bluuebunny/crossref_metadata_2025 huggingface dataset:
EFFECTS OF MOLINDONE AND FLUPHENAZINE ON THE BRAIN CONCENTRATION OF SOME PHENOLIC AND CATECHOLIC AMINES IN THE MOUSE AND THE RAT
Authors: JUORIO A.V.
Published: July 2012

The concentrations of p‐ and m‐tyramine, dopamine, 3,4‐dihydroxyphenylacetic acid and homovanillic acid were measured in the mouse or rat striatum following the subcutaneous injection of molindone or fluphenazine. The mouse hypothalamic levels of the m‐ or p‐isomers of octopamine were also analysed.

Endogenous concentrations of p‐ and m‐tyramine in the mouse striatum and p‐ and m‐octopamine in the mouse hypothalamus were 20.6, 5.7, 9.4 and 1.2ng/g respectively. The rat striatum concentrations of p‐ and m‐tyramine were 12.8 and 3.8 ng/g.

The administration of low doses of molindone (1 to 10 mg/kg) produced a reduction in striatal p‐tyramine, an increase in m‐tyramine and an increase in dopamine turnover. Similar effects were produced by all doses of fluphenazine (0.1 to 5 mg/kg) employed. These findings are consistent with those observed after blockade of dopamine postsynaptic receptors.

With high doses of molindone (100 mg/kg) the effects on both tyramines and on dopamine metabolism were reversed. These results can be interpreted as molindone acting as a partial agonist.

The concentrations of hypothalamic p‐ and m‐octopamine were increased by the higher doses of molindone (20 to 100 mg/kg) employed while lower doses produced no significant effects. All doses of fluphenazine reduced hypothalamic p‐octopamine. These changes seem to depend on differences in the availability of p‐tyramine to be converted into p‐octopamine.

These results suggest that molindone acts as a blocker or a partial agonist of dopamine receptor sites and fit well with the proposal of a reciprocal relation between dopamine and tyramine. It is not possible yet to ascertain whether tyramine controls dopamine or vice versa or if it is a direct or a more remote relation.
INTRACELLULAR OBSERVATIONS ON THE EFFECTS OF MUSCARINIC AGONISTS ON RAT SYMPATHETIC NEURONES
Authors: BROWN D.A. , CONSTANTI A.
Published: July 2012

Responses of single neurones in isolated superior cervical ganglia of the rat to muscarinic agonists were recorded with intracellular microelectrodes.

(±)‐Muscarine (1 to 10 μm) and methylfurmethide (1 to 3 μm) produced reversible membrane depolarizations (≤ 15 mV) accompanied by a fall in input conductance and an increased tendency toward repetitive spike discharges. The spike configuration was unchanged.

Analysis of steady‐state current/voltage curves revealed the most consistent muscarinic effect to be a large reduction (∼50% at 10 μm muscarine) in input slope conductance around rest potential. This conductance decrease diminished as the membrane was hyperpolarized, and the normal increase in slope conductance with membrane depolarization was depressed. The current/voltage curves in the presence and absence of agonist did not usually intersect; in a few tests, the curves intersected at between −65 and −88 mV (i.e. 9 to 28 mV hyperpolarized to rest potential).

Divalent cations (10 mm [Ca2+] or [Mg2+]) showed a small muscarine‐like effect on the current/voltage and slope conductance/voltage curves, but did not affect the action of muscarine itself.

Tetraethylammonium (TEA, 5 mm) also had a small muscarine‐like effect, and depressed or reversed the action of muscarine. However, TEA differed from muscarine in blocking orthodromic transmission and prolonging direct spike repolarization.

It is concluded that the primary effect of muscarinic agonists is to alter the rectifying properties of the cell within the potential range −80 to −40 mV.
γ‐AMINOBUTYRIC ACID AGONISTS: AN in vitro COMPARISON BETWEEN DEPRESSION OF SPINAL SYNAPTIC ACTIVITY AND DEPOLARIZATION OF SPINAL ROOT FIBRES IN THE RAT
Authors: ALLAN R.D. , EVANS R.H. , JOHNSTON G.A.R.
Published: July 2012

Relative molar potencies, of a range of γ‐aminobutyrate (GABA)‐related agonists, for depolarization of isolated spinal roots have been compared with their potencies for depression of spontaneous synaptic activity, recorded in ventral roots of hemisected spinal cord preparations from 3 to 9‐day‐old rats. Both effects were sensitive to antagonism by bicuculline.

The depolarizing potencies of the series were not parallelled by their depressant potencies. This disparity was shown most strongly by 4,5,6,7‐tetrahydroisoxazolo[5,4‐c]pyridin‐3‐ol (THIP) which was 20 times stronger than GABA in depolarizing root fibres and 20 times stronger than GABA in its depressant action and by (+)‐cis‐3‐aminocyclopentane‐carboxylic acid (17 times weaker than GABA on root fibres and 42 times stronger than GABA as a depressant).

The effect of uptake on these relative potencies is discussed and it is concluded that fibre depolarization and depression are probably mediated by different types of bicuculline‐sensitive receptor.

