bluuebunny/crossref_metadata_2025 huggingface dataset:
EFFECTS OF CHLORPROMAZINE ON THE ELECTRICAL AND MECHANICAL PROPERTIES OF INTACT AND SKINNED MUSCLE CELLS OF GUINEA‐PIG MESENTERIC ARTERY
Authors: ITOH TAKEO , KURIYAMA HIROSI , SUZUKI HIKARU
Published: July 2012

Effects of chlorpromazine on the contraction evoked in intact muscles, and of chlorpromazine or calmodulin on the contraction evoked in the saponin‐treated skinned muscles of the guinea‐pig mesenteric artery were investigated.

Chlorpromazine, above 5 × 10−7 m, depolarized the membrane and reduced the membrane resistance measured from the current‐voltage relationships at the depolarized and resting membrane potential levels.

The contraction evoked by excess [K]o, NaCl‐free Krebs and by caffeine was suppressed by application of chlorpromazine; contractions induced by the former two treatments were suppressed to a greater extent than those induced by the latter. Contractions induced by excess [K]o or NaCl‐free Krebs ceased in Ca‐free solution, but not those induced by caffeine, i.e. influxes of Ca across the membrane were more suppressed than was the release of Ca from the storage sites by chlorpromazine.

In skinned muscles, chlorpromazine suppressed and calmodulin enhanced the Ca‐induced contraction in a dose‐dependent fashion. The minimum concentration of chlorpromazine required to suppress the Ca‐induced contraction (10−5 m) was 10−6 m and that of calmodulin to enhance the Ca‐induced contraction was 10−7m.

After skinned muscles had been loaded with Ca, chlorpromazine or calmodulin itself did not induce the contraction by the release of stored Ca in the cell. However, calmodulin increased and chlorpromazine suppressed the accumulation of Ca into the storage site (presumably sarcoplasmic reticulum).

From the present results, it is suggested that chlorpromazine acts on the surface membrane and suppresses Ca‐influx, thus causing a relaxation of the mesenteric artery. However, when chlorpromazine or calmodulin was applied to skinned muscles, the former suppresses and the latter enhances the Ca accumulation into the storage site and the activation of contractile proteins. Thus chlorpromazine causes the relaxation of the vascular tissue. However, a lower concentration of chlorpromazine was required to suppress the Ca influx than to suppress the Ca accumulation into the storage site or the activity of calmodulin in contractile protein. Thus vasodilatation induced by chlorpromazine in vitro, is mainly due to the suppression of Ca influx.
IS RECEPTOR ACTIVATION INVOLVED IN THE MECHANISM BY WHICH (+)‐FENFLURAMINE AND (+)‐NORFENFLURAMINE DEPLETE 5‐HYDROXYTRYPTAMINE IN THE RAT BRAIN?
Authors: INVERNIZZI R. , KMIECIAK‐KOLADA K. , SAMANIN R.
Published: July 2012

The effects of (+)‐fenfluramine, (+)‐norfenfluramine and reserpine on the concentrations of 5‐hydroxytryptamine (5‐HT) and 5‐hydroxyindoleacetic acid (5‐HIAA) in brainstem and telencephalon were studied in rats treated with methergoline, a 5‐HT antagonist.

Methergoline significantly reduced the effect of (+)‐norfenfluramine (5 mg/kg) on 5‐HT levels in telencephalon and brainstem but did not modify the effect of (+)‐norfenfluramine (2.5 mg/kg).

Neither the effect of (+)‐fenfluramine on 5‐HT levels nor the decrease of 5‐HT metabolism caused by (+)‐fenfluramine and (+)‐norfenfluramine was significantly modified by methergoline treatment.

Methergoline potentiated the effects of reserpine on brain indoles. The effect was particularly evident on 5‐HIAA levels in the brainstem, although significant effects were found on 5‐HT in the brainstem and 5‐HIAA in the telencephalon depending on the dose of reserpine used.

The results show that postsynaptic receptor activation may partially contribute to the depletion of brain 5‐HT caused by (+)‐norfenfluramine in the rat. This mechanism does not seem to play a significant role in the effect of (+)‐fenfluramine.
MECHANISM OF CADMIUM‐INDUCED CONTRACTION IN ILEAL LONGITUDINAL MUSCLE OF GUINEA‐PIG
Authors: ASAI FUMITOSHI , NISHIMURA MASAKAZU , SATOH EIKI , URAKAWA NORIMOTO
Published: July 2012

The mechanism of cadmium (Cd2+)‐induced contraction was studied in isolated ileal longitudinal muscle of guinea‐pig.

CdCl2 (1 × 10−8 to 1 × 10−4 m) caused a transient contraction which subsided within approximately 6 min of application. The contraction was reproducible and dependent on the concentration. The dose‐response curve was bell‐shaped. A maximal response was observed at concentrations of 5 × 10−6 to 1 × 10−5 m.

The contractile effect was inhibited to some degree at 20°C or by tetrodotoxin (0.1 μg/ml), hyoscine (0.1 μg/ml) or hexamethonium (10 μg/ml), but completely inhibited by Ca2+‐removal from the medium.

Cd2+ increased the output of [14C]‐acetylcholine biosynthesized from [14C]‐choline by the preparation depending on the concentration. The increase terminated within the first 6 min and was reduced by tetrodotoxin (0.1 μg/ml) or by removal of Ca2+ from the medium.

Both the contractile and transmitter releasing effects of Cd2+ were dependent on the concentration of external Ca2+. Strontium ions were able to replace Ca2+ for Cd2+‐induced transmitter release.

It is suggested that Cd2+ contracts ileal longitudinal muscle through a release of cholinergic transmitter from the parasympathetic nerve terminals, which is dependent on external Ca2+. It also has a smaller hyoscine‐resistant contractile effect, presumably due to a direct action on smooth muscle cells.
INHIBITION BY THE TETRAMINE DISULPHIDE, BENEXTRAMINE, OF CARDIAC CHRONOTROPIC HISTAMINE H2‐RECEPTOR‐MEDIATED EFFECTS
Authors: BELLEAU B. , BENFEY B.G. , BENFEY T.J. , MELCHIORRE C.
Published: July 2012

Benextramine (N,N'‐bis[o‐methoxybenzylamino)‐n‐hexyl]cystamine), which irreversibly blocks α‐adrenoceptors and does not inhibit the H1‐receptor‐mediated contractile effect of histamine on guinea‐pig isolated ileum, also did not inhibit the H1‐receptor‐mediated inotropic effect of histamine on guinea‐pig isolated atrium.

