFERTILITY EFFECTS OF ALKYLATING AGENTS AND VINCA ALKALOIDS IN MALE RATS
Authors: COOKE R.A. , NIKLES A. , ROESER H.P.
Published: July 2012

The anti‐fertility effects of cyclophosphamide, nitrogen mustard, vincristine and vinblastine were studied and compared in male rats.

The effects of the drugs on body weight and haematological values were used to monitor the pharmacological actions of the drugs.

All four drugs impaired fertility, the severity of the impairment depending on dose and duration of treatment.

Testicular size and histological appearances remained mostly normal, even in infertile animals, but seminiferous tubules were fewer in number and maturation arrest at the spermatid level was evident in some sections.

Recovery of drug‐induced infertility occurred in 64% of treated animals, 9 to 40 weeks after cessation of treatment.

Morbidity and mortality were much higher with alkylating agents than with vinca alkaloids for approximately similar degrees of impairment in fertility.
THE EFFECT OF STIMULUS INTENSITY ON α‐ADRENOCEPTOR‐MEDIATED FEED‐BACK CONTROL OF NORADRENALINE RELEASE
Authors: HARPER BARBARA , HUGHES I. E.
Published: July 2012

Mouse vas deferens stimulated transmurally (2.5 Hz, 2–32 V, 40–620 mA, for 45 s) responded with a twitch and a secondary contraction. Both responses were abolished by cinchocaine and were voltage‐dependent.

In tissues previously incubated with [3H]‐(—)‐noradrenaline, stimulation also produced an increase in tritium overflow from the tissue. Phentolamine increased tritium overflow by 19% at high stimulus intensities (30 V, 600 mA) and by 130% at low stimulus intensities (11 V, 200 mA).

It is concluded that α‐adrenoceptor‐mediated feed‐back control of noradrenaline release is more marked at low stimulus intensities and that this is compatible with a role for calcium ions in this control mechanism.
AN INVESTIGATION OF THE ROLE OF GANGLIA IN THE INNERVATION OF THE RAT ANOCOCCYGEUS MUSCLE: AN ELECTRICAL AND MECHANICAL STUDY
Authors: McKIRDY H.C. , MUIR T.C.
Published: July 2012

A preparation is described which allows the rat anococcygeus muscle to be stimulated via its two extrinsic nerves. Each nerve contains both excitatory and inhibitory fibres. A ganglionated nerve plexus lies on the surface of the muscle.

The possibility that at least part of the excitatory pathway was interrupted by a ganglion synapse lying in one of the nodes of plexus close to the muscle was suggested by the observations that (a) the excitatory response to extrinsic nerve stimulation was reduced by the nicotinic antagonists tubocurarine (0.13 to 0.26 mm) and dihydro β‐erythroidine (0.1 to 0.14 mm), (b) Fibres from one extrinsic nerve were shown to synapse on a ganglion cell from which intracellular recordings were made while the output from this ganglion cell was traced microscopically to the muscle.

Intracellular recording from ganglion cells in this plexus indicated that cholinergic synaptic transmission occurred in these ganglia. Tubocurarine (0.13 mm) and hexamethonium (1.3 mm) reversibly abolished intracellularly‐recorded synaptic potentials.

Hexamethonium (0.1 to 1 mm) initially enhanced the motor response to nerve stimulation and raised muscle tone, probably by an action involving pre‐ and postsynaptic sites. Subsequently, hexamethonium inhibited the response to extrinsic nerve stimulation presumably by an effect at ganglia lying along the excitatory pathway. Hexamethonium enhanced, without subsequently inhibiting, the response to exogenously added noradrenaline in both untreated and 6‐hydroxydopamine‐treated rats. These results suggest that the initial enhancement produced by hexamethonium involved sites at postganglionic nerve endings and on smooth muscle receptors.