The depolarizing potencies of the agonists showed a strong correlation with previously reported data for displacement of labelled GABA from in vitro rat brain membrane preparations (correlation coefficient 0.90, P < 0.001). However, the relative depressant potencies showed no such correlation with binding data (correlation coefficient 0.50, P > 0.05).
EFFECT OF MIANSERIN ON NORADRENERGIC TRANSMISSION IN THE RAT ANOCOCCYGEUS MUSCLE
Authors: DOGGRELL SHEILA A.
Published: July 2012

The effects of mianserin on the accumulation of (−)‐[3H]‐noradrenaline and on contractile responses to field stimulation, exogenously applied (−)‐noradrenaline, and to tyramine were studied in the rat anococcygeus muscle.

Mianserin (10−9to 10−5m) and nortriptyline (10−9to 10−5m) inhibited the accumulation of (−)‐[3H]‐noradrenaline. In this aspect mianserin had a similar potency to nortriptyline, the most potent tricyclic antidepressant in inhibiting noradrenaline accumulation in this tissue.

Mianserin 10−9or 10−8m alone had no effect on contractile responses to field stimulation and to (−)‐noradrenaline but inhibited the responses to tyramine. The responses to field stimulation at low frequencies and to (−)‐noradrenaline were potentiated by 10−7and 10−6m mianserin. It is suggested that the inhibitory effect mianserin has on neuronal accumulation is primarily responsible for these effects. Mianserin 10−5m inhibited responses to field stimulation and to (−)‐noradrenaline.

In the presence of nortriptyline (10−6m), the contractile responses to field stimulations were potentiated by mianserin (10−8, 10−7and 10−6m), 10−8m being the most potent in this aspect. Mianserin 10−8, 10−7, 10−6and 10−5m had a similar inhibitory effect on responses to (−)‐noradrenaline. In the absence of neuronal uptake, the potentiating effect of mianserin on responses to field stimulation may be due to antagonism at presynaptic α‐adrenoceptors. In the presence of 10−6m nortriptyline, 10−5m mianserin abolished responses to field stimulation.

Following incubation of the tissue in the presence of 6‐hydroxydopamine (10−3m for 3 h), mianserin (10−7, 10−6and 10−5m) nortriptyline (10−7and 10−6m) and phentolamine (5 × 10−8and 5 × 10−7m) inhibited contractile responses to (−)‐noradrenaline. This illustrates the ability of these agents to inhibit the responses to noradrenaline at a postsynaptic site. The inhibitory effect was dose‐related with nortriptyline and phentolamine; this illustrates the ability of these agents to antagonize postsynaptic α‐adrenoceptors. The inhibitory effect observed with mianserin was not dose‐related. This suggests that in addition to its reported ability to antagonize postsynaptic α‐adrenoceptors, mianserin may have another post‐synaptic action at the level of, or distal to, the α‐adrenoceptor.

These results illustrate that, in the rat anococcygeus muscle, mianserin is a potent inhibitor of noradrenaline accumulation and may be an antagonist at presynaptic α‐adrenoceptors. Mianserin also inhibits the responses to exogenously applied noradrenaline in this tissue by an action or actions at the level of, or distal to, the postsynaptic α‐adrenoceptor.
INFLUENCE OF CELLULAR TRANSPORT ON THE INTERACTION OF AMINO ACIDS WITH γ‐AMINOBUTYRIC ACID (GABA)‐RECEPTORS IN THE ISOLATED OLFACTORY CORTEX OF THE GUINEA‐PIG
Authors: BROWN D.A. , COLLINS G.G.S. , GALVAN M.
Published: July 2012

Freshly cut guinea‐pig olfactory cortex slices contained 2.2 mmol γ‐aminobutyric acid (GABA)/kg tissue weight. This declined during in vitro incubation at 25°C in the absence of exogenous GABA, but increased to 6.95 mmol/kg after 1.5 h incubation in 1 mm GABA.

Uptake of [3H]‐GABA (1 μm) was inhibited by 1 mm (±)‐nipecotic acid (−83%), β‐amino‐n‐butyric acid (BABA) (−59%), l‐2,4‐diaminobutyric acid (DABA) (−63%), (±)cis‐3‐aminocyclohexane carboxylic acid (ACHC) (−53%), and 3‐aminopropanesulphonic acid (3‐APS) (−26%), but was increased by β‐alanine (BALA) (+23%).

Autoradiographs showed steep concentration gradients of radioactivity across slices incubated for short periods in [3H]‐GABA.

Efflux of [3H]‐GABA from pre‐loaded slices was accelerated strongly by nipecotic acid, BABA, DABA and ACHC but weakly or not all by BALA or 3‐APS.

Nipecotic acid (1 mm) potentiated the surface‐depolarization of the slice produced by GABA but not that produced by 3‐APS.

The depolarizing actions of DABA, BABA, nipecotic acid and ACHC, but not that of 3‐APS or BALA, were potentiated when the endogenous GABA content of slices was raised.

It is concluded that: (a) the depolarizing action of exogenous GABA is limited by cellular uptake; (b) surface‐depolarizations produced by nipecotic acid, DABA, BABA and ACHC may be mediated by the release of GABA; and (c) neuronal, rather than glial, transport systems are responsible for these effects.
CENTRAL RESPIRATORY AND CIRCULATORY DEPRESSION CAUSED BY INTRAVASCULAR SAXITOXIN
Authors: BORISON H.L. , CULP W.J. , GONSALVES S.F. , McCARTHY L.E.
Published: July 2012

In cats anaesthetized with pentobarbitone and vagotomized, observations were made on the phrenic nerve action potential and the diaphragm electromyogram (EMG) at constant end‐tidal Pco2. Arterial blood pressure was stabilized by intravenous infusions of noradrenaline.