Benextramine irreversibly inhibited the H2‐receptor‐mediated chronotropic effect of histamine on guinea‐pig isolated atrium.

Since its combination with the competitive H2‐receptor blocking drug cimetidine had an additive blocking effect, benextramine appears to act directly on the chronotropic H2‐receptor.
EFFECTS OF DIVALENT CATIONS AND NORMORPHINE ON SPONTANEOUS EXCITATORY JUNCTION POTENTIALS IN THE MOUSE VAS DEFERENS
Authors: ILLES P. , NORTH R.A.
Published: July 2012

Excitatory junction potentials (e.j.ps) occurring spontaneously or evoked by nerve stimulation were recorded intracellularly from smooth muscle cells of the mouse isolated vas deferens.

The amplitude of the evoked e.j.ps and the amplitude and frequency of spontaneous e.j.ps were measured before and during application of normorphine or solutions which might be expected to change the influx of calcium ions into the nerve terminals.

Spontaneous e.j.ps could be recorded even in solutions which contained tetrodotoxin (1 μm), no added calcium and EGTA (1 mm). A four fold increase in calcium concentration from 1.25 to 5 mm greatly increased the amplitude of the evoked e.j.ps but had no effect on the amplitude or frequency of the spontaneous e.j.ps.

Magnesium (12 mm) and cobalt (4 mm) both greatly reduced the evoked e.j.ps and also reduced the frequency of spontaneous e.j.ps.

Normorphine (2 μm) reduced the amplitude of the evoked e.j.p. by 70% but had no effect on the amplitude or frequency of spontaneous e.j.ps.

It is suggested that normorphine inhibits noradrenaline secretion from nerve varicosities by a mechanism different from that of magnesium and cobalt. One possibility is a block of action potential propagation along varicose fibres.
HYPOTHALAMIC CATECHOLAMINES AND TOLERANCE FOR SEVERE COLD IN ETHANOL‐TREATED GUINEA‐PIGS
Authors: HUTTUNEN PIRKKO
Published: July 2012

The effect of ethanol (2g/kg) on hypothalamic catecholamines in guinea‐pigs kept at room temperature (20°C) and in severe cold (—20°C) for 1.5 h was determined. Serum glucose, triacylglycerols and free fatty acids (FFAs), glycogen in liver and skeletal muscle and total lipid and triacylglycerols in the interscapular adipose tissue were also determined.

Ethanol increased the noradrenaline and adrenaline content of the hypothalamus at 20°C and reduced the rectal temperature by about 2°C. The hypothalamic noradrenaline content of the ethanol‐treated guinea‐pigs exposed to cold, in which the fall in rectal temperature was about 8°C, was higher than in the controls, whose rectal temperature decreased only by about 2°C.

Cold exposure increased FFA concentration in serum and reduced skeletal muscle glycogen and serum glucose concentrations in both groups, but no significant differences were found in the carbohydrate and lipid values between the groups at — 20°C.

It is possible that the diminished cold tolerance in the ethanol‐treated guinea‐pigs might be due, at least in part, to the effect of ethanol on the catecholamines in the hypothalamus.
PRESYNAPTIC EFFECT OF CLONIDINE ANTAGONIZED BY THE TETRAMINE DISULPHIDE, BENEXTRAMINE
Authors: BELLEAU B. , BENFEY B.G. , MELCHIORRE C.
Published: July 2012

The presynaptic α‐adrenoceptor blocking activity of the newly synthesized α‐adrenoceptor blocking drug, benextramine, was evaluated in the isolated left atrium of the guinea‐pig heart.

High‐voltage stimulation increased the force of contraction of electrically driven atrial strips, presumably by releasing noradrenaline from sympathetic nerve endings. Like phentolamine, benextramine increased the effect of high‐voltage stimulation, presumably by blocking presynaptic α‐adrenoceptors.

Clonidine reduced the effect of high‐voltage stimulation, presumably by stimulating presynaptic α‐adrenoceptors. The inhibitory effect of clonidine was antagonized noncompetitively by benextramine and competitively by phentolamine.

Combined administration of benextramine and phentolamine only resulted in the competitive phentolamine antagonism. Thus phentolamine protected the presynaptic α‐adrenoceptors against benextramine blockade.
DISSOCIATION OF β‐ADRENOCEPTOR‐INDUCED EFFECTS ON AMYLASE SECRETION AND CYCLIC ADENOSINE 3′,5′‐MONOPHOSPHATE ACCUMULATION
Authors: CARLSÖÖ BENGT , DANIELSSON ÅKE , HENRIKSSON ROGER , IDAHL LARS‐ÅKE
Published: July 2012

By using a multi‐channel microperifusion system the effects of noradrenaline, the β1‐adrenoceptor agonist prenalterol, and the β2‐selective agonist terbutaline were studied on amylase release and cyclic adenosine 3′,5′‐monophosphate (cyclic AMP) content in rat parotid and guinea‐pig submandibular glands.

Noradrenaline caused significant amylase discharge and cyclic AMP accumulation.

Prenalterol was as effective as noradrenaline in causing amylase release but did not significantly affect the cyclic AMP content.

Terbutaline stimulated cyclic AMP accumulation, but had little effect on amylase secretion.

The present study reveals that there is a dissociation of the β‐adrenoceptor‐induced amylase release and cyclic AMP formation, and that this dissociation may be due to different β‐adrenoceptor subtypes.
THE ACTIONS OF PENTOBARBITONE, PROCAINE AND TETRODOTOXIN ON SYNAPTIC TRANSMISSION IN THE OLFACTORY CORTEX OF THE GUINEA‐PIG
Authors: RICHARDS C.D.
Published: July 2012

It has been suggested that the depression of excitatory synaptic potentials produced by general anaesthetics can be attributed to a partial blockade of impulse conduction in the terminal branches of axons. This hypothesis has been tested by comparing the actions of pentobarbitone, procaine and tetrodotoxin (TTX) on synaptic transmission in the guinea‐pig olfactory cortex.