Inhibitory responses were obtained following extrinsic nerve stimulation when the tone of the muscle was raised and the excitatory response abolished by either guanethidine (3 μm) alone or by carbachol (10 μm) followed by phentolamine (3 μm). The inhibitory response was not reduced by hexamethonium (up to 2.8 mm) tubocurarine (up to 1.3 mm) or by atropine (up to 1 μm).
β‐ADRENOCEPTOR ANTAGONISTS INHIBIT THE BEHAVIOURAL RESPONSES OF RATS TO INCREASED BRAIN 5‐HYDROXYTRYPTAMINE
Authors: COSTAIN D.W. , GREEN A.R.
Published: July 2012

The effect of various β‐adrenoceptor blocking agents on the 5‐hydroxytryptamine (5‐HT)‐induced hyperactivity response produced in rats by administration of tranylcypromine (10 mg/kg i.p.) followed by L‐tryptophan (50 mg/kg i.p.) has been investigated.

(±)‐Alprenolol, (±)‐timolol, (+)‐sotalol, (±)‐pindolol (all at 40 mg/kg) all inhibited the hyperactivity response to some degree when given 45 min before the tranylcypromine, as did (±)‐oxprenolol when given after the L‐tryptophan.

β‐Adrenoceptor antagonists that are not found in the brain in appreciable amount after peripheral injection, (+)‐atenolol, (±)‐practolol, (+)‐labetalol and (+)‐acebutalol, did not inhibit the 5‐HT‐mediated behaviour.

Neither the β‐selective drug (±)‐metoprolol, nor the β2‐selective drug (±)‐butoxamine inhibited the behavioural response.

The drugs that blocked the 5‐HT‐mediated behaviour did not alter brain 5‐HT concentrations, synthesis rate or the accumulation of 5‐HT following tranylcypromine/L‐tryptophan. However, they did inhibit the hyperactivity produced by the suggested 5‐HT agonist, 5‐methoxy N,N‐dimethyltrypt‐amine, indicating that the β‐adrenoceptor blocking drugs were inhibiting the post‐synaptic 5‐HT‐mediated response.

Circling produced by methamphetamine (3 mg/kg) in unilateral nigro‐striatal lesioned rats was not altered by alprenolol, sotalol, pindolol or metaprolol, indicating that these drugs do not alter dopamine‐mediated behaviour.

It is concluded that non‐selective (fix and p2) adrenoceptor antagonists which have a high brain/ blood ratio following their peripheral injection, block 5‐HT‐mediated behavioural responses in the rat.
THE RELEASE OF PROSTAGLANDINS AND THROMBOXANES FROM GUINEA‐PIG LUNG BY SLOW REACTING SUBSTANCE OF ANAPHYLAXIS, AND ITS INHIBITION
Authors: ENGINEER DINAZ M. , MORRIS H.R. , PIPER PRISCILLA J. , SIROIS P.
Published: July 2012

Rabbit aorta contracting substance (RCS; consisting mainly of thromboxane A2) and prostaglandin‐like material were released from guinea‐pig isolated perfused lungs by injection of slow reacting substance of anaphylaxis (SRS‐A).

SRS‐A was resistant to boiling and proteolytic enzymes and was therefore distinguished from rabbit aorta contracting substance releasing factor (RCS‐RF).

The release of RCS and prostaglandin‐like material by SRS‐A was anatagonized by indomethacin (1 μg/ml), betamethasone and dexamethasone (4 to 50 μg/ml).

Imidazole (200 μg/ml) inhibited the formation of thromboxane A2 but not that of prostaglandins.

The activity of SRS‐A on guinea‐pig ileum and its ability to release RCS and prostaglandins were destroyed by incubation with arylsulphatase (0.83 μg to 1 mg/ml) and with lipoxidase (16.5 to 50 μg/ml): SRS‐A lost activity on incubation with bovine serum albumin (9 μg/ml) due to protein binding.
LOCALIZATION OF VASODILATOR DOPAMINE RECEPTORS IN THE CANINE HINDLIMB
Authors: BELL C. , STUBBS A.
Published: July 2012

Vascular responses to local injection of dopamine and isoprenaline have been compared in the blood‐perfused gracilis muscle and hind paw pads of dogs anaesthetized with chloralose.

In the paw pads, dopamine (0.5 to 5.0 ug) caused a transient vasoconstriction followed by dose‐dependent vasodilatation. α‐Adrenoceptor blockade converted this response to pure vasodilatation, which was attenuated or abolished by the dopamine‐receptor antagonist, haloperidol (1 to 2mg i.a.). In the gracilis, dopamine produced only vasoconstriction. Following α‐adrenoceptor blockade this was abolished, but only a very small dilator response was revealed.