Intravenous administration of saxitoxin (STX) initially abolished respiratory activity in the EMG and caused a slowing of oscillation in the central phrenic neurogram. Additional STX produced apneustic phrenic discharges followed by a progressive loss of nerve action potentials.

The inspiratory centre in the medulla oblongata was stimulated electrically to evoke a sustained phrenic nerve discharge. STX, given intravenously, resulted in the elimination of spontaneous nerve activity without interfering with the evoked response.

The cephalic intravascular infusion of STX into a carotid or vertebral artery depressed spontaneous respiratory activity while sparing EMG activity evoked by electrical stimulation of the intact phrenic nerve.

Spontaneous respiratory discharge in the phrenic nerve was eliminated by smaller doses of STX administered intra‐arterially than were required intravenously. In addition, onset of and recovery from neural silence occurred faster following intra‐arterial injection of STX.

Depressant effects on arterial blood pressure coincided with those on respiration when STX was given intra‐arterially.

An electrophysiological assay on frog sartorius muscle was used to measure STX in the cerebrospinal fluid. Levels of STX detected were proportional to amounts of the toxin infused intra‐arterially.

It is concluded that STX exchanges rapidly between blood and brain to bring about central depression and this adds to its peripheral paralytic actions.
COMPARISON OF MIANSERIN WITH DESIPRAMINE, MAPROTILINE AND PHENTOLAMINE ON CARDIAC PRESYNAPTIC AND VASCULAR POSTSYNAPTIC α‐ADRENOCEPTORS AND NORADRENALINE REUPTAKE IN PITHED NORMOTENSIVE RATS
Authors: CAVERO I. , GOMENI R. , LEFÈVRE‐BORG FRANÇOISE , ROACH A.G.
Published: July 2012

The cardiovascular effects of intravenous desipramine (0.03 and 0.1 mg/kg), maprotiline (0.5 mg/kg), mianserin (1.0 and 3.0 mg/kg) and phentolamine (0.25 mg/kg) were examined and compared in pithed rats. Several experimental procedures were used in order to distinguish between the effects of the compounds on cardiac presynaptic α‐adrenoceptors and on neuronal noradrenaline reuptake, as inhibition of either mechanism produces an increase of neurotransmitter concentration within the sympathetic synapse and therefore results in a greater end organ response.

Pressor responses elicited by noradrenaline were potentiated by desipramine and maprotiline, reduced by phentolamine and not significantly modified by mianserin. However, all four compounds inhibited the pressor action of tyramine. Furthermore, mianserin reduced the pressor response to adrenaline.

Desipramine, maprotiline and mianserin, but not phentolamine enhanced the positive chronotropic effects of noradrenaline, without affecting those of isoprenaline.

All four compounds abolished the clonidine‐induced inhibition of heart rate responses to short term electrical stimulation of the spinal cord. Moreover, in rats with a persistent tachycardia (induced by continuous stimulation of the thoracic spinal cord) desipramine, maprotiline and mianserin further increased heart rate. This effect was also observed in animals pretreated with phentolamine, administered in order to inhibit cardiac presynaptic α‐adrenoceptors.

In rats with a sustained tachycardia (100 beats/min produced by electrical stimulation of the spinal cord) both mianserin and phentolamine, in contrast to desipramine, shifted the clonidine heart rate dose‐response curve to the right. Phentolamine was about 34 times more potent than mianserin in this respect.

In pithed, reserpine‐treated rats, the pressor responses to clonidine were not significantly modified by desipramine. The dose‐response curves were shifted to the right by phentolamine (0.25 mg/kg) and mianserin (3.0 mg/kg).

These results indicate that mianserin is an antagonist of both cardiac presynaptic and vascular postsynaptic α‐adrenoceptors and also inhibits the neuronal reuptake of noradrenaline.
DETERMINATION OF SPECIFIC INHIBITORS OF THROMBOXANE A2 FORMATION
Authors: LADD N. , LEWIS G.P.
Published: July 2012

Activation of platelets by contact with collagen leads to the simultaneous formation of a prostaglandin and thromboxane (TXA2), which can be assayed biologically with the superfused rabbit aorta and rat stomach strip. By this method it has been shown that a cyclo‐oxygenase inhibitor, aspirin, inhibited formation of both prostaglandin and TXA2 while a specific TXA2 synthetase inhibitor, clotrimazole, inhibited only TXA2 formation. The method is suitable as a primary screen in the search for TXA2 specific synthetase inhibitors.
INCREASE IN EPITHELIAL CYCLIC ADENOSINE 3′,5′‐MONOPHOSPHATE FOLLOWING VANADATE
Authors: CUTHBERT A.W. , HERRERA F.C. , SCHUZ A.D. , WILSON S.A.
Published: July 2012

Vanadate increases the cyclic adenosine 3′,5′‐monophosphate (cyclic AMP) content of frog skin epithelium and apparently antagonizes the stimulation by isoprenaline. The effect appears to be a direct activation of adenyl cyclase. This new effect of vanadate together with the inhibitory effects on Na‐K ATPase may explain the irregular effects on sodium transport.
EVIDENCE FOR BOTH HISTAMINE H1‐ AND H2‐RECEPTORS IN THE GASTRIC VASCULATURE OF THE CAT
Authors: HARVEY CAROL A. , OWEN D.A.A. , SHAW K.D.
Published: July 2012

Experiments have been done to study the gastric vascular response to histamine given intra‐arterially in the cat.