Pentobarbitone (0.1–0.3 mm) depressed the evoked synaptic potentials without any significant depression of impulse conduction in the afferent fibres of the lateral olfactory tract (l.o.t.). It had no effect on the electrical excitability of either the l.o.t. axons or the postsynaptic neurones.

Tetrodotoxin (TTX; 1–5 × 10−8 m) slowed conduction of impulses in the l.o.t. and decreased the amplitude of the l.o.t. compound action potential in proportion to the concentration applied. All concentrations of TTX elevated the electrical threshold of the l.o.t. axons and there was evidence to suggest that the threshold of the postsynaptic neurones was also elevated. The synaptic potentials were depressed in direct proportion to the depression of the l.o.t. compound action potential.

Procaine (0.1–0.5 mm) exhibited a pattern of activity intermediate between pentobarbitone and TTX. The most marked effect, seen at all concentrations tested, was a slowing of impulse conduction and a decrease in the electrical excitability of the l.o.t. axons.

It is concluded that general anaesthetics (exemplified by pentobarbitone) depress synaptic transmission by interfering with the processes involved in chemical transmission and not by blocking impulse conduction in the terminal branches of afferent nerves.
STEREOCHEMICAL REQUIREMENTS FOR CENTRAL AND PERIPHERAL MUSCARINIC AND ANTIMUSCARINIC ACTIVITY OF SOME ACETYLENIC COMPOUNDS RELATED TO OXOTREMORINE
Authors: DAHLBOM R. , JENDEN D.J. , RESUL B. , RINGDAHL B.
Published: July 2012

The enantiomers of some analogues of the central muscarinic agent, oxotremorine, were prepared and investigated for tremorogenic and tremorolytic activity in intact mice and for muscarinic and antimuscarinic activity on the isolated ileum of the guinea‐pig.

The R‐isomers were more potent than the S‐isomers both in vivo and in vitro regardless of whether the compounds are agonists, partial agonists or competitive antagonists.

It is suggested that in the oxotremorine series, agonists and antagonists interact with a common receptor site, in contrast to classical muscarinic antagonists which are believed to bind also to accessory receptor areas, located close to the agonist binding site.
EFFECTS OF IMPROMIDINE, A SPECIFIC H2‐RECEPTOR AGONIST AND 2‐(2‐PYRIDYL)‐ETHYLAMINE, AN H1‐RECEPTOR AGONIST, ON STIMULATION‐INDUCED RELEASE OF [3H]‐NORADRENALINE IN GUINEA‐PIG ISOLATED ATRIA
Authors: RAND M.J. , STORY D.F. , WONG‐DUSTING HELEN
Published: July 2012

The specific histamine H2‐receptor agonist, impromidine (3–100 nmol/l), increased the rate and force of beating of guinea‐pig isolated atria. These effects were blocked by the H2‐receptor antagonist, cimetidine (30 μmol/l), but not by the H1‐receptor antagonist, mepyramine (0.1 μmol/l).

In atria that had previously been incubated in [3H]‐noradrenaline, impromidine (3–100 nmol/l) had no effect on the resting efflux of radioactivity, but concentrations of 50 and 100 nmol/l significantly increased the efflux induced by electrical stimulation (2 Hz for 10 s) of the intramural sympathetic nerves by approximately 38%; lower concentrations (3, 10 and 25 nmol/l) had no effect.

The effect of impromidine in enhancing stimulation‐induced efflux of radioactivity was abolished by cimetidine (30 μmol/l) and by mepyramine (0.1 μmol/l). It was unaffected by the α‐adrenoceptor antagonist, phentolamine (30 μmol/l).

Impromidine produced some inhibition of the uptake of [3H]‐noradrenaline, but this did not account for the enhancement of the stimulation‐induced efflux of radioactivity, since impromidine (50 nmol/l) still increased release in the presence of cocaine (30 μmol/l).

The specific H1‐receptor agonist, 2‐(2‐pyridyl)‐ethylamine (10–100 μmol/l), increased both the resting and stimulation‐induced efflux of radioactivity. These effects were not blocked by mepyramine (0.1 μmol/l) or the β‐adrenoceptor antagonist, metoprolol (0.1 μmol/l).

The prejunctional inhibitory histamine receptors in guinea‐pig atria are not classifiable into H1‐or H2‐type by the use of relatively specific postjunctional histamine H1‐ or H2‐receptor agonists and antagonists.
DESENSITIZATION BY TERBUTALINE OF β‐ADRENOCEPTORS IN THE GUINEA‐PIG SOLEUS MUSCLE: BIOCHEMICAL ALTERATIONS ASSOCIATED WITH FUNCTIONAL CHANGES
Authors: BUUR T. , CLAUSEN T. , HOLMBERG E. , JOHANSSON U. , WALDECK B.
Published: July 2012

The effects of adrenaline and terbutaline on cyclic adenosine 3′,5′‐monophosphate (cyclic AMP) content, 22Na‐efflux, 42K‐influx and subtetanic contractions have been assessed in soleus muscles isolated from guinea‐pigs which had been maintained on food with or without terbutaline for 5 days.

Terbutaline and adrenaline increased cyclic AMP content and suppressed subtetanic contractions, and regression analysis indicates a statistically significant correlation between these two effects (P<0.01).

In muscles obtained from terbutaline‐treated animals, the effects of terbutaline and adrenaline on cyclic AMP content, active Na‐K‐transport and subtetanic contractions were all considerably suppressed, but insulin stimulated 22Na‐efflux and affected subtetanic contractions to the same extent as in the muscles obtained from the control group.

The results suggest that terbutaline treatment leads to a reduction in the number of β2‐adrenoceptors in skeletal muscle or an impairment of their function.

The results provide further support for the idea that the effect of adrenaline or insulin on skeletal muscle contractions is the outcome of stimulation of active Na‐K‐transport.
EFFECT OF SULPHASALAZINE ON PULMONARY INACTIVATION OF PROSTAGLANDIN F2α IN THE PIG
Authors: HELLEWELL P.G. , PEARSON J.D.
Published: July 2012

The metabolism of prostaglandin F2α (PGF2α) 15 nM in 100,000 g supernatant fractions from piglet lung homogenates was inhibited by sulphasalazine with an IC50 value of 25 μm.