Isoprenaline (0.05 to 0.5 ug) caused dose‐dependent dilatation in both beds, which was attenuated by propranolol (0.1 mg/kg i.v.).

Glyceryl trinitrate (0.2 to 5.0 ug) was used to assess vascular reactivity. When responses to isoprenaline and dopamine were compared with those to glyceryl trinitrate, both beds had approximately equal reactivity to isoprenaline. In contrast the paw pads were 10 fold more responsive to dopamine than was the gracilis.

We conclude that the vessels of the paw pads play an important part in the femoral dilator response to dopamine.
PROSTAGLANDIN D2 IS THE PREVAILING PROSTAGLANDIN IN THE ACUTE INFLAMMATORY EXUDATE OF URATE ARTHRITIS IN THE CHICKEN
Authors: ANHUT HENNING , BRUNE KAY , FRÖLICH JURGEN C. , PESKAR BERNHARD A.
Published: July 2012

An acute inflammation was elicited in intertarsal joints of chicken by injection of urate crystals. Inflammatory exudates recovered at different times were assayed for prostaglandin D2(PGD2) E2 and F2α and thromboxane B2 content by specific radioimmunoassays. We found that PGD2 was the prevailing prostaglandin reaching concentrations up to 10 times in excess of PGE2. This finding was confirmed by gas chromatography‐mass spectrometry. It is concluded that PGD2 should be considered as a possible mediator of acute inflammation.
COMPARATIVE PHARMACOLOGICAL AND HISTOCHEMICAL EVIDENCE FOR PURINERGIC INHIBITORY INNERVATION OF THE PORTAL VEIN OF THE RABBIT, BUT NOT GUINEA‐PIG
Authors: BURNSTOCK GEOFFREY , CROWE RAHIMA , WONG HELEN K.
Published: July 2012

Intramural nerve stimulation elicited a powerful relaxation of the longitudinal muscle of the rabbit portal vein in the presence of atropine and guanethidine, but not of the guinea‐pig portal vein.

Intramural nerve stimulation of the rabbit portal vein produced a 13 fold increase in release of 3H‐adenyl compounds after preloading with [3H]‐adenosine. About 50% of this release was abolished by guanethidine. All release was abolished by tetrodotoxin. No significant release of radioactive compounds was observed during intramural nerve stimulation of the guinea‐pig portal vein in the presence of guanethidine, although there was a 6 fold increase in release of radioactivity in the absence of drugs.

Histochemical studies using quinacrine, which binds ATP showed a fine fluorescent nerve plexus, nerve bundles, and ganglion cells in the rabbit portal vein, but not in the guinea‐pig portal vein. This plexus was still present after chemical sympathectomy with 6‐hydroxydopamine.

Adenosine 5′‐triphosphate (ATP) relaxed the rabbit portal vein, but usually produced a biphasic response, consisting of a contraction followed by a relaxation, of the guinea‐pig portal vein.

Prostaglandins E1 and E2 caused contraction of the rabbit portal vein. Indomethacin, a prostaglandin synthesis inhibitor, potentiated the relaxations of the rabbit portal vein produced by both non‐adrenergic, non‐cholinergic nerve stimulation and ATP.

High concentrations of antazoline and phentolamine, which antagonize purinergic responses in the guinea‐pig taenia coli, caused a loss of basal tone so that it was not possible to assess their effects on the responses of the portal vein to either non‐adrenergic, non‐cholinergic nerve stimulation, or ATP.

Comparison of the results on the portal vein of the rabbit and guinea‐pig provides support for the view that: (i) quinacrine fluorescence can be used to localize purinergic nerves and that the rabbit portal vein is supplied by these nerves; (ii) ATP is released from adrenergic nerve fibres, although, based on histochemical analysis, about 3 to 7 times less than is released from purinergic nerve fibres.
SATURABLE ADENOSINE 5′‐TRIPHOSPHATE‐INDEPENDENT BINDING OF [3H]‐OUABAIN TO BRAIN AND CARDIAC TISSUE in vitro
Authors: AKERA TAI , BRODY THEODORE M. , WIEST SALLY A.
Published: July 2012

Several investigators have proposed that membrane Na+, K+‐adenosine 5′‐triphosphatase (Na+, K+‐ATPase) is a mechanism for the transmembrane transport of cardiac glycosides, rather than the receptor for pharmacological actions of these agents. This implies that the glycosides bind to an intracellular constituent (receptor) other than Na+, K+‐ATPase.

In search for such a receptor site, saturable ATP‐independent [3H]‐ouabain binding was studied in rat brain and dog and guinea‐pig heart homogenates. The binding of the glucoside to this site results in a relatively unstable complex which is stabilized by K+ to a lesser extent than is the complex formed with the ATP‐dependent binding to Na+, K+‐ATPase.

The ATP‐independent ouabain binding sites are more abundant in rat brain tissue than in cardiac tissue, and have a lower ouabain affinity compared to the binding sites on Na+, K+‐ATPase.

These results do not support the contention that there are intracellular inotropic receptors for digitalis.
PRESYNAPTIC AND POSTSYNAPTIC CONTRIBUTIONS TO ONTOGENY OF SYMPATHETIC CONTROL OF HEART RATE IN THE PRE‐WEANLING RAT
Authors: SEIDLER F.J. , SLOTKIN T.A.
Published: July 2012

The dependence of heart rate on sympathetic nerve development and on ontogeny of cardiac responses to sympathetic neurotransmitters was evaluated in neonatal rats by use of the ganglionic blocking agent, chlorisondamine, and the β‐adrenoceptor agonist, isoprenaline.

Basal heart rates of anaesthetized 4, 7 and 11 day old rats were the same as in adult rats, but the heart rate in 16 day old rats (an age at which sympathetic tone appears to be elevated) was significantly higher.

Chlorisondamine failed to lower heart rate significantly in 4 or 7 day old rats, but lowered the rate by 50 to 80 beats per min in the older animals and eliminated the difference in rate between 16 day old and the other ages; atropine had little or no effect on heart rate.

Heart rate responses to isoprenaline were lower in 4, 7 and 11 day old rats than they were in adults but were indistinguishable from them by 16 days of age, indicating that the heart is less sensitive to β‐adrenoceptor stimulation early in neonatal life.

The ontogeny of sympathetic control of heart rate in the rat depends upon maturational changes in both presynaptic and postsynaptic elements.
TIME‐DEPENDENT STIMULATORY AND INHIBITORY EFFECTS OF PROSTAGLANDIN Ex ON EXUDATIVE AND TISSUE COMPONENTS OF GRANULOMATOUS INFLAMMATION IN RATS
Authors: BONTA I.L. , PARNHAM M.J.
Published: July 2012

The effects of prostaglandin (PGE1), following local administration during different phases of developing sponge‐induced granulomata, were studied in normal and essential fatty acid deficient (EFAD) rats.

In normal rats, a single dose of 1 μg PGE1 on implantation (day 1) increased exudate production without altering total leucocyte counts after 6 h and stimulated granulomatous tissue formation after 8 days.

Repeated daily administration of the same dose of PGEX on days 1 to 3 had no effect, while administration on days 4 to 7 (i.e. when tissue growth is already in progress) inhibited granuloma formation.

In EFAD rats, which are known to produce only very small amounts of endogenous prostaglandins, acute (6 h) exudate formation was unaffected by 0.05 μg PGEj. However, early stimulatory and later inhibitory effects of 0.05 μg PGE1 per day were obtained on the granulomatous tissue, similar to those obtained with the 20 fold higher dose in normal rats.

The early stimulatory action of PGEX on granulomatous tissue formation was enhanced, in normal rats, by concomitant administration of 10 jag theophylline. This latter compound did not influence the later inhibitory effect of PGEj.

These results indicate that PGE1 exerts either pro‐ or anti‐inflammatory actions on the proliferative (tissue) component of the inflammatory process, depending on the time of administration. While the stimulatory effect following early administration may have been secondary to an initial cyclic adenosine 3′, 5′‐monophosphate‐mediated, vascular response, such a mechanism is unlikely to have been responsible for the later anti‐inflammatory action of PGEj.

The implications of these results are discussed in relation to the postulated negative‐feedback role of endogenous PGE in chronic inflammation.
THE EFFECT OF PARGYLINE AND DESMETHYLIMIPRAMINE ON MONOAMINE CONCENTRATIONS AND AMPHETAMINE‐INDUCED GLYCOGENOLYSIS IN THE MOUSE BRAIN
Authors: HUTCHINS D.A.
Published: July 2012

Pargyline (100 mg/kg) increased the concentration of cerebral noradrenaline dopamine and 5‐hydroxytryptamine in the mouse. Amphetamine (5 mg/kg) reduced the concentration of noradrenaline and increased the concentrations of 5‐hydroxytryptamine and dopamine.

When amphetamine was administered 4 h after an injection of pargyline, the effect of the sympathomimetic drug on the concentrations of noradrenaline and 5‐hydroxytryptamine was not altered. The effect on the dopamine content was reversed, amphetamine causing a decrease instead of an increase.

Pargyline increased the concentration of cerebral glycogen, whereas amphetamine caused a decrease.

The administration of amphetamine 4 h after pargyline resulted in a decrease in brain glycogen similar to that seen after amphetamine alone.

These results suggest that the potentiation of the effect of amphetamine on animal behaviour by pretreatment with an inhibitor of monoamine oxidase is not mediated through a central action on noradrenaline release.

Amphetamine‐induced glycogenosis was antagonized by 71% by desmethylimipramine (10 mg/kg).

The change in glycogen concentration as a function of time after an injection of amphetamine was not modified when 2 consecutive doses of amphetamine were given with an interval between doses of 30 minutes.
PHARMACOLOGICAL PROPERTIES OF ACETYLCHOLINE‐INDUCED EXCITATION OF SUBTHALAMIC NUCLEUS NEURONES
Authors: FEGER JEAN , HAMMOND CONSTANCE , ROUZAIRE‐DUBOIS BEATRICE
Published: July 2012

In 15 rats anaesthetized with ketamine, microiontophoretically applied acetylcholine (ACh) excited all 58 cells studied in the subthalamic nucleus (STN).

The ACh‐evoked excitation was slow in onset and outlasted the ACh application. There was no sign of desensitization when the ACh application was prolonged or repeated. The excitation was prolonged by a concomitant application of physostigmine.

Acetyl‐β‐methyl choline and oxotremorine were effective cholinomimetics. Nicotine had no effect.

The ACh excitation was antagonized by atropine and scopolamine but not by mecamylamine.

It was concluded that STN ACh receptors are muscarinic in character.

Since large microiontophoretic applications of Mg2+ did not suppress ACh‐evoked excitation, it is suggested that ACh acts postsynaptically.

The excitatory response of STN cells to striatal or pallidal stimulation was unaffected by atropine administered either microiontophoretically to single cells or intravenously (3 mg/kg) to the whole animal.
SPECIES DIFFERENCES IN THE BINDING OF COMPOUNDS DESIGNED TO FIT A SITE OF KNOWN STRUCTURE IN ADULT HUMAN HAEMOGLOBIN
Authors: BEDDELL C.R. , GOODFORD P.J. , STAMMERS D.K. , WOOTTON R.
Published: July 2012

Oxygen dissociation curves are reported for human haemoglobins A1, FII, FI, A1C and Raleigh ifil valine → acetylalanine) and for horse haemoglobin in the absence and presence of 2,3‐diphos‐phoglycerate (DPG), or 4,4′‐diformyl‐2‐bibenzyl oxyacetic acid, or the bisulphite addition compound of the latter.

These haemoglobins were selected because their amino acid sequences are different at the DPG receptor site of human adult deoxyhaemoglobin.

The size of the shifts of the dissociation curves are in the sequence expected from the postulated numbers of interactions made by each compound with each haemoglobin type, based on the assumption of a common receptor site for the three compounds.

Multiple linear regression analysis shows that the free energies of interaction of the compounds with the haemoglobins may be predicted, to a first approximation, by summing the number of ionic and covalent bonds predicted for each effector‐receptor combination, a reversible covalent bond contributing about twice as much energy (‐6.78 kJmol−1) as an ionic interaction (−3.14 kJmol−1).