In experiments utilising pump perfusion of the stomach at constant flow rates, rapid intra‐arterial injections of histamine elicited dose‐dependent vasodilatation. The dose‐response curve to histamine was displaced to the right by mepyramine and further to the right by mepyramine plus cimetidine. Cimetidine alone did not displace the histamine dose‐response curve. This interaction between histamine and histamine antagonists is very similar to the interaction observed in other vascular beds.

Intra‐arterial infusions of histamine also caused vasodilatation with increased gastric blood flow, measured with an electromagnetic flow probe. Mepyramine reduced the immediate increase in blood flow during each infusion, although responses in the later stages of the infusions were unaltered. Cimetidine had no effect on the immediate response but reduced sustained responses to histamine. Treatment with mepyramine and cimetidine was required to abolish histamine responses.

Infusions of 2‐(2‐aminoethyl) pyridine and dimaprit also increased gastric blood flow.

These results indicate the involvement of both H1‐ and H2‐receptors in histamine‐induced gastric vasodilatation. There appears to be a time‐base in the interaction between histamine and vascular histamine receptors; H1‐receptor responses preceding H2‐receptor responses.
ORIGIN OF GUINEA‐PIG PLASMA DOPAMINE β‐HYDROXYLASE
Authors: ARNAIZ J.M. , GARCÍA A.G. , HORGA J.F. , PASCUAL R. , SÁNCHEZ‐GARCÍA P.
Published: July 2012

Exposure of guinea‐pigs to a CO2‐enriched atmosphere (20% CO2, 25% O2, 55% N2) for 1 to 5 h caused a marked, progressive increase of plasma dopamine β‐hydroxylase (DBH) activity which reached its peak after 2 h of CO2 exposure and then gradually decreased. The increase was abolished by mecamylamine administration before exposure to CO2. Plasma levels of noradrenaline (NA) also increased after CO2 exposure.

Guanethidine administration, before exposure to CO2, abolished the increase of plasma NA but potentiated the increase of circulating DBH. Phenoxybenzamine injection, before exposure to CO2, also potentiated the increase of plasma enzyme activity. In both cases, DBH activity was increased to almost 10 times the basal circulating enzyme levels.

Injection of 6‐hydroxydopamine (6‐OHDA) caused a pronounced decrease of DBH activity in the right atrium, thoracic aorta and spleen; the adrenal enzyme activity was unchanged. Exposure to CO2 of 6‐OHDA‐treated animals still evoked a dramatic increase of plasma DBH activity comparable to that found in control animals.

The increase of plasma DBH activity evoked by exposure to CO2 of adrenalectomized animals was considerably diminished.

These data suggest that in the guinea‐pig, the adrenal is the main source of the increase of circulating DBH activity evoked by exposure of the animals to a CO2‐enriched gas mixture.
ADENOSINE INHIBITION OF γ‐AMINOBUTYRIC ACID RELEASE FROM SLICES OF RAT CEREBRAL CORTEX
Authors: HOLLINS CAROLYN , STONE TREVOR W.
Published: July 2012

The effect of purine compounds on the potassium‐evoked release of 14C‐labelled γ‐aminobutyric acid (GABA) has been studied in 400 μm slices of rat cerebral cortex in vitro.

Adenosine and adenosine 5′ monophosphate (AMP) inhibited the release of GABA at 10−5 to 10−3 m. Adenosine triphosphate (ATP) produced a significant inhibition of release only at 10−3 m.

Theophylline 10−4 or 10−3 m reduced the inhibitory effect of adenosine, but did not change basal release of GABA.

Dipyridamole 10−5 m itself reduced evoked GABA release, but did not prevent the inhibitory effect of adenosine, implying that adenosine was acting at an extracellularly directed receptor.

Calcium removal or antagonism by verapamil reduced the evoked release of GABA, but adenosine did not produce any further reduction of the calcium‐independent release. This may indicate that the inhibitory effect of adenosine on GABA release results from interference with calcium influx or availability within the terminals.
RELATIONSHIP BETWEEN DURATION OF URETHANE OR PENTOBARBITONE ANAESTHESIA IN MALE AND FEMALE RATS AND ADENOHYPOPHYSEAL RESPONSE TO LUTEINISING HORMONE‐RELEASING HORMONE
Authors: DYER R.G. , MANSFIELD SANDRA
Published: July 2012

Luteinizing hormone releasing hormone (50 ng/100 g body weight) was injected into male and female rats which had been anaesthetized with either urethane (1.2 g/kg) or pentobarbitone (45 g/kg) for 15, 100 or 240 min and serial blood samples were taken for estimation of plasma luteinizing hormone concentrations.

The rats anaesthetized with urethane tended to show a greater response to the releasing hormone than those given pentobarbitone.