The piglet isolated lung perfused with Krebs solution, containing either albumin or Ficoll 70 to prevent oedema and vascular damage, efficiently metabolized PGF2α given as a bolus injection (1 ng in 0.1 ml; 30 nM).

In Krebs solution containing Ficoll 70, sulphasalazine inhibited the pulmonary inactivation of PGF2α in a dose‐dependent manner with an IC50 value of 110 μm. No inhibition of inactivation by sulphasalazine was found when the perfusion fluid contained albumin, which is known to bind this drug effectively.

Analysis of the separated efflux profiles for PGF2α and its metabolites with reference to the dilution curve for an extracellular marker provided evidence that sulphasalazine inhibited PGF2α uptake into lung cells.

We conclude that the effect of sulphasalazine on pulmonary prostaglandin inactivation is primarily due to inhibition of prostaglandin transport, and not to inhibition of prostaglandin metabolism.
AN EXAMINATION OF THE PRE‐ AND POSTSYNAPTIC α‐ADRENOCEPTORS INVOLVED IN NEUROEFFECTOR TRANSMISSION IN RABBIT AORTA AND PORTAL VEIN
Authors: DOCHERTY JAMES R. , STARKE KLAUS
Published: July 2012

The α‐adrenoceptor agonists, Clonidine and xylazine, reduced and the α‐antagonists, yohimbine and rauwolscine, increased the stimulation‐evoked tritium overflow from rabbit aorta and portal vein pre‐incubated with [3H]‐noradrenaline.

Based on an order of agonist potency of Clonidine > xylazine > phenylephrine and antagonist potency of rauwolscine = yohimbine > prazosin, the presynaptic receptor mediating these effects is of the α2‐type.

In the aorta, stimulation‐evoked contractions were abolished by prazosin (0.1 μm) and potentiated by rauwolscine and yohimbine in concentrations that increased the stimulation‐evoked overflow of tritium.

In the portal vein, prazosin was less potent in reducing, and rauwolscine and yohimbine failed to potentiate, the stimulation‐evoked contraction.

In experiments in which tissues were pre‐exposed to phenoxybenzamine (30 nM) to block some of the postsynaptic α‐receptors, rauwolscine in concentrations that increased stimulation‐evoked tritium overflow, reduced the evoked contraction in the portal vein but not in the aorta.

It is concluded that presynaptic α2‐autoreceptors are present in both tissues and that the postsynaptic α‐receptors which mediate nerve stimulation‐evoked contractions are α1 in the aorta but a mixture of α1 and α2 in the portal vein.
ELECTROPHYSIOLOGICAL AND OTHER EFFECTS ON RABBIT HEARTS OF CCI 22277, A NEW STEROIDAL ANTIARRHYTHMIC DRUG
Authors: CAMPBELL T.J. , WILLIAMS E.M. VAUGHAN
Published: July 2012

CCI 22277 (methyl 2β‐ethoxy‐2α‐hydroxy‐1 1α‐(3‐methylbutylamino)‐5α‐androstane‐17β‐carboxylate hydrochloride) is an aminosteroid with antiarrhythmic properties in animal models.

It slowed significantly conduction velocity and spontaneous frequency.

CCI 22277 was a local anaesthetic on frog nerve, 62 times more potent than procaine. It greatly reduced the maximum rate of depolarization (MRD) in atria, Purkinje cells and ventricles, and reduced the overshoot potential. The effects were frequency‐dependent and it was concluded that the drug probably delayed recovery from inactivation of fast inward current.

CCI 22277 had no anti‐adrenergic actions, nor did it prolong action potential duration (APD) in any cardiac tissues.

The drug was negatively inotropic, and depressed the positive inotropic responses of atria to increased extracellular calcium.

At high concentrations and at rapid pacing frequency, the action potential plateau disappeared and APD became very short.

It was concluded that CCI is primarily a class I antiarrhythmic drug at low concentration, with additional class IV action at higher concentrations.
EXPERIMENTAL DISSOCIATION OF THE EFFECTS OF PROSTAGLANDINS ON RENAL SODIUM AND WATER REABSORPTION BY CYCLO‐OXYGENASE INHIBITORS IN THE RAT
Authors: BARTOLI ETTMORE , BRANCA GIAN FRANCO , FAEDDA ROSSANA , OLMEO NINA A. , SATTA ANDREA , SOGGIA GIOVANNI
Published: July 2012

The relative importance of the effect of prostaglandins on renal sodium and water reabsorption was assessed in rats.

Clearance experiments were performed on 24 anaesthetized rats divided into 3 groups. Each group was infused throughout either with Ringer solution at 9 ml/h (Protocol I), or at 3 ml/h (Protocol II) or with hypotonic fluid at 5 ml/h (Protocol III). Clearance periods were performed before and after intravenous injection of indomethacin (5 mg/kg) and then of aspirin (20 mg/kg). The natriuretic response to different degrees of volume expansion was not modified during the action of the inhibitors.

When baseline urine osmolality (Uosm) was high (Protocol II) no further increase occurred in the presence of prostaglandin inhibition. Conversely, Uosm rose from 771 ± 134 to 1356 ± 414 and from 575 ± 245 to 841 ± 407 mosm/kg (P < 0.05) in Protocol I and Protocol III respectively, when antidiuretic hormone secretion was inhibited by the higher degree of volume expansion.

There was a significant correlation between the change in urine flow rate induced by cyclo‐oxygenase inhibitors and the attendant variations in Na excretion, r = 0.42, n = 41, P < 0.01.

Thus, prostaglandins affect Na loss during saline load as a side effect of their action on water permeability. They could play an important role in volume depletion by counterbalancing the large secretion rate of renal vasoconstrictors.
THE EFFECT OF NALOXONE ON OPIOID‐INDUCED INHIBITION AND FACILITATION OF ACETYLCHOLINE RELEASE IN BRAIN SLICES
Authors: BEANI L. , BIANCHI C. , SINISCALCHI A.
Published: July 2012

The effect of morphine, methionine‐enkephalin (Met‐enkephalin) and d‐Ala2‐d‐Leu5‐enkephalin (DADLE) were tested on the spontaneous and electrically‐evoked release of acetylcholine (ACh) from superfused slices of guinea‐pig thalamus, caudate nucleus and cerebral cortex.

At no concentration did morphine, Met‐enkephalin or DADLE modify the outflow of ACh at rest but Met‐enkephalin in the presence of naloxone, reduced the resting ACh release.

Morphine, at a low dose (3 μm) had no effect in slices of cerebral cortex, but it enhanced the evoked release of ACh in thalamic and caudate, slices. At higher doses of morphine (10–30 μm), the ACh release evoked by electrical pulses was significantly inhibited in every area.

Met‐enkephalin behaved like morphine in thalamic slices, whereas DADLE, a specific < 5 agonist, produced a slight inhibition of ACh outflow only at 10 μm.

Naloxone antagonized the inhibitory effect of morphine in the cerebral cortex and caudate nucleus slices. Naloxone and also spiroperidol blocked the releasing effect of morphine in caudate slices. In contrast naloxone did not affect the increase of ACh release caused by morphine and Met‐enkephalin in thalamic slices. The inhibitory effect of both opioids at high doses was reversed by naloxone so that they then enhanced ACh release.

A two fold increase of calcium concentration in the Krebs solution prevented the inhibitory effects of morphine 10 μm.

It is suggested that two receptors are present in thalamic slices, one of which inhibits and the other facilitates ACh release.
REVERSIBLE EFFECTS OF TETANUS TOXIN ON STRIATAL‐EVOKED RESPONSES AND [3H]‐γ‐AMINOBUTYRIC ACID RELEASE IN THE RAT SUBSTANTIA NIGRA
Authors: COLLINGRIDGE GRAHAM L. , DAVIES JOHN
Published: July 2012

The effects of sublethal doses of tetanus toxin on γ‐aminobutyric acid (GABA)‐mediated synaptic transmission and [3H]‐GABA release were studied in the rat substantia nigra.

Intranigral injections of tetanus toxin at 1–5 times the mouse LD50 dose produced ipsiversive circling behaviour which was maximal after 1 week and lasted 2–3 weeks. Rats then displayed normal behaviour suggesting that the effects of the toxin were fully reversible.

In the treated nigra of circling rats there was a reduction in the striatal‐evoked inhibition of compacta and reticulata neurones, but no change in their spontaneous firing rates. Some forms of striatal‐evoked excitation were also reduced. Once rats had recovered from circling no alterations in the synaptic responses were detected.

In circling rats there were no differences in the sensitivities of neurones in the treated and untreated nigra to GABA or to other inhibitory neurotransmitters.

The Ca2+‐dependent, K+‐evoked release of [3H]‐GAB A from slices prepared from the treated nigra of circling rats was less than that from the untreated nigra of circling rats. No differences in nigral [3H]‐GABA release were observed once rats had recovered from the circling behaviour.

The results demonstrate that doses of tetanus toxin which produce reversible behavioural effects can interfere reversibly with GABA‐mediated synaptic transmission by a presynaptic mechanism which probably involves a reduction in transmitter release.
DRUGS THAT INCREASE γ‐AMINOBUTYRIC ACID TRANSMISSION PROTECT AGAINST THE HIGH PRESSURE NEUROLOGICAL SYNDROME
Authors: BICHARD A.R. , LITTLE H.J.
Published: July 2012

The effects on the high pressure neurological syndrome (HPNS) of drugs which facilitate γ‐aminobutyric acid (GABA) transmission were investigated. Threshold pressures for the onset of the behavioural signs of the HPNS in mice — tremors and convulsions were established.

Flurazepam hydrochloride 20 and 10 mg/kg and sodium valproate 800 and 400 mg/kg substantially raised the threshold pressures for both tremor and convulsions.

Amino‐oxyacetic acid 35 and 25 mg/kg and diaminobutyric acid 600 mg/kg also significantly increased the thresholds. Muscimol 1 mg/kg (and 150 ngi.c.v.) was ineffective at non‐toxic doses.

These effects paralleled the drugs' ability to raise the convulsion threshold to intravenous infusion of bicuculline in mice.

These results demonstrate that drugs with actions more selective than those of the general anaesthetics are effective against the HPNS. It is also possible that there is a GABAergic component to the effects of general anaesthetics on the HPNS.
EFFECT OF DIPYRIDAMOLE ON THE FORMATION OF 6‐OXO‐PROSTAGLANDIN F1α BY THE RAT ISOLATED AORTA AND RAM SEMINAL VESICLE MICROSOMES
Authors: BULT HIDDE , HERMAN ARNOLD G. , VAN DE VELDE VERA J.S.
Published: July 2012

Dipyridamole (1 and 10 μm) enhanced the production of 6‐oxo‐prostaglandin F1α by rat aortic tissue.

Dipyridamole (5 to 40 μm) did not influence the PGI2‐synthetase activity in ram seminal vesicle microsomes whereas, in concentrations ranging from 100 to 200 μM, it reduced the metabolism of exogenously added arachidonic acid. The latter effect may be due to an inhibition of the cyclo‐oxygenase.
DETECTION BY FLUORESCENCE OF PEROXIDES AND CARBONYLS IN SAMPLES OF ARACHIDONIC ACID
Authors: GUTTERIDGE JOHN M.C. , KERRY PHILIP J.
Published: July 2012

Products of lipid peroxidation were compared in two different grades of commercially‐obtained arachidonic acid.

The less pure 90% sample was yellow in colour, had low reactivity with 2‐thiobarbituric acid and diene conjugation but high u.v. fluorescence, whereas the 99% pure sample, which was clear in colour, showed a reverse pattern of oxidation products.

The significance of these findings is discussed.
THE EFFECTS OF CYCLIC DICARBOXYLIC ACIDS ON SPONTANEOUS AND AMINO ACID‐EVOKED ACTIVITY OF RAT CORTICAL NEURONES
Authors: BIRLEY S. , COLLINS J.F. , PERKINS M.N. , STONE T.W.
Published: July 2012

A series of cyclic dicarboxylic acids were applied by microiontophoresis to neurones in the cerebral cortex of rats anaesthetized with urethane. The object was to examine effects on spontaneous firing rates and any ability to antagonize responses to excitatory amino acids.

At relatively low ejecting currents (10–25 nA) cis‐2,3‐piperidine dicarboxylic acid (cis‐2,3‐PDA) had no effect on spontaneous firing but selectively antagonized the excitation evoked by N‐methyl‐D‐aspartate (NMDA) without affecting responses to quisqualate or kainate. At higher ejecting currents (60–100 nA) responses to all three agonists were reduced.

Other cis‐piperidine dicarboxylic acids and piperazine‐2, 3‐dicarboxylic acid had only weak and variable effects on cell firing and responses to NMDA, quisqualate, kainate, glutamate and aspartate.

2, 3‐Pyridine dicarboxylic acid (quinolinic acid) produced excitation of all cortical neurones tested.

2‐Amino‐5‐phosphono‐valeric acid, an NMDA antagonist, reduced responses to quinolinate, implying that this compound can act at NMDA receptors.

It is suggested that quinolinic acid may be of physiological interest as a potential endogenous excitant in the nervous system and that cis‐2,3‐PDA and its N‐methyl derivative may be of use in studies of receptor pharmacology and the identification of synaptic transmitters.
FIBRIN, RED CELL AND PLATELET INTERACTIONS IN AN EXPERIMENTAL MODEL OF THROMBOSIS
Authors: SMITH J.R. , WHITE A.M.
Published: July 2012

Insertion of a cotton thread into an arteriovenous shunt of an anaesthetized rat causes an increase in the weight of the thread due to deposition of thrombus.

The thrombus formed was of the venous (red) type, being sensitive to heparin, yet possessed important characteristics of an arterial thrombus, in that it was dependent on platelets and on rate of blood flow.

Thromboxane synthetase inhibitors had no effect on thrombus deposition.

Cyclo‐oxygenase inhibitors did not significantly depress thrombus formation at doses which inhibited platelet function ex vivo.

Compounds which can modify the release or action of adenosine 5′‐diphosphate partly inhibited thrombus formation.

A depression in clotting factor levels induced by sodium warfarin led to a highly significant reduction in thrombus formation at doses which caused a prolongation of prothrombin clotting time.
ELECTRICAL SLOW WAVES AND TONE OF GUINEA‐PIG ISOLATED TRACHEALIS MUSCLE: EFFECTS OF DRUGS AND TEMPERATURE CHANGES
Authors: SMALL ROGER C.
Published: July 2012

Simultaneous recordings of electrical and mechanical activity have been made from guinea‐pig isolated trachealis muscle. Electrical activity was recorded both by extracellular and intracellular techniques.

Extracellular studies showed that the spontaneous development of tone was accompanied by electrical slow waves which frequently exhibited pronounced waxing and waning. Intracellular recording confirmed the discharge of these slow waves in individual cells. Extracellularly‐recorded slow waves were often of greatest amplitude while the tissue was developing rather than maintaining tension. Some tissues became electrically quiescent on reaching peak tone.

Cooling to 27.5°C caused some relaxation. Slow wave amplitude and frequency fell, slow waves eventually being abolished. Subsequent rapid rewarming initially evoked a more profound relaxation. An intense discharge of slow waves then occurred as the tension rapidly rose again towards the pre‐cooling value.

Sodium nitrite, (−)‐isoprenaline, adenosine and adenosine triphosphate (ATP) each evoked relaxation and reduced the frequency and amplitude of slow waves. High concentrations of these agents often abolished slow waves. The actions of these drugs were reversible.

Treatment with methoxyverapamil (D600) 1 μmol/l for 15 min abolished slow wave activity but only evoked partial relaxation of the tissue.

Acetylcholine, histamine and tetraethylammonium (TEA) each evoked contraction, but TEA was unique in consistently promoting slow waves and (in high concentration) spike activity. Spasm evoked by acetylcholine and histamine did not usually involve the initiation or promotion of slow waves. Indeed in appropriate concentration these two agents always suppressed slow wave activity. The actions of the spasmogens were reversible.

It is concluded that the smooth muscle cells of the trachealis are electrically coupled. While co‐ordinated slow wave activity is associated with the spontaneous development of tension in trachealis, it may not be necessary for the maintenance of the major part of the spontaneous tension exhibited by the tissue or for the spasm evoked by histamine or acetylcholine. Slow wave promotion by TEA suggests that the tissue may have a high resting potassium conductance which normally attenuates the slow waves. Slow waves may be suppressed by a variety of drugs acting by different mechanisms. Since D600 suppresses slow waves of the trachealis the mechanisms underlying the waves may be similar to those underlying spike activity in other smooth muscles.
EFFECTS OF LYSINE‐VASOPRESSIN AND OXYTOCIN ON CENTRAL CARDIOVASCULAR CONTROL
Authors: TRAN LAC DANG , MONTASTRUC JEAN‐LOUIS , MONTASTRUC PAUL
Published: July 2012

The cardiovascular effects of intravenous and intracisternal administration of neurohypophysial peptides were compared in dogs anaesthetized with chloralose.

Intravenous lysine‐vasopressin (0.1 to 100 mu/kg) induced a dose‐dependent increase in blood pressure and a decrease in heart rate. In contrast, intracisternal lysine‐vasopressin (0.01 to 10 mu/kg) induced a dose‐related decrease in blood pressure and did not change heart rate.

Intracisternal oxytocin (1 and 10 mu/kg) increased blood pressure and did not change heart rate, whereas the same doses injected intravenously were inactive.

Pretreatment with guanethidine (15 mg/kg i.v. 24 h beforehand) abolished the hypotensive responses to intracisternal vasopressin but not the pressor action of intravenous vasopressin.

The pressor responses to central injections of oxytocin were not modified by guanethidine.

Hypotension elicited by intracisternal vasopressin was probably due to a decrease in sympathetic tone whereas the hypertension induced by intracisternal oxytocin was independent of variations in sympathetic tone.
PRESYNAPTIC MUSCARINIC RECEPTORS INHIBITING ACTIVE ACETYLCHOLINE RELEASE IN THE BULLFROG SYMPATHETIC GANGLION
Authors: KOKETSU K. , YAMADA M.
Published: July 2012

The effects of bethanechol and atropine on the release of acetylcholine (ACh) from bullfrog sympathetic preganglionic nerve terminals were examined electrophysiologically.

Bethanechol (1 mm) caused no depolarization of sympathetic preganglionic nerve terminals, whereas carbachol or ACh in the same concentration induced marked depolarizations of these terminals.

Bethanechol (10 μm) depressed the amplitude of fast excitatory postsynaptic potentials (e.p.s.ps) recorded in low Ca2+‐high Mg2+ solution, without depolarizing ganglion cells. The quantal content measured from these fast e.p.s.ps by the variance method showed a significant reduction.

Amplitudes of both miniature e.p.s.ps and ACh‐potentials induced by iontophoresis of ACh were not affected by addition of bethanechol (10 μm).

The depressant effect of bethanechol (10 μm) on fast e.p.s.ps disappeared in the presence of atropine (3 μm).

Atropine (3 μm) increased the quantal content measured from fast e.p.s.ps recorded in low Ca2+‐high Mg2+ solution.

The depressant effect of bethanechol (10 μm) on fast e.p.s.ps was unaffected by α‐adrenoceptor blocking agents (phenoxybenzamine (10 μm) or phentolamine (10 μm)).

These results suggest that presynaptic nerve terminals in bullfrog sympathetic ganglia possess a muscarinic receptor which inhibits active release of ACh.
THE EFFECTS OF VASOACTIVE INTESTINAL POLYPEPTIDE AND OF ADENOSINE 5′‐TRIPHOSPHATE ON THE ISOLATED ANOCOCCYGEUS MUSCLE OF THE MOUSE
Authors: GIBSON A. , TUCKER J.F.
Published: July 2012

Vasoactive intestinal polypeptide (VIP, 0.01–5 μm) produced dose‐related relaxations of the mouse anococcygeus muscle.

Following incubation with indomethacin (2.8 μm 1 h) adenosine 5′‐triphosphate (ATP, 0.5–10 mm) produced dose‐related relaxations of the mouse anococcygeus.

Haemolysed blood reduced inhibitory responses of the mouse anococcygeus to field stimulation but had no effect on relaxations to VIP or ATP.

Apamin (0.5 μm) had no effect on the relaxation of mouse anococcygeus to field stimulation, VIP, or ATP.

2‐2′‐Pyridylisatogen tosylate (PIT, 50 μm) itself reduced muscle tone but it did not abolish inhibitory responses to field stimulation, VIP, or ATP.

During prolonged inhibitory nerve stimulation the relaxation of the mouse anococcygeus in response to VIP was reduced greatly while that to ATP was unaffected.

Bundles of VIP‐immunoreactive sites were detected in sections of the mouse anococcygeus treated by the peroxidase‐antiperoxidase (PAP) immunocytochemical technique.

The results suggest that the mechanisms underlying non‐adrenergic, non‐cholinergic inhibitory transmission in the mouse anococcygeus are similar to those in the bovine retractor penis and unlike those in the guinea‐pig taenia caeci.

The possibility that VIP or ATP might be involved in inhibitory neurotransmission in the mouse anococcygeus is discussed.
A STUDY OF α1‐ADRENOCEPTORS IN RAT RENAL CORTEX: COMPARISON OF [3H]‐PRAZOSIN BINDING WITH THE α1‐ADRENOCEPTOR MODULATING GLUCONEOGENESIS UNDER PHYSIOLOGICAL CONDITIONS
Authors: McPHERSON G.A. , SUMMERS R.J.
Published: July 2012

A comparison has been made of the α1‐adrenoceptor controlling gluconeogenesis in tubules from rat renal cortex and [3H]‐prazosin binding in membranes prepared from the same tissue under physiological conditions.

In renal tubules the α‐adrenoceptor agonists, oxymetazoline, (−)‐noradrenaline, (−)‐α‐methylnoradrenaline and (−)‐phenylephrine, stimulated gluconeogenesis from pyruvate. Oxymetazoline was the most potent agonist (EC50 15.7 nm) but produced only 61% of the maximum response elicited by (−)‐noradrenaline.

The α‐adrenoceptor antagonists, BE2254, prazosin, indoramin and phentolamine inhibited (−)‐noradrenaline‐mediated increases in gluconeogenesis. The α1‐adrenoceptor selective compounds, BE2254 and prazosin, were the most effective antagonists with KB values of 0.74 and 1.47 nm respectively.

[3H]‐prazosin binding to membranes prepared from rat renal cortex in physiological saline at 37°C was best described by a two site model. High affinity, but not low affinity sites had characteristics consistent with α‐adrenoceptors.

High affinity [3H]‐prazosin binding could be completely displaced by the α‐adrenoceptor agonists, oxymetazoline, (−)‐noradrenaline, (−)‐phenylephrine, and (−)‐α‐methylnoradrenaline. Slope factors for the displacement curves were all significantly less than unity. The concentrations of agonists required to displace [3H]‐prazosin binding were markedly higher than those required to stimulate gluconeogenesis.

High‐affinity [3H]‐prazosin binding was also displaced by the α‐adrenoceptor antagonists, prazosin, BE2254, phentolamine and indoramin. Slope factors for the displacement curves were close to unity. Ki values calculated from the binding experiments were very similar to KB values obtained in the gluconeogenesis studies. These results suggest that in rat renal cortex the α1‐adrenoceptor labelled by [3H]‐prazosin is probably that which stimulates gluconeogenesis.
The biological activity of a single dose of tamoxifen in the adult ovariectomized rat
Authors: Bowman Susan P. , Jones Christine A. , Leake A. , Morris I.D.
Published: July 2012

The peripheral and central activities of tamoxifen were studied in the ovariectomized adult rat, up to 16 d after a single dose of 7.0 or 0.7 mg/kg.

Food consumption and body weight were decreased; only food consumption returned to control values after 16 d.

The weights of the uterus and of the uterine luminal fluid were increased for up to 8 d.

Serum follicle‐stimulating hormone (FSH) concentrations decreased, but only significantly 1 and 8 d after 7.0 mg tamoxifen/kg. Serum luteinizing hormone (LH) and prolactin concentrations were elevated for up to 4 d.

Lordosis behaviour was absent throughout the period studied.

Within 3 d of administration, tamoxifen partially antagonized the oestrogen‐induced changes in uterine luminal fluid, prolactin and LH secretion and lordosis behaviour.

Tamoxifen did not alter oestrogen‐induced changes in uterine weight, food consumption and body weight.

The experiments demonstrate that tamoxifen is active for up to 16 d after a single intraperitoneal dose; oestrogen agonist, partial agonist and antagonist activities were demonstrated. The duration and type of activity depends upon the dose of tamoxifen and the target tissue response examined.
The role of nicotinic receptors in dog pancreatic exocrine secretion
Authors: Devaux M.A. , Diaz G.R. , Kubota K. , Magee D.F. , Sarles H.
Published: July 2012

The effects of pentamethonium, an autonomic ganglion blocker, were studied on the exocrine pancreatic secretion of six conscious dogs given intravenous infusions of urecholine, caerulein or pentagastrin on a background of submaximal doses of secretin.

Urecholine‐induced protein secretion was not affected but both caerulein‐ and to a smaller extent, pentagastrin‐induced protein secretions were depressed by pentamethonium.

These results indicate that intravenous caerulein and pentagastrin, but not urecholine, act at least partially via nicotinic receptors.

Volume and bicarbonate output were depressed by pentamethonium when stimulated by intravenous caerulein with a background of secretin, but not when stimulated by pentagastrin on a background of secretin.

From these data it is suggested that caerulein and pentagastrin may potentiate secretin‐stimulated hydrelatic secretion by different mechanisms.
Release of [3H]‐amezinium from cortical noradrenergic axons: a model for the study of the α‐autoreceptor hypothesis
Authors: Hedler Liselotte , Starke Klaus , Steppeler Anton
Published: July 2012

[3H]‐amezinium is taken up selectively into noradrenergic axons and their transmitter‐storing vesicles and is released from these axons by action potentials. We used it as a non‐α‐adrenergic marker in order to study the α‐adrenergic autoinhibition of noradrenaline release.

Rat occipitocortical slices were preincubated with [3H]‐amezinium 0.03 μm and then superfused and stimulated electrically (3 Hz for 3 min). The stimulation‐evoked overflow of tritium was measured in six groups of slices: from saline‐pretreated rats; from saline‐pretreated rats, the slices being exposed to exogenous noradrenaline before preincubation with [3H]‐amezinium; from saline‐treated rats, slices from which were exposed simultaneously to noradrenaline and cocaine before preincubation with [3H]‐amezinium; from rats in which noradrenaline stores had been depleted by pretreatment with α‐methyltyrosine (α‐MT); from α‐MT‐treated rats, the slices being exposed to noradrenaline before preincubation with [3H]‐amezinium; and from α‐MT‐treated rats, slices from which were exposed to noradrenaline plus cocaine before preincubation with [3H]‐amezinium.

The stimulation‐evoked overflow of tritium, expressed as a percentage of the tritium content of the tissue, was 1.15% in slices from saline‐pretreated rats, and was similar in slices from saline‐pretreated rats after exposure to noradrenaline or noradrenaline plus cocaine. It was 2.56% in slices from α‐MT‐treated rats, 1.20% from α‐MT‐treated rats after exposure to noradrenaline, and 2.88% from α‐MT‐treated rats after exposure to noradrenaline plus cocaine.

Yohimbine 0.1 and 1 μm increased the stimulation‐evoked overflow of tritium in slices from all groups of saline‐pretreated rats and in those slices from α‐MT rats that had been in contact with exogenous noradrenaline. Yohimbine did not change the evoked overflow in slices from α‐MT rats that had not been exposed to noradrenaline, or had been exposed to noradrenaline plus cocaine.

Clonidine 0.01 — 1 μm decreased the stimulation‐evoked overflow of tritium moderately in slices from saline‐pretreated rats, markedly in slices from α‐MT‐treated rats, and moderately again when the latter slices had been exposed to noradrenaline.

It is concluded that the action potential‐evoked release of [3H]‐amezinium as well as the modulation of this release by yohimbine and clonidine depend on the presence or absence of α‐adrenergic autoinhibition caused by the co‐secretion of noradrenaline. When there is co‐secretion of noradrenaline, the evoked release of [3H]‐amezinium is relatively small, yohimbine increases the release, and clonidine can cause only moderate inhibition. When there is no or very little co‐secretion of noradrenaline, the evoked release of [3H]‐amezinium is at least doubled, yohimbine causes no further increase and clonidine produces strong inhibition.
An investigation of presynaptic α‐adrenoceptor subtypes in the pithed rat heart
Authors: Docherty James R.
Published: July 2012

The presynaptic cardio‐inhibitory and postsynaptic pressor responses to the α‐adrenoceptor agonists xylazine and cirazoline, and the interaction with the antagonists yohimbine and prazosin, were examined in the pithed rat.

Evidence was found to suggest that, as well as the already established pre‐ and postsynaptic α2‐and postsynaptic α1‐receptors, presynaptic α1‐receptors are present.
Topical capsaicin pretreatment inhibits axon reflex vasodilatation caused by somatostatin and vasoactive intestinal polypeptide in human skin
Authors: Anand P. , Bloom S.R. , McGregor G.P.
Published: July 2012

Wheal and flare reactions are described following intradermal injections of somatostatin, vasoactive intestinal polypeptide, substance P and histamine in normal human forearm skin. Bombesin failed to produce a significant wheal and flare.

Pretreatment of skin with capsaicin in all cases dramatically inhibited the flare but not the wheal. This result is in accord with the hypothesis that capsaicin blocks the effector side of the axon reflex, perhaps by depleting nerve terminals of vasodilatory peptide(s).
Evidence against vasoactive intestinal polypeptide (VIP) as a dilator and in favour of substance P as a constrictor in airway neurogenic responses
Authors: Karlsson J.‐A. , Persson C.G.A.
Published: July 2012

Propranolol‐resistant neurogenic relaxation persisted in (carbachol‐contracted) guinea‐pig tracheae already relaxed by supramaximal concentrations of vasoactive intestinal polypeptide (VIP). Also, VIP relaxed preparations that were under neurogenic inhibition. In hilus bronchi, about 60% of a neurogenic contraction was atropine‐resistant. (Arg5, d‐Trp7,9) SP5–11 specifically antagonized this contraction and those produced by exogenous substance P. Substance P, but not VIP, seems to be involved in nerve‐mediated effects on guinea‐pig airway tone.