bluuebunny/crossref_metadata_2025 huggingface dataset:
A COMPARISON OF AN IMPROVED O‐PHTHALALDEHYDE FLUORO‐METRIC METHOD AND HIGH PRESSURE LIQUID CHROMATOGRAPHY IN THE DETERMINATION OF BRAIN 5‐HYDROXYINDOLES OF RATS TREATED WITH L‐TRYPTOPHAN AND p‐CHLOROPHENYL‐ALANINE
Authors: CURZON G. , KANTAMANENI B.D. , TRICKLEBANK M.D.
Published: July 2012

The determination of 5‐hydroxytryptamine (5‐HT) and 5‐hydroxyindoleacetic acid (5‐HIA A) by reaction with o‐phthalaldehyde (OPT) in the presence of cysteine and subsequent fluorometry was compared with determination by a new high pressure liquid chromatography (h.p.l.c.) electrochemical method.

The methods were used to investigate a claim that the OPT method gives falsely high brain 5‐HT values for rats given tryptophan (> 25mg/kg i.p.) and as a consequence an inhibition of 5‐HT synthesis by tryptophan is obscured.

High concentrations of tryptophan caused some increase of fluorescence when added to 5‐HT solutions and carried through the OPT method, e.g. tryptophan (80 μg/ml) gave fluorescence = 5‐HT (0.13 mUg/ml). This interference was decreased by more than half and the sensitivity of the method increased if cysteine was added at more stages and fluorescence developed at 77°C instead of 100°C.

The h.p.l.c. and modified OPT methods did not give significantly different mean brain 5‐HT or 5‐HIAA values in rats given 0,25,100,250 mg/kg L‐tryptophan though values were somewhat higher by the OPT method with the highest dose. This method gave significantly higher residual brain 5‐HT values (12% of control) than did the h.p.l.c. method (8% of control) after inhibiting 5‐HT synthesis by p‐chlorophenylalanine (150 mg/kg× 3).

There was no indication that tryptophan inhibited 5‐HT synthesis even when brain tryptophan was increased about 30 fold (from 3.8 to 124 μg/g).

Results confirm the general reliability of the OPT method although h.p.l.c. has some advantages i.e. separation of 5‐hydroxyindoles from tryptophan, greater sensitivity, ease of automation.
PRE‐ AND POSTSYNAPTIC α‐ADRENOCEPTOR BLOCKING ACTIVITY OF RAUBASINE IN THE RAT VAS DEFERENS
Authors: DEMICHEL PATRICIA , GOMOND PATRICK , ROQUEBERT JACQUES
Published: July 2012

The actions of raubasine, yohimbine and corynanthine at pre‐ and postsynaptic α‐adrenoceptors were studied in the rat vas deferens.

Low frequency electrical stimulation of the isolated vas deferens of the rat produced regular contractions that were inhibited by low concentrations of clonidine. This inhibition was presynaptic in origin and involved α‐adrenoceptors.

Presynaptic α‐adrenoceptor antagonist activity was assessed by studying the effect of increasing antagonist concentrations on cumulative clonidine dose‐response curves on the stimulated vas deferens.

Postsynaptic α‐adrenoceptor antagonist activity in the isolated vas deferens was assessed by comparing control cumulative noradrenaline dose‐response curves in the absence and in the presence of increasing concentrations of antagonists.

The results indicate that raubasine and corynanthine preferentially block postsynaptic α‐adrenoceptors. Yohimbine is more potent in blocking pre‐ than postsynaptic α‐adrenoceptors. The ratio of the pre/postsynaptic potency declines in the order yohimbine > raubasine > corynanthine.
EFFECT OF INTRACISTERNAL 5,7‐DIHYDROXYTRYPTAMINE ON THE ACUTE ANTIHYPERTENSIVE ACTION OF PROPRANOLOL IN THE SINO‐AORTIC DENERVATED ANAESTHETIZED DOG
Authors: MONTASTRUC JEAN‐LOUIS , MONTASTRUC PAUL
Published: July 2012

The anti‐hypertensive effects of intravenously and intracisternally administered (±)‐propranolol were studied in anaesthetized dogs with acute neurogenic (sino‐aortic denervation) hypertension. The animals were pretreated 7 days earlier with intracisternally administered 5,7‐dihydroxytryptamine (5,7‐DHT 200 μg/kg plus desipramine 5 mg/kg i.v.).

5,7‐DHT (plus desipramine) failed to decrease both basic blood pressure and heart rate measured before sino‐aortic denervation. After 5,7‐DHT (plus desipramine) pretreatment, acute sino‐aortic denervation induced a rise in blood pressure and stimulated the heart rate, these effects being similar (in intensity and duration) to those observed in control (saline‐pretreated) debuffered dogs during the first hour following the deafferentation.

In debuffered dogs, (±)‐propranolol given by intracisternal (50 μg/kg) or intravenous (300 μg/kg) routes descreased both blood pressure and heart rate.

5,7‐DHT (plus desipramine) pretreatment abolished the antihypertensive effect of intracisternal propranolol whereas the action of intravenous propranolol was only delayed. In contrast, this pretreatment failed to reduce and even sometimes enhanced the negative chronotropic response induced by propranolol.

These results suggest that central 5‐hydroxytryptaminergic pathways play an important role in the acute hypotension elicited by intracisternal (±)‐propranolol in debuffered hypertensive anaesthetized dogs, but little, if any in propranolol‐induced bradycardia.
5′‐N‐ETHYLCARBOXAMIDOADENOSINE: A POTENT INHIBITOR OF HUMAN PLATELET AGGREGATION
Authors: CUSACK N.J. , HOURANI S.M.O.
Published: July 2012

5′‐N‐ethylcarboxamidoadenosine (NECA) is an adenosine analogue which is 22,900 times more potent than adenosine as a vasodilator. Adenosine and some of its analogues are also inhibitors of human platelet aggregation. NECA was tested for its effects on human platelets.

NECA (1 μm) inhibited human platelet aggregation induced by adenosine 5′‐diphosphate (ADP), adrenaline, 5‐hydroxytryptamine (5‐HT) and thrombin more powerfully than adenosine. NECA was 5 to 10 times more potent than adenosine at inhibiting ADP‐ and adrenaline‐induced aggregation.

NECA, like adenosine, caused dose‐dependent increases in levels of platelet adenosine 3′,5′‐cyclic monophosphate (cyclic AMP), which were competitively inhibited by theophylline, an adenosine antagonist.

These effects of NECA, like those of adenosine, were completely stereospecific as the l‐enantiomer of NECA was inactive.

NECA did not interfere with the inhibition by ADP of prostaglandin E1 (PGE1)‐stimulated adenylate cyclase.

NECA is the most potent analogue of adenosine tested so far on human platelets, and is the first example of a 5′ modification to retain affinity for the platelet adenosine receptor.
STUDIES OF THE EFFECTS OF AGENTS WHICH ALTER CALCIUM METABOLISM ON ACETYLCHOLINE TURNOVER IN THE RAT DIAPHRAGM PREPARATION
Authors: GUNDERSEN CAMERON B. , JENDEN DONALD J.
Published: July 2012

We measured the effects of agents, which are thought to alter the Ca2+ concentration in cells, on tissue and released acetylcholine and choline of rat diaphragm using a gas chromatographic mass spectrometric assay for acetylcholine and choline.

Lanthanum and ouabain increased the resting output of acetylcholine, while 4‐aminopyridine enhanced the evoked output of acetylcholine.

Guanidine first increased and then depressed acetylcholine release.

Theophylline, dinitrophenol and the ionophore, A‐23187, had no measurable effect on acetylcholine release and tetraethylammonium inhibited the release of acetylcholine.

Dinitrophenol caused a highly significant increase of the tissue and released choline.

None of these agents increased the tissue acetylcholine content. Tetraethylammonium caused a large decline of tissue acetylcholine while ouabain and guanidine caused smaller reductions of acetylcholine in diaphragm.

These results are discussed in relation to the hypothesis that intraterminal Ca2+ activity regulates the synthesis of acetylcholine in diaphragm nerve endings.
DIFFERENT HYPOTHALAMIC RECEPTORS MEDIATE 5‐HYDROXYTRYPTAMINE‐ AND TRYPTAMINE‐INDUCED CORE TEMPERATURE CHANGES IN THE RAT
Authors: COX B. , LEE T.F. , MARTIN D.
Published: July 2012

Unilateral intrahypothalamic injection of 5‐hydroxytryptamine (5‐HT) caused a dose‐related fall in core temperature in rats, whereas injection of tryptamine into the same site caused a dose‐related rise in core temperature.

The core temperature changes induced by 5‐HT or tryptamine were inhibited by intrahypothalamic pretreatment with indoleamine receptor antagonists in a dose‐related manner.

Other neurotransmitter antagonists, haloperidol, atropine, phentolamine and (—)‐propranolol, had no significant effect on core temperature changes induced by 5‐HT or tryptamine.

A differential antagonism was observed for the indoleamine receptor antagonists against 5‐HT and tryptamine‐induced core temperature changes. Methergoline and triflupromazine were more selective against tryptamine‐induced hyperthermia, while cyproheptadine was more selective against 5‐HT‐induced hypothermia.

Intrahypothalamic pretreatment with 5,7‐dihydroxytryptamine (5,7‐DHT) 42 nmol in 2 μl inhibited tryptamine‐induced hyperthermia, but was without effect on 5‐HT‐induced hypothermia.

These results suggest the possible existence of two different receptor populations within the preoptic anterior hypothalamus in rats; one specific for 5‐HT and the other for tryptamine.
PERIVASCULAR ACTION OF THE LOCAL ANAESTHETIC, LIDOCAINE, ON PIAL TERMINAL ARTERIOLES: DIRECT OBSERVATIONS ON THE MICROCIRCULATION
Authors: ALTURA BURTON M. , LASSOFF SAMUEL
Published: July 2012

Considerable controversy currently exists with respect to whether or not local anaesthetics exert direct action on cerebral arteriolar tone. In situ experiments were therefore undertaken on pial terminal arterioles of rats to determine whether or not perivascular application of lidocaine exerts any action on such cerebral vessels. Vessel size was assessed with an image‐splitting television microscope recording system. The vessels studied ranged in size from 25 to 30μm. Lidocaine was applied in artificial CSF in dosages of 0.01, 0.1, 1.0 and 2.0 mg. Significant dose‐dependent dilatation (i.e., 15.7–45.3% increases in lumen sizes) of the pial terminal arterioles was observed. The results are discussed in light of current developments concerning the mechanism whereby local anaesthetics alleviate increased intracranial pressure and cerebral vasospasm.
BIPHASIC MECHANICAL RESPONSES OF THE GUINEA‐PIG ISOLATED ILEUM TO THE VENOM OF THE MARINE SNAIL Conus striatus
Authors: KOBAYASHI JUN'ICHI , NAKAMURA HIDESHI , OHIZUMI YASUSHI
Published: July 2012

Venom extract of Conus striatus elicited a rhythmic, transient contraction of the guinea‐pig isolated ileum followed by a relaxation at concentrations greater than 1μg/ml, which was abolished by tetrodotoxin and a low‐Na medium. The contraction induced by the venom was inhibited by atropine but not mecamylamine, whereas the relaxation was not affected by bretylium, guanethidine or phentolamine. These results suggest that the contraction of the ileum induced by the venom is due to the excitation of cholinergic nerves, while the relaxation is mediated through non‐adrenergic inhibitory nerves.
THE EFFECTS OF ATENOLOL ON SPONTANEOUS AND REFLEX ACTIVITY OF THE SYMPATHETIC NERVES IN THE ANAESTHETIZED CAT
Authors: EVELYN M.SCOTT
Published: July 2012

The reduction in the sympathetic efferent discharge observed after propranolol may be due to either a central or a peripheral effect. The β‐adrenoceptor blocking drug, atenolol, is not thought to enter the brain and therefore any reduction in the level of sympathetic efferent discharge observed after atenolol is likely to be mediated peripherally rather than centrally.

Cats were anaesthetized with α‐chloralose and artificially ventilated and a number of variables known to affect the sympathetic nerves were monitored throughout the experiment and maintained within normal limits. Recordings were made from few fibre preparations from the lumbar trunk and the renal nerves. Blood pressure was either raised or lowered by the injection of phenylephrine (1–4 μg/kg) or glyceryl trinitrate (2–20 μg/kg) and the sympathetic efferent discharge was recorded over a range of blood pressures when the blood pressure was steady.

Thirty min after giving atenolol (3 mg/kg) the blood pressure, heart rate and sympathetic efferent discharge were significantly reduced. Atenolol also attenuated the reflex responses of the sympathetic nerves to changes in the blood pressure.

It is suggested that atenolol has its actions on sympathetic nerves at a site outside the CNS and some possible mechanisms are discussed.
EVIDENCE IN SUPPORT OF THE P1/P2 PURINOCEPTOR HYPOTHESIS IN THE GUINEA‐PIG TAENIA COLI
Authors: BROWN CHRISTINE M. , BURNSTOCK G.
Published: July 2012

The relaxations induced by adenosine 5′‐triphosphate (ATP), adenosine 5′‐diphosphate (ADP), adenosine 5′‐monophosphate (AMP) and adenosine on the carbachol‐contracted taenia coli of the guinea‐pig have been studied. ATP and ADP produce similar responses which differ in nature and time course from those of AMP and adenosine.

Theophylline, at concentrations (25–200μm) lower than those which produce significant phosphodiesterase inhibition, blocks the effects of AMP and adenosine but fails to antagonize the responses elicited by ATP and ADP. The antagonism of adenosine by theophylline appears to be competitive.

Apamin (1–100 nM) blocks the inhibitory effects of ATP and ADP but fails to antagonize the responses to AMP and adenosine. The antagonism by apamin is non‐competitive.

The results indicate that ATP and adenosine relax the taenia coli by activating different receptors and are consistent with the P1 P2 purinoceptor hypothesis.
INHIBITION OF PROSTAGLANDIN E1‐RESPONSIVE PLATELET ADENYLATE CYCLASE BY HEPARIN: A STUDY OF THE MECHANISM OF INHIBITION AND ITS RELEVANCE TO PLATELET AGGREGATION
Authors: AMIRRASOOLI H. , NEIL S. MAC , TOMLINSON S.
Published: July 2012

Heparin can produce platelet aggregation in vitro and in vivo; it has been proposed that this may be due to the reported inhibition of the prostaglandin E1 (PGE1)‐stimulated adenylate cyclase of the platelet by heparin.

The effect of heparin on the cyclic adenosine 3′, 5′‐monophosphate (cyclic AMP) response to PGE1 was measured in intact and broken platelets both in vitro and in platelets obtained from normal subjects during intravenous infusion with herapin.

In platelet lysates, heparin produced a dose‐related inhibition of PGE1‐stimulated adenylate cyclase. The maximum response to PGE1 was reduced, with half‐maximal inhibition occurring at

μg/ml heparin. This inhibition could be prevented by protamine sulphate.

Heparin did not affect PGE1‐stimulated cyclic AMP production in intact platelets either in vitro or in platelets taken during the infusion of 5,000 iu heparin over 2h to 2 normal volunteers. Similarly, preincubation of platelets with heparin for up to 3 h at 37°C did not affect platelet adenylate cyclase.

The effects of heparin were very similar to those of fluoride on the platelet adenylate cyclase: heparin and fluoride increased basal enzyme activity slightly (3–4 fold) but their effects were not additive; both inhibited the response to PGE1 by approximately 50% when added directly to the assay and the inhibitory effects of the two were not additive; preincubation of membranes with either heparin or fluoride produced an irreversible state of inhibition.

As heparin inhibits PGE2‐stimulated adenylate cyclase activity only in broken platelets, we suggest that the aggregatory effects of heparin are probably independent of any action on cyclic AMP production.
TRAPPED BLOOD ELEMENTS WITHIN THE DECIDUA OF THE RAT PREGNANT UTERUS GENERATE A LIPOXYGENASE PRODUCT(S) WHICH INHIBITS MYOMETRIAL PROSTACYCLIN SYNTHESIS
Authors: TAHIR K.E.H. EL , WILLIAMS K.I.
Published: July 2012

Prostacyclin (PGI2) production by chopped segments of rat pregnant uterus was low compared with synthesis by separated myometrial tissue. Incubation of separated myometrium with decidua (2:1 by weight) led to an inhibition of myometrial PGI2 output.

Boiling decidual tissue abolished the inhibitory influence on myometrial PGI2 output. Preincubation of decidua with 5, 8, 11, 14‐eicosatetraynoic acid (ETA) (30 m̀g/ml) also suppressed decidual inhibitory activity but indomethacin (30 m̀g/ml) was ineffective.

Incubation of decidual and myometrial tissue with arachidonic acid (AA) 10m̀g/ml did not increase the inhibition of myometrial PGI2 synthesis, even if the decidua were pre‐incubated with indomethacin.

Myometrial PGI2 production was reduced if the chopped tissue was pre‐incubated with soya bean lipoxidase for 10 min at 4°C. This reduction was reversed if the lipoxidase was incubated with ETA (30°g/ml) for 30 min at 37°C before addition to the myometrial tissue.

Perfusion of the uterus to remove blood elements removed the inhibitory action that the decidua exerted upon myometrial PGI2 production. PGI2 synthesis by separated decidual and whole uterine tissue was markedly elevated.

The addition of rat blood platelets (0.75 × 109/ml) to incubations of perfused decidual tissue reduced PGI2 output and restored the inhibitory action that the decidua exerted on myometrial PGI2 synthesis.

It is concluded that a lipoxygenase enzyme contained in blood platelets trapped within the decidual vasculature produces a hydroperoxy acid which inhibits decidual PGI2 production or myometrial PGI2 synthesis when the tissues are incubated together. It is suggested that perfusion is a pre‐requisite before study of PGI2 synthesis in highly vascularised tissues.

The pathophysiological importance of such platelet lipoxygenase products is discussed.
AN INVESTIGATION INTO THE TYPE OF β‐ADRENOCEPTOR MEDIATING SYMPATHETICALLY ACTIVATED RENIN RELEASE IN THE CAT
Authors: JOHNS EDWARD J.
Published: July 2012

Stimulation of the renal nerves in the cat was previously shown to cause renin release which could be blocked by propranolol. An attempt was made in this study to determine the type of β‐adrenoceptor mediating this response.

In anaesthetized, unilaterally nephrectomized cats, a comparison was made of the ability of two selective β‐adrenoceptor antagonists to block the tachycardia and hypotension caused by isoprenaline (mediated respectively by β1‐ and β2‐adrenoceptors) and the release of renin caused by renal nerve stimulation.

Isoprenaline (mean dose of 0.224 ±0.022 nmol/kg), increased heart rate by approximately 43 beats/min and decreased mean blood pressure by 47 mmHg. Stimulation of the distal cut ends of the renal nerves, at a rate sufficient to reduce renal blood flow by 30%, resulted in an approximately 150% increase in plasma renin activity.

Administration of the selective β1‐adrenoceptor antagonist, atenolol (0.38 to 11.28μmol/kg), caused a dose‐related inhibition of nerve stimulated renin release and of isoprenaline‐induced tachycardia, with no diminution of the vasodepressor response to isoprenaline; in contrast, the selective β2‐adrenoceptor antagonist, erythro‐DL‐(7‐methylindan‐4‐yloxy)‐3‐isopropylamino‐butan‐2‐ol (ICI 118, 551, 0.03 to 2.86μmol/kg), caused a dose‐related inhibition of the isoprenaline‐induced vasodepression without altering the increase in plasma renin activity caused by renal nerve stimulation. Only at the highest dose of ICI 118, 551 was there a reduction of isoprenaline‐induced tachycardia, by about 40%.

The selective inhibition of neurally activated renin release by atenolol but not by ICI, 118, 551 is consistent with the suggestion that the β‐adrenoceptors mediating renin release resemble those in the heart more closely than those in peripheral blood vessels.
SITE OF ANALGESIC ACTION OF A NON‐STEROIDAL, ANTIINFLAMMATORY DRUG, TOLMETIN SODIUM, IN RATS
Authors: NAKAMURA HIDEO , SHIMIZU MASANAO
Published: July 2012

The site of the analgesic action of tolmetin sodium was investigated by use of the acetic acid writhing test in rats.

Tolmetin sodium was administered to the rat between 15 and 60 min after an intraperitoneal injection of 1 ml of a 1% acetic acid aqueous solution. Number of writhings was counted for 20 min beginning from 60 min after acetic acid injection.

When the rat was given tolmetin sodium 5 mg/kg orally, a relatively large quantity of tolmetin was found in the peritoneal exudate and there was a rough correlation between anti‐writhing activity and the exudate tolmetin content.

Anti‐writhing ED50 of tolmetin sodium was 1.42 (0.82‐2.91) and 92.0 (57.0–140) μg/kg when given intraperitoneally and intravenously, respectively, and the potency ratio of intraperitoneal to intravenous tolmetin sodium was 40.0 (18.5–80.2). This potency ratio for salicylic acid and morphine hydrochloride was 19.4 and 1.0, respectively.

When equipotent doses (5 fig/kg i.p.; 200 μg/kg i.v.) of tolmetin sodium were administered to the rat, the plasma tolmetin level after the intraperitoneal administration was less than one‐fortieth that after the intravenous administration during the counting time of 20 min, while both the peritoneal exudate contents of tometin were nearly equal.

From these results, it is concluded that the site of anti‐writhing action of tolmetin sodium is in the peritoneum and that tolmetin sodium produces its anti‐writhing action mainly by a peripheral mechanism in the rat.
MECHANISM OF ACTION OF ANGIOTENSIN II ON EXCITATION‐CONTRACTION COUPLING IN THE RAT PORTAL VEIN
Authors: HAMON GILLES , WORCEL MANUEL
Published: July 2012

The action of angiotensin II (At II) has been studied on the electrical and mechanical activity of the vascular smooth muscle of the rat portal vein.

At low concentrations (between 5 × 10−10 and 10−9m) At II induces an acceleration of spontaneous action potential (AP) discharge without change in the resting membrane potential. The frequency and size of the associated contractions are simultaneously augmented. Under these conditions the size of the spikes is not affected, thus suggesting that At II triggers the release of Ca from internal stores.

The increase in AP discharge rate produced by low concentrations of At II results from an acceleration of the pacemaker potential. Furthermore, in the presence of 10 mm tetraethylammonium (TEA), there is an acceleration of the repolarizing phase of AP.

Ouabain (10−3 m) inhibits the increase in rhythmic activity induced by low concentrations of At II (in the presence of 10 mm TEA), thus suggesting that the Na‐K pump is directly or indirectly involved in this action of the peptide.

At higher concentrations, At II produces a concentration‐dependent depolarization with an EC50 of 1.2 × 10−8m and a maximum of 10−7m. The associated contraction has an EC50 of 3.3 × 10−8 m and a maximum of 3 × 10−7 m.

Ouabain (3 × 10−3 m) depolarizes the cell membrane. Under these conditions, At II (10−7 m) has a slight depolarizing effect, but it still produces a large tonic contraction.

7 It is concluded, that At II acts on different steps of excitation‐contraction coupling, depending on the concentration. At low levels, the peptide mainly accelerates spike discharge, through a mechanism involving the Na‐K pump. At higher concentrations, At II depolarizes the cell membrane. The contraction is then activated by the influx of Ca2+ due to secondary AP discharge and the release of Ca2+ from intracellular stores. Pharmacomechanical coupling has an important role in the triggering of contractions both at high and at low concentrations of At II.
POSTSYNAPTIC EFFECTS OF SOME CENTRAL STIMULANTS AT THE NEUROMUSCULAR JUNCTION
Authors: GAGE PETER W. , SAH PANKAJ
Published: July 2012

Miniature endplate currents (m.e.p.cs) were recorded with extracellular electrodes from sartorius muscles of toads.

Central excitant analogues of amylobarbitone (3M2B) and halothane (DBE) decreased the amplitude and time constant of decay of m.e.p.cs and hence reduced the amplitude of miniature endplate potentials. The decay remained exponential with single time constant.

A central excitant analogue of ether (indoklon) reduced the amplitude of m.e.p.cs and made their decay biphasic. The decay could be fitted by the sum of two exponentials.

Bemegride, a central excitant, prolonged m.e.p.cs. Their decay remained exponential with single time constant. The effect was not due to inhibition of acetylcholinesterase.

All of the drugs tested, including amylobarbitone, reduced the temperature‐sensitivity of the decay of m.e.p.cs.

The biphasic decay of m.e.p.cs caused by indoklon could not be explained simply by supposing that the drug blocked open endplate channels unless it was assumed that the normal rate of channel closing also increased and became much less temperature‐sensitive than normal.
CHANGES IN THE RESPONSE OF GUINEA‐PIG AIRWAYS in vivo AND in vitro TO CIMETIDINE AND PROPRANOLOL DURING DEVELOPMENT
Authors: BRINK CHARLES , DOUGLAS JAMES S. , DUNCAN PAMELA G.
Published: July 2012

Airway responses were examined in isolated tissues and in whole animal preparations of female albino guinea‐pigs of known age.

Tone induced with acetylcholine in tracheal and bronchial tissues from young and old female guinea‐pigs was not reduced by dimaprit or 4‐methyl histamine even in tissues pretreated with mepyramine maleate.

Antagonism of H2‐receptors with cimetidine did not affect the potency or efficacy of histamine in tracheal tissues from animals of either age group.

After cimetidine treatment the potency of histamine was increased in bronchial tissues from old but not young animals. The sensitizing effect was still demonstrable in tissues incubated with indomethacin.

In vivo airway sensitivity to threshold concentrations of histamine in animals from either age group was unaffected by cimetidine treatment.

Propranolol enhanced airway responses to histamine aerosols in young but not old guinea‐pigs.

Cimetidine was without effect on histamine sensitivity in young guinea‐pigs after propranolol treatment but significantly reduced airway sensitivity to histamine in old guinea‐pigs.

Our data show that (a) H2‐receptors are of no physiological significance for airway responses to histamine in vitro or in vivo and (b) during development the modulating actions of catecholamines upon airway responses are significantly reduced.
DIFFERENTIAL PULSE VOLTAMMETRY IN THE ANAESTHETIZED RAT: IDENTIFICATION OF ASCORBIC ACID, CATECHOL AND INDOLEAMINE OXIDATION PEAKS IN THE STRIATUM AND FRONTAL CORTEX
Authors: BRAZELL M.P. , MARSDEN C.A.
Published: July 2012

Differential pulse voltammetric scans recorded using graphite paste working electrodes implanted in the striatum and frontal cortex of anaesthetized rats exhibited up to three distinct oxidation peaks at potentials between —0.1 and + 0.5 V.

The first peak at about +0.12 V was selectively increased by the micro‐infusion of ascorbic acid (5 × 10−6m) close to the surface of the working electrode implanted in either the striatum or the frontal cortex.

The second peak at about + 0.22 V was selectively increased by micro‐infusing either dopamine or 3,4‐dihydroxyphenylacetic acid, (5 × 10−6 m).

The third peak at approximately + 0.35 V was selectively increased in a dose‐related manner by the micro‐infusion of either 5‐hydroxytryptamine, (7.5 × 10−6 m to 7.5 × 10−5 m) or 5‐hydroxyindole‐3‐acetic acid, (2.5 × 10−5 m to 6 × 10−4m).

The results show that differential pulse voltammetry can be used to obtain qualitative and quantitative information about catechol and indoleamine neurones in vivo.
MODIFICATION OF THE ANTINOCICEPTIVE EFFECT OF MORPHINE BY CENTRALLY ADMINISTERED DIAZEPAM AND MIDAZOLAM
Authors: MANTEGAZZA PAOLO , PARENTI MARCO , TAMMISO REMIGIO , VITA PAOLO , ZAMBOTTI FERNANDA , ZONTA NERINA
Published: July 2012

Intracerebroventricular administration of diazepam or midazolam decreased the antinociceptive effect of morphine in rats as measured by the ‘tail flick’ method.

Midazolam, injected into the periaqueductal grey matter (PAG) antagonized the analgesic effect of morphine. The action of midazolam was partially reversed by bicuculline.

These findings support the view that the effect of benzodiazepines on morphine antinociception may be mediated through γ‐aminobutyric acid receptors.
INVOLVEMENT OF 5‐HYDROXYTRYPTAMINE IN THE ANALGESIC ACTION OF PETHIDINE AND MORPHINE IN MICE
Authors: BOTTING REGINA , MORINAN ALUN
Published: July 2012

Groups of mice were pretreated with the 5‐hydroxytryptamine (5‐HT) depletors, fenfluramine or p‐chlorophenylalanine (PCPA), followed by pethidine or morphine.

Fenfluramine alone produced a short lasting analgesia but PCPA was without any effect.

Pethidine and morphine both increased hot plate reaction times measured after 30 min.

Pre treatment with PCPA attenuated morphine analgesia but did not affect pethidine analgesia. Fenfluramine did not alter the response to either analgesic.

PCPA produced a significant depletion of brain 5‐HT levels which was not reversed by the analgesics. The fenfluramine‐induced decrease in 5‐HT was reversed by morphine but not by pethidine.

The results support the involvement of 5‐HT in the antinociceptive action of morphine in the mouse.
PROSTAGLANDIN ENDOPEROXIDES, THROMBOXANE A2 AND ADENOSINE DIPHOSPHATE IN COLLAGEN‐INDUCED AGGREGATION OF RABBIT PLATELETS
Authors: LEWIS G. P. , WATTS I. S.
Published: July 2012

A bioassay technique is described for simultaneously monitoring rabbit platelet aggregation with measurement of thromboxane A2 (TXA2) and prostaglandins released in response to collagen or arachidonic acid (AA).

Five imidazole derivatives were examined as inhibitors of thromboxane synthetase and compared with the effect of the cyclo‐oxygenase inhibitor indomethacin; 1‐(7‐carboxyheptyl) imidazole was identified as the most potent and selective inhibitor of thromboxane synthetase and was used with indomethacin to investigate the relative contribution of the prostaglandin endoperoxides prostaglandin G2 (PGG2)/PGH2 and TxA2 in mediating platelet aggregation induced by collagen or AA.

Platelet aggregation induced by a low concentration of collagen was abolished by indomethacin and carboxyheptylimidazole whilst in response to a high concentration or collagen only partial inhibition of aggregation occurred.

The contribution of adenosine diphosphate (ADP) released from platelets during collagen or AA‐induced aggregation was examined using the substrate/enzyme complex creatine phosphate/creatine phosphokinase (CP/CPK). The CP/CPK complex abolished aggregation induced by a low dose of collagen whilst aggregation to a high dose of collagen was only partially inhibited.

Aggregation induced by a high dose of collagen was abolished by a combination of CP/CPK with indomethacin or carboxyheptylimidazole.

AA‐induced aggregation was abolished by indomethacin. Carboxyheptylimidazole abolished aggregation induced by a low dose of AA but inhibition was surmounted with increasing concentrations of AA in the absence of TxA2 formation.

PGH2‐induced aggregation was unaffected by indomethacin and only partially inhibited by carboxyheptylimidazole. AA or PGH2‐induced platelet aggregation was unaffected by CP/CPK.

In conclusion, aggregation of rabbit platelets induced by a low concentration of collagen was dependent on synergism between TxA2 and ADP whilst at high concentrations of collagen, sufficient TxA2 and ADP were released to induce aggregation independently of each other.

The small amounts of prostaglandin endoperoxides produced from endogenous arachidonate have apparently no direct pro‐aggregatory role. However, the relatively large amount which can be produced by a high concentration of exogenous AA when TxA2 formation is prevented can cause aggregation of rabbit platelets.
BENZTROPINE‐INDUCED PROLONGATION OF RESPONSES TO VASODILATOR NERVE STIMULATION IN THE CANINE PAW PAD
Authors: BELL C.
Published: July 2012

After blockade of noradrenergic transmission with guanethidine in anaesthetized dogs, stimulation of the peripheral end of the cut tibial nerve (1 Hz, 10 pulses) produces a vasodilator response which is localized to the circulation of the paw pads. The time course of the response is considerably prolonged after systemic administration of the dopamine‐uptake blocking drug, benztropine (1 mg/kg). This effect is not due to inhibition of Uptake1, as benztropine, unlike desmethylimipramine, does not prolong responses to noradrenergic vasoconstrictor nerve stimulation. The results support previous evidence suggesting that the dilator response to tibial nerve stimulation involves neural release of dopamine.
In vivo STUDIES ON AN ANTAGONIST OF PARATHYROID HORMONE [Nle‐8, Nle‐18, Tyr‐34]bPTH‐(3–34)AMIDE
Authors: GRAY DAVID A. , PARSONS JOHN A. , POTTS JOHN T. , ROSENBLATT MICHAEL , STEVENSON RALPH W.
Published: July 2012

The actions of parathyroid hormone (PTH) are antagonized in vitro by the peptide [Nle‐8, Nle‐18, Tyr‐34]‐bPTH‐(3–34)amide, an analogue of PTH. In this paper, the actions of the inhibitory peptide were investigated in vivo.

Native parathyroid hormone (bPTH‐(1–84)), administered i.v. (0.17–1.51 nmol in a volume of 0.3 ml) to 7 day old chicks produced hypercalcemia but administration of the analogue in doses up to 173 nmol was ineffective in this respect.

The analogue failed to antagonize the hypercalcaemia produced by bPTH‐(1–34) when injected, in 10 fold molar excess, 2 min before or simultaneously with bPTH‐(1–34).

Normocalcaemia was restored in parathyroidectomized rats by intravenous infusion of bPTH‐(1–84) at 32 pmol kg−1 h−1. Addition of the analogue to the infusion fluid in a 200 fold molar excess did not affect the concentrations of calcium and phosphate in the plasma, cyclic adenosine 3′,5′‐monophosphate (cyclic AMP) in the urine or phosphate clearance but produced a significant (P< 0.05) rise in urinary calcium clearance.

The results suggest that the peptide [Nle‐8, Nle‐18, Tyr‐34]‐bPTH‐(3–34)amide does not antagonize the actions of PTH in vivo and demonstrate an important dichotomy between in vitro and in vivo biological properties of the PTH analogue.
INHIBITORY ACTIONS OF CATECHOLAMINES ON ELECTRICALLY INDUCED CONTRACTIONS OF THE SUBMUCOUS PLEXUS‐LONGITUDINAL MUSCULARIS MUCOSAE PREPARATION OF THE GUINEA‐PIG OESOPHAGUS
Authors: KAMIKAWA YUICHIRO , SHIMO YASUO , UCHIDA KOHSUKE
Published: July 2012

The submucous plexus‐longitudinal muscularis mucosae preparation of the guinea‐pig oesophagus was used to study the actions of catecholamines on the twitch responses to electrical stimulation.

When the preparation was stimulated coaxially (0.1 Hz, 0.5 ms, supramaximal voltage), stable twitch‐like contractions were obtained. These were abolished by tetrodotoxin (0.1 μm) and atropine (0.1 μm), potentiated by physostigmine (0.1 μm), and were mediated presumably by stimulation of intramural cholinergic nerves.

The twitch contractions of the muscularis mucosae were inhibited by catecholamines, in a concentration‐dependent manner. The order of potency was isoprenaline > adrenaline > noradrenaline > dopamine.

The inhibitory actions of noradrenaline (1 μm) and adrenaline (1 μm) were partly reversed by phentolamine (1 μm) or by propranolol (1$ mUM), and completely abolished by both antagonists together. The inhibitory effect of dopamine (300 μm)> was largely reversed by phentolamine (1 μm), but not by propranolol (1 μm), while the inhibitory action of isoprenaline was competitively antagonized only by propranolol (pA2 of 7.6).

The contraction of the muscularis mucosae to exogenously applied acetylcholine (ACh, 20 nM) which was comparable in magnitude with that to electrical stimulation was also inhibited by isoprenaline (0.1 μm), adrenaline (1 μm) and noradrenaline (1 μm), but not by dopamine (300 μm). In the presence of propranolol (1 μm), noradrenaline, adrenaline and dopamine potentiated the ACh‐induced contraction, while the effect of isoprenaline was mainly antagonized. The potentiating effects were antagonized by further treatment with phentolamine (1 μm).

Adrenaline, noradrenaline and dopamine but not isoprenaline, produced a weak contraction of the longitudinal muscularis mucosae in the presence of propranolol (3 μm). The contractile responses were completely inhibited by phentolamine (3 μm). Tone in the muscularis mucosae induced by carbachol (3 μm) in the presence of phentolamine (10 μm) was inhibited by catecholamines, in a concentration‐dependent manner, an effect that was competitively antagonized by propranolol.

In the submucous plexus‐longitudinal muscularis mucosae preparation of the guinea‐pig oesophagus there are three types of adrenoceptor, inhibitory prejunctional α‐adrenoceptors, excitatory postjunctional α‐adrenoceptors and inhibitory postjunctional β‐adrenoceptors, and cholinergic neurotransmission is inhibited by catecholamines acting at both prejunctional α‐ and postjunctional β‐adrenoceptors.
AGGREGATION OF RAT NEUTROPHILS BY NUCLEOTIDE TRIPHOSPHATES
Authors: FORD‐HUTCHINSON A.W.
Published: July 2012

Adenosine 5′‐triphosphate (ATP) and uridine 5′‐triphosphate (UTP) at concentrations of 3 × 10−7 m and greater cause a rapid partially reversible aggregation of rat polymorphonuclear leucocytes.

Other neucleotide phosphates are much less active at producing aggregation responses; the agonist potencies being UTP > ATP > guanosine 5′‐triphosphate, cytidine 5′‐triphosphate, thymidine 5′‐triphosphate; ATP > adenosine 5′‐diphosphate (ADP) > adenosine 5′‐monophosphate (AMP); and ADP > uridine 5′‐diphosphate, thymidine 5′‐diphosphate, guanosine 5′‐diphosphate, cytidine 5′‐diphosphate. Adenosine is inactive.

The hydrolysis resistant analogues of ATP, α‐β‐methylene ATP and β‐γ‐methylene ATP, do not cause neutrophil aggregation suggesting that hydrolysis of ATP and UTP may be required to initiate the aggregation response.

It is postulated that ATP and UTP may be important stimulants of neutrophil function and may be involved in the adherence of these cells to the vascular endothelium.
EFFECT OF LIPID PEROXIDATION ON p‐AMINOHIPPURATE TRANSPORT BY RAT KIDNEY CORTICAL SLICES
Authors: FUJIMOTO YOHKO , FUJITA TADASHI
Published: July 2012

The effect of lipid peroxidation on p‐aminohippurate transport by rat kidney slices was examined.

Ascorbic acid and Fe2+ promoted lipid peroxidation of rat renal cortical slices in a dose‐related manner.

Ascorbic acid (1.0 mM) and Fe2+ (0.4 mM) increased tissue water and decreased the accumulation of p‐aminohippurate.

The addition of N,N'‐diphenyl‐p‐phenylenediamine (antioxidant), at a concentration of 1 × 10−6m, completely inhibited the peroxidation and recovered the accumulation of p‐aminohippur ate.

The apparent Km of p‐aminohippurate uptake was increased by ascorbic acid and Fe2+ with no change in the apparent V.

These data suggest that ascorbic acid and Fe2+ can cause a significant alteration in p‐aminohippurate and water transport of renal cortical slices and that these effects can be correlated with lipid peroxidation.
A STUDY OF THE INHIBITORY EFFECTS OF SCH 28080 ON GASTRIC SECRETION IN MAN
Authors: ENE M.D. , KHAN‐DANESHMEND T. , ROBERTS C.J.C.
Published: July 2012

SCH 28080 (2‐methyl‐8‐(phenyl methoxy) imidazo‐(1–2‐a) pyrine‐3‐acetonitrile) is a novel drug unrelated to existing anti‐ulcer agents.

The effect of placebo and increasing doses of the drug on gastric acid output and peptic activity was examined in four healthy men, in the resting state and following pentagastrin stimulation.

Significant inhibition of gastric acid secretion and peptic activity occurred with the 50 mg dose in both the stimulated and unstimulated states. Approximately 90% inhibition of acid output was achieved with the 200 mg dose.

Antisecretory activity of SCH 28080 is confirmed in man. This drug or an analogue may have potential in anti‐ulcer therapy.
EFFECTS OF 4‐AMINOPYRIDINE ON ACETYLCHOLINE OUTPUT FROM THE CEREBRAL CORTEX OF THE RAT in vivo
Authors: CASAMENTI FIORELLA , CORRADETTI R. , LÖFFELHOLZ K. , MANTOVANI P. , PEPEU G.
Published: July 2012

The effects of 4‐aminopyridine (4AP) on the output of acetylcholine (ACh) from the cerebral cortex were investigated in unanaesthetized freely moving rats and in anaesthetized rats by means of the ‘cup technique’. ACh was determined by bioassay on the dorsal muscle of the leech.

In unanaesthetized rats intraperitoneal injection of 4AP (3 mg/kg) had no effect on the cortical output of ACh.

After injection of morphine (10 mg/kg s.c), which depressed the spontaneous output of ACh, 4AP increased the cortical output to a level significantly higher than that determined before morphine injection.

In rats anaesthetized with either urethane or pentobarbitone, drugs known to decrease cortical output of ACh, 4AP (i.v. or i.p.) elicited a significant increase in the output of ACh. The time‐courses of the 4AP‐induced effects were different depending on the anaesthetic drug used: an immediate increase slowly fading in urethane anaesthesia and a gradual increase after delayed onset in pentobarbitone‐anaesthetized rats.

In some urethane‐anaesthetized rats, respiratory frequency was kept constant (tracheotomy, connection to respirator, bilateral vagotomy) and prazosin (1 mg/kg i.v.) was administered to reduce the 4AP‐induced increase of blood pressure. Cortical output of ACh was not related to changes in blood pressure. Moreover, the 4AP‐induced increase in cortical ACh output was not related to changes in respiratory frequency.

In summary systemic administration of 4AP in subconvulsive doses (1 and 3 mg/kg) increased cortical output of ACh in rats anaesthetized with urethane or pentobarbitone or after injection of morphine, but not in untreated freely moving rats. It is suggested that the anaesthetic agents and morphine may cause an imbalance between excitatory and inhibitory central pathways, and that this imbalance may play a role in their depressant effect on cortical output of ACh and/or in the 4AP‐induced facilitation described in this paper.
EFFECTS OF RITODRINE, A β2‐ADRENOCEPTOR AGONIST, ON SMOOTH MUSCLE CELLS OF THE MYOMETRIUM OF PREGNANT RATS
Authors: IZUMI HIDETAKA , KISHIKAWA TADAO
Published: July 2012

Effects of ritodrine on the electrical and mechanical activities of the myometrium of pregnant rats were investigated in relation to cyclic adenosine 3′,5′‐monophosphate (cyclic AMP) production and the actions of isoprenaline.

In the longitudinal muscle cells of the 22nd day of gestation, ritodrine (> 10−8 m) hyperpolarized the membrane, reduced the membrane resistance and suppressed the amplitude of contraction. Increased concentrations of ritodrine (> 10−7 m) suppressed the generation of spikes and increased the amount of cyclic AMP produced. These actions of ritodrine were much the same as those of isoprenaline but the dose‐response curves of all parameters were shifted to the right.

The effects of ritodrine on the circular muscle cells at the 22nd day of gestation were similar to those observed in the longitudinal muscle cells.

In the circular muscle cells at the 17–19th days of gestation, ritodrine produced neither a hyperpolarization nor an increase in cyclic AMP production (up to 10−5m) but did reduce the plateau potential and did relax the tissue (> 10−7 m).

In the longitudinal muscle cells, during the 17–19th days of gestation, the responses of the tissues were similar to those observed in circular muscles on the 22nd day of gestation. These actions of ritodrine were suppressed by propranolol (10−6 m).

These results indicate that ritodrine is a β‐adrenoceptor agonist and its mechanism of action similar to that of isoprenaline. However, the potency of ritodrine was approximately 100 times less than that of isoprenaline.
ANTIGEN‐INDUCED CONTRACTION OF GUINEA‐PIG TRACHEA: SEARCH FOR MEDIATOR RELEASE WITH CASCADE SUPERFUSION BIOASSAY
Authors: BURKA JOHN F.
Published: July 2012

Ovalbumin induces contraction of sensitized guinea‐pig trachea, both in the presence and absence of indomethacin. Cascade superfusion bioassay was employed to detect mediator release. A prostaglandin E‐like material was released in response to antigen in the absence of indomethacin but, no biologically active material could be detected from trachea in the presence of indomethacin. Thus the substance responsible for antigen‐induced tracheal contraction, although appearing to be a lipoxygenase product, is as yet undefined.
RELATIONSHIP BETWEEN TYRAMINE POTENTIATION AND SELECTIVE INHIBITION OF MONOAMINE OXIDASE TYPES A AND B IN THE RAT VAS DEFERENS
Authors: FINBERG J.P.M. , TENNE M.
Published: July 2012

The degree of selective monoamine oxidase (MAO) inhibition produced by (−)‐(deprenyl, clorgyline, LY51641 and tranylcypromine was examined in relation to modification of tyramine and noradrenaline contractile responses of the rat isolated vas deferens.

All inhibitors possessed reversible α‐adrenoceptor blocking activity, determined against noradrenaline on the denervated vas deferens. For LY51641 and tranylcypromine, antagonism was competitive, with pA2 values of 6.17 and 5.26.

Clorgyline, LY51641 and (−)‐deprenyl (10−5m) inhibited the tyramine response while present in the organ bath: LY51641, which was the most potent as an α‐adrenoceptor blocker, produced this effect at 10−6m. Responses to tyramine and noradrenaline were potentiated on washing out the inhibitors, but noradrenaline potentiation was seen only when tyramine had been present in the system.

Tranylcypromine (10−6m) potentiated responses to noradrenaline and tyramine while present in the organ bath.

Potentiation of tyramine responses by clorgyline and LY51641 occurred at 91% and 64% inhibition of MAO type A respectively, although full potentiation of the tyramine response was elicited only when substantial inhibition of both enzyme types occurred. Selective inhibition of MAO type B by 67% (with deprenyl) was not associated with tyramine potentiation.
CONTRIBUTION OF PROSTAGLANDINS AND THROMBOXANES TO THE ADENOSINE AND ATP‐INDUCED CONTRACTION OF GUINEA‐PIG ISOLATED TRACHEA
Authors: ADVENIER C. , BIDET D. , FLOCH‐SAINT‐AUBIN A. , RENIER A.
Published: July 2012

In in vitro experiments adenosine 5′‐triphosphate (ATP) and adenosine were found to exert different effects on the guinea‐pig isolated trachea depending on whether the trachea had previously been contracted with acetylcholine (ACh) (6.6 × 10−6 m) or was at resting tone.

ATP and adenosine (10−5 and 10−3 m) were equipotent in relaxing the precontracted guinea‐pig trachea, since concentrations of 1.09 ± 0.35 and 0.39 ± 0.16 mm respectively reduced by 25% the ACh‐induced contraction.

ATP and adenosine (10−5 and 10−4 m) caused a moderate contraction of the guinea‐pig trachea under resting tone. This effect was antagonized by inhibitors of cyclo‐oxygenase (indomethacin 10−6m, aspirin 0.3 × 10−3m and 3 × 10−3m) and of thromboxane synthetase (nictindole 10−7m, imidazole 5 × 10−5 m), which suggests an indirect mechanism of action with release of arachidonic acid derivatives.
EVIDENCE FOR THE CARRIAGE OF SILVER BY SULPHADIMIDINE: INHIBITION OF PROTEOLYTIC ENZYMES
Authors: BALLINGER P.M. , GRIFFIN M.M. , ITZHAKI S. , STEVEN F.S.
Published: July 2012

Trypsin in free solution and trypsin‐sepharose were shown to be inhibited by Ag+ in the absence of Cl‐.

In the presence of Cl‐ and absence of a suitable carrier, Ag+ has no inhibitory action on trypsin or chymotrypsin.

Sulphadimidine bound Ag+ in the presence of Cl‐, and carried the Ag+ to both trypsin and chymotrypsin in free solution as well as to trypsin‐sepharose leading to the inhibition of all these enzyme systems.

The neutral protease of tumour cell surfaces was inhibited by Ag+ transported by sulphadimidine in the presence of Cl‐.

Kinetic data demonstrated the requirements for both Ag+ and carrier to effect inhibition, the degree of inhibition being directly related to the molarity of each of these reagents.

The known inhibition of trypsin by Ag+ binding to histidine in the active site has been defined in mechanistic terms employing the sulphonamide drug, sulphadimidine, to illustrate this exchange mechanism.
PRESYNAPTIC γ‐AMINOBUTYRIC ACID RECEPTORS IN THE RAT ANOCOCCYGEUS MUSCLE AND THEIR ANTAGONISM BY 5‐AMINOVALERIC ACID
Authors: MUHYADDIN M. , ROBERTS P.J. , WOODRUFF G.N.
Published: July 2012

The effects of γ‐aminobutyric acid (GABA) and related drugs on the isolated anococcygeus muscle of the rat were determined.

GABA caused a dose‐related inhibition of the electrically‐evoked twitch response.

The maximum response to GABA was a 56.8% depression of twitch response, with an EC50 of 0.68 μm.

(±)‐Baclofen mimicked the effect of GABA (EC50 0.9 μm). (+)‐Baclofen was more than 100 times less active than (−)‐baclofen.

The response to GABA was unaffected by picrotoxin or bicuculline but was antagonized by 5‐aminovaleric acid (0.5 mm).

Our results suggest that GABAB receptors are present on motor nerve terminals in the rat anococcygeus muscle and that 5‐aminovaleric acid is an antagonist of these receptors.