The magnitude of the responses observed in male rats and in female rats anaesthetized with pentobarbitone did not change as the period of anaesthesia prior to injection of releasing hormone was lengthened from 15 min to 4 h. By contrast, in the groups of female rats anaesthetized with urethane the magnitude of the response to luteinizing hormone releasing hormone was related to the length of pretreatment anaesthesia. Thus both dioestrous and pro‐oestrous rats given releasing hormone only 15 min after the onset of urethane anaesthesia had significantly (P < 0.001 and <0.05 respectively) higher concentrations of luteinizing hormone (LH) in the plasma than rats treated with the releasing hormone after 240 min of anaesthesia.

These effects were not due to a differential action of the anaesthetics on the mechanism for clearing LH from the plasma.
MODULATION BY ACETYLCHOLINE OF THE ELECTRICALLY‐EVOKED RELEASE OF [3H]‐ACETYLCHOLINE FROM THE ILEUM OF THE GUINEA‐PIG
Authors: FOSBRAEY P. , JOHNSON E.S.
Published: July 2012

Acetylcholine (ACh) stores within neurones of the myenteric plexus of the guinea‐pig were labelled with [3H]‐choline and the influence of unlabelled ACh, atropine, or atropine and unlabelled ACh on the electrically‐evoked output of [3H]‐ACh was evaluated.

Electrical transmural stimulation (5 Hz) of the ileum led to an increase in the output of [3H]‐ACh over that released spontaneously. Superfusion with unlabelled ACh (6.8 μm) caused a marked reduction in the release of [3H]‐ACh which was reversed by atropine (3.5 μm). Atropine itself had no effect on the electrically‐evoked [3H]‐ACh.

These experiments provide further evidence for the existence in the guinea‐pig ileum of neuronal muscarinic receptors for ACh subserving an inhibitory role on transmitter release.
THE INTERACTION OF TRAZODONE WITH RAT BRAIN MUSCARINIC CHOLINOCEPTORS
Authors: HYSLOP DEBORAH K. , TAYLOR DUNCAN P.
Published: July 2012

The muscarinic receptor binding of trazodone, a new nontricyclic antidepressant, was compared with established tricyclic antidepressants. The ability to inhibit the binding of [3H]‐quinuclidinyl benzilate in vitro was used for comparing atropine‐like effects. Trazodone was found to have essentially no activity at the muscarinic acetylcholine binding site in comparison to the tricyclic antidepressants.
ADRENALINE ACTIVATION OF PREJUNCTIONAL β‐ADRENOCEPTORS IN GUINEA‐PIG ATRIA
Authors: MAJEWSKI H. , McCULLOCH M.W. , RAND M.J. , STORY D.F.
Published: July 2012

Adrenaline in a concentration of 1.0 μm depressed the stimulation‐induced efflux of tritium from the guinea‐pig atria incubated with [3H]‐noradrenaline, whereas adrenaline in a concentration of 0.5 nm significantly enhanced the stimulation‐induced efflux of tritium. This enhancement was blocked by metoprolol (0.1 μm) and thus appears to be mediated by β‐adrenoceptors.

In guinea‐pig atria incubated with unlabelled adrenaline and then with [3H]‐noradrenaline, both catecholamines were released by field stimulation. In such atria metoprolol, practolol, oxprenolol or propranolol decreased the stimulation‐induced efflux of tritium. These effects did not occur if the atria were incubated with unlabelled noradrenaline and then with [3H]‐noradrenaline, suggesting that neuronally released adrenaline activates prejunctional β‐adrenoceptors.

The effect of oxprenolol in decreasing the release of tritium from guinea‐pig atria, incubated with unlabelled adrenaline and then with [3H]‐noradrenaline was greater in the presence of phentolamine. This may reflect the α‐adrenoceptor blocking activity of oxprenolol.
POTENTIATION OF THE EFFECTS OF ADENOSINE ON ISOLATED CARDIAC AND SMOOTH MUSCLE BY DIAZEPAM
Authors: CLANACHAN A.S. , MARSHALL R.J.
Published: July 2012

Adenosine (10−7 to 3 times 10−4 m) or 2‐chloroadenosine (10−8 to 10−5 m) produced concentration‐dependent inhibition of the responses of the rat isolated vas deferens to electrical field stimulation. In electrically driven (2 Hz) guinea‐pig isolated left atria, adenosine (10−6 to 10−3 m) or 2‐chloroadenosine (10−8 to 10−7 m) produced concentration‐dependent decreases in isometric tension.

Diazepam (10−6 and 10−5 m) had no direct effect per se, but significantly potentiated the inhibitory action of adenosine on both tissues without altering the inhibitory effect of 2‐chloroadenosine.

The adenosine uptake inhibitors, hydroxynitrobenzylthioguanosine (HNBTG, 10−5 m) and dipyridamole (10−5 m) also potentiated the inhibitory actions of adenosine in rat vas deferens, but not those of 2‐chloroadenosine.

Following adenosine uptake inhibition in rat vas deferens by HNBTG (10−5 m), diazepam (10−5 m) failed to produce any significant further potentiation of the inhibitory action of adenosine.

It is concluded that the potentiation of adenosine by diazepam is possibly due to an inhibition of adenosine uptake.
THE EFFECTS OF α‐ AND β‐ADRENOCEPTOR ACTIVATION ON TENSION AND MEMBRANE PROPERTIES OF THE LONGITUDINAL SMOOTH MUSCLE OF THE CHICKEN RECTUM
Authors: KOMORI S. , OHASHI H. , TAKEWAKI T.
Published: July 2012

Isolated longitudinal muscle strips from the chicken rectum responded to isoprenaline, adrenaline and noradrenaline with a prolonged relaxation. The concentrations required to produce 50% of the maximum relaxation were 1.3 times 10−8 m for isoprenaline, 1.7 times 10−8 m for adrenaline and 10−6 m for noradrenaline. The relaxing potency of isoprenaline is about equal to that of adrenaline, but more than 50 times that of noradrenaline.

Propranolol, 3.4 times 10−6 m, blocked the isoprenaline‐induced relaxation, and in the presence of this drug the responses to adrenaline and noradrenaline were converted into small, transient relaxations. The residual relaxation was blocked by phentolamine, 2.6 times 10−6 m.

These catecholamines suppressed spontaneous spike discharge and produced membrane hyperpolarization. Propranolol, 3.4 times 10−6 m, prevented the inhibitory effects of isoprenaline, and reduced but did not completely abolish those of adrenaline and noradrenaline.

Adrenaline and noradrenaline, but not isoprenaline, reduced membrane resistance in some preparations.

In the rectal muscle of the chicken, the β‐adrenoceptor mediates a prolonged relaxation and the α‐adrenoceptor a fast and short‐lasting relaxation which is usually obscured by the β‐response and unmasked only after blockade of the β‐adrenoceptors. The α‐ and β‐mediated relaxations are each associated with the suppression of spontaneous spike activity.
CALCIUM IONOPHORE A23187 INDUCES RELEASE OF CHEMOKINETIC AND AGGREGATING FACTORS FROM POLYMORPHO‐NUCLEAR LEUCOCYTES
Authors: BRAY M.A. , FORD‐HUTCHINSON A.W. , SHIPLEY M.E. , SMITH M.J.H.
Published: July 2012

Rat and human polymorphonuclear leucocytes (PMNs) when exposed to calcium ionophore A23187 10 μm release products which cause aggregation of rat PMNs and chemokinesis of human PMNs.

Aggregating and chemokinetic activities are rapidly generated; maximal release occurs after 4 min, and can be detected in dilutions of the supernatant of up to 1:1000.

Generation of aggregating and chemokinetic activities is inhibited by nordihydroguaiaretic acid 10−4 to 10−7 m, 5,8,11,14‐eicosatetraynoic acid 10−4 and 10−5 m, BW 755C 10−4 m and benoxaprofen 10−4 m, all compounds known to inhibit lipoxygenase pathways of arachidonic acid (AA) metabolism.

Conventional non‐steroidal anti‐inflammatory agents, such as aspirin and indomethacin, inhibited little or not at all the generation of these activities.

We conclude that the aggregating and chemokinetic activities induced by A23187 represent generation of biologically active products of lipoxygenase pathways of AA metabolism.
PREJUNCTIONAL ACTIONS OF PIRIBEDIL ON THE ISOLATED KIDNEY OF THE RABBIT: COMPARISON WITH APOMORPHINE
Authors: CHEVILLARD C. , MATHIEU M.N. , RECOMMIS D.
Published: July 2012

The effects of piribedil on contractile responses and noradrenaline release evoked by sympathetic nerve stimulation have been studied in the isolated kidney of the rabbit. These effects were compared to those of apomorphine.

Electrical stimulation (2, 5 and 10 Hz) of sympathetic renal nerves produced frequency‐dependent increases in perfusion pressure and noradrenaline release. Piribedil did not affect (0.1 μg/min) or diminished (1 and 10 μg/min) the stimulation‐evoked increase in perfusion pressure, and increased noradrenaline release in a dose‐dependent manner.

Increases in renal perfusion pressure and noradrenaline release induced by electrical stimulation were decreased by apomorphine (0.1 and 1 μg/min). These inhibitory effects were more marked at low frequencies of stimulation and were prevented by haloperidol (0.2 μmol/1).

Piribedil (0.1 and 1 μg/min) and apomorphine (0.1, 1 and 10 μg/min) did not affect the increases in renal perfusion pressure elicited by exogenously administered noradrenaline, but piribedil (10 μg/min) diminished them.

In the presence of desipramine (0.5 μmol/1), piribedil (0.1, 1 and 10 μg/min) produced a dose‐dependent inhibition of the increases in renal perfusion pressure and noradrenaline release evoked by sympathetic nerve stimulation; the inhibitory effect of piribedil was more marked at low frequencies of stimulation and was prevented by haloperidol.

Piribedil increased the resting release of noradrenaline from the rabbit kidney, in contrast to apomorphine, which was without effect.

It is suggested that piribedil has a complex effect on sympathetic transmission. This drug exhibits an ‘amphetamine‐like’ action, causing noradrenaline release from its postganglionic stores. This releasing effect masks an action on prejunctional inhibitory dopamine receptors. In addition, at high doses, piribedil exhibits a marked action on postjunctional sites, since it reduces the vasoconstrictor effect of exogenous noradrenaline.
EFFECTS OF INTRACEREBROVENTRICULAR FLOCTAFENINE AND INDOMETHACIN ON BODY TEMPERATURE IN FEBRILE RABBITS
Authors: LABURN HELEN , MITCHELL D. , STEPHEN J.
Published: July 2012

We injected the potent prostaglandin synthesis inhibitors, floctafenine and indomethacin, intravenously and intracerebroventricularly in rabbits made febrile by intravenous injection of leucocyte pyrogen.

Floctafenine (75 μmol) injected intravenously failed to affect the fever, whereas indomethacin (15 μmol) markedly reduced the fever.

When injected into the cerebral ventricles, floctafenine was feebly antipyretic, and then only at a dose ten times the antipyretic dose of indomethacin.

Our results support the suggestion that floctafenine has no antipyretic action when administered peripherally. However, its lack of antipyretic effect cannot be explained solely on the grounds that it fails to cross the blood‐brain barrier.
THE POTENT DEPOLARIZING ACTION OF PALYTOXIN ISOLATED FROM Palythoa Tubercurosa ON THE ISOLATED SPINAL CORD OF THE FROG
Authors: KUDO YOSHIHISA , SHIBATA SHOJI
Published: July 2012

The effects of palytoxin (PTX) isolated from Palythoa tubercurosa were tested on the isolated intra‐arterially perfused spinal cord of the frog. The resting and evoked potentials were recorded by means of a sucrose‐gap technique.

PTX caused a marked depolarization of both ventral and dorsal roots. The minimum effective concentration was extremely low, approximately 10−11 m. During the depolarization the evoked ventral and dorsal root potentials were markedly reduced in amplitude. The ventral root reflex was first augmented and then decreased.

The depolarization caused by PTX was markedly reduced when the preparation was perfused with NaCl ‐deficient medium. However, tetrodotoxin (10−7 m) only slightly inhibited the depolarization.

In a high Ca2+ medium (3.6 mm), the time required to reach the maximum depolarization evoked by PTX was significantly prolonged. In contrast, in a low Ca2+ medium (0.9 mm), PTX caused a marked depolarization soon after application. In a Ca2+‐free, Mg2+ (9.0 mm) medium, PTX caused rhythmic oscillatory potentials in both ventral and dorsal roots.

The potency of N‐acetyl PTX was one hundredth that of the parent compound.

It is suggested that PTX may interfere with the stabilizing action of Ca2+ on the neuronal membrane, consequently facilitating Na+ permeability. The primary amine in the PTX molecule may be important for its pharmacological action.
PHAGOCYTOSIS STIMULATES THE RELEASE OF A SLOW REACTING SUBSTANCE IN CULTURED MACROPHAGES
Authors: BRETZ U. , DEWALD B. , PAYNE T. , SCHNYDER J.
Published: July 2012

A slow‐reacting substance (SRS) was released from non‐elicited mouse peritoneal macrophages during phagocytosis of zymosan particles, whereas no detectable SRS was produced by resting cells.

The macrophage SRS induced a delayed and slow contraction of the guinea‐pig ileum but not of the chick rectum.

The myotonic activity was antagonized by low concentrations of FPL 55712 (sodium 7‐[3‐(4‐acetyl‐3‐hydroxy‐2‐propylphenoxy)‐2‐hydroxypropoxy]‐4‐oxo‐8‐propyl‐4H‐1‐benzopyran‐2 carboxylate) but was not affected by mepyramine or hyoscine, and was not associated with tachyphylaxis.

SRS release was increased by indomethacin and was abolished by the lipoxygenase and cyclo‐oxygenase inhibitor, BW755C (3‐amino‐1‐[m‐(trifluoromethyl)‐phenyl]‐2‐pyrazoline).

Addition of exogenous arachidonic acid or cysteine enhanced SRS production.
AN ELECTROPHYSIOLOGICAL ANALYSIS OF THE EFFECTS OF NORADRENALINE AND α‐RECEPTOR ANTAGONISTS ON NEUROMUSCULAR TRANSMISSION IN MAMMALIAN MUSCULAR ARTERIES
Authors: HOLMAN MOLLIE E. , SURPRENANT ANNMARIE
Published: July 2012

The effects of exogenously applied noradrenaline (NA) and α‐adrenoceptor antagonists on the mechanical and intracellularly recorded responses to perivascular nerve stimulation were examined in the rabbit ear artery, rabbit saphenous artery and rat tail artery.

Excitatory junction potentials (e.j.ps) and action potentials recorded from these smooth muscles were not blocked or depressed by phentolamine, phenoxybenzamine, prazosin, or labetolol in concentrations as high as 10 μg/ml. Phentolamine (1 to 10 μg/ml) depressed neurally‐evoked contractions of the ear and saphenous, but not the tail artery, and also depressed the contractions produced by direct muscle stimulation in the ear and saphenous arteries. Prazosin and labetolol (0.1 to 10 μg/ml) had no effect on the neurally evoked contractile response in any of the arteries examined.

The amplitude of the steady‐state e.j.p. during repetitive stimulation at 0.45 to 2 Hz was increased by phentolamine or phenoxybenzamine but not by prazosin or labetolol. Phentolamine and phenoxybenzamine also increased the amplitude of the e.j.p. evoked by a single stimulus in the majority of the preparations.

Concentrations of NA ≥ 1 μg/ml depolarized the smooth muscle while concentrations ≥ 0.5 μg/ml depressed the amplitude of the e.j.ps recorded from these arteries. α‐Antagonists did not suppress either the NA‐induced membrane depolarization or depression of e.j.ps.

These observations call into question the physiological relevance of both pre‐ and postsynaptic α‐receptors in regard to adrenergic neuromuscular transmission in muscular arteries.
EFFECT OF PROLONGED β‐ADRENOCEPTOR BLOCKADE ON HEART WEIGHT AND ULTRASTRUCTURE IN YOUNG RABBITS
Authors: NAYLER WINIFRED G. , SLADE A. , WILLIAMS E.M. VAUGHAN , YEPEZ CARMEN E.
Published: July 2012

Young rabbits were treated for 30 days or 6 weeks with propranolol or oxprenolol to provide dose‐levels similar to those used clinically.

Relative to litter matched controls the treated rabbits exhibited a reduced rate of growth.

Morphometric studies showed that prolonged β‐adrenoceptor blockade had no effect on the myofibrillar volume as a proportion of cell volume.

Prolonged β‐blockade increased the proportion of the extracellular space occupied by vascular tissue.
THE EFFECTS OF PROPRANOLOL AND ACEBUTOLOL ON LEFT VENTRICULAR FUNCTION AND CORONARY HAEMODYNAMICS IN THE CONSCIOUS DOG WITH MYOCARDIAL ISCHAEMIA
Authors: HILLIS W.S. , HUTTON I. , LAWRIE T.D.V.
Published: July 2012

The cardiovascular effects of the β‐adrenoceptor blocking drugs, propranolol and acebutolol, on regional coronary blood flow and left ventricular function have been investigated in the conscious dog with developing myocardial infarction.

Propranolol (1 to 1.5 mg/kg) or acebutolol (4 to 5 mg/kg) were administered intravenously 2 to 3 h after occlusion of the left anterior descending coronary artery.

Propranolol or acebutolol administration resulted in a relative increase in flow to the ischaemic area of the myocardium, particularly to the subendocardium.

Propranolol produced a greater reduction in heart rate and myocardial contractility than acebutolol.

These results demonstrate that β‐adrenoceptor blocking drugs reduce myocardial oxygen consumption and increase coronary flow to the ischaemic area of the myocardium after coronary artery occlusion in the conscious dog.
ACUTE EFFECTS OF MORPHINE AND OPIOID PEPTIDES ON THE MOTILITY AND RESPONSES OF RAT COLON TO ELECTRICAL STIMULATION
Authors: GILLAN MAUREEN G.C. , POLLOCK DAVID
Published: July 2012

Morphine and leucine‐ and methionine‐enkephalins inhibited the contractile response of the pithed rat colon to electrical stimulation of the spinal motor outflows and inhibited motor responses of the isolated colon to field stimulation.

Morphine and the opioid peptides also had an excitatory action in the colon. In the pithed rat, opiates caused regular fluctuations in intracolonic pressure and in the isolated colon, caused regular waves of contraction. This excitatory response was produced by low concentrations of the enkephalins (2 × 10−8 m, 2 × 10−9 m), was stereospecific and was antagonized by naloxone.

Opiate‐induced contractions in the isolated colon were inhibited by catecholamines, adenine nucleotides and by phosphodiesterase inhibitors. These contractions were unaffected by ergotamine and tolazoline, or by propranolol.

The excitatory action of opiates in the isolated colon was not antagonized and usually was potentiated by atropine, (+)‐tubocurarine and hexamethonium. In the absence of opiates, these drugs also produced similar waves of contraction, which were unaffected by naloxone.

Opiate‐induced contractions occurred in colon rendered unresponsive to 5‐hydroxytryptamine (5‐HT) and these contractions were potentiated by the 5‐HT antagonist, lysergic acid diethylamide, which, when administered alone, caused similar contractions. The 5‐HT antagonist, cyproheptadine, inhibited opiate‐induced contractions but was non‐specific, since it also inhibited responses of the colon to carbachol and KCl.

Opiate‐induced contractions were unaffected by procaine and were potentiated by tetrodotoxin. Both of these drugs, when administered alone, produced waves of contractions, which were similar to those produced by opiates but were unaffected by naloxone.

Contractions produced in the isolated colon either by opiates, atropine or (+)‐tubocurarine, or any combination of these drugs, were inhibited by field stimulation applied at the peak of a wave of contraction. This inhibitory response to field stimulation occurred at low frequencies of stimulation (< 10 Hz), and persisted in colon from rats pretreated with reserpine to deplete, or 6‐hydroxydopamine to destroy, adrenergic nerve endings. It was unaffected by guanethidine but abolished by tetrodotoxin.

The implications of these results are considered and it is concluded that the excitatory action of opiates in the rat colon is probably not mediated by the release of acetylcholine or 5‐HT but instead, may be due either to a direct action on smooth muscle or to a presynaptic inhibitory action at a ganglionic site in a non‐adrenergic inhibitory mechanism, which normally suppresses myogenic activity.
A POSSIBLE NEGATIVE FEEDBACK CONTROL OF EXCITATORY TRANSMISSION VIA PROSTAGLANDINS IN CANINE SMALL INTESTINE
Authors: NAKAHATA N. , NAKANISHI H. , SUZUKI T.
Published: July 2012

Contractile responses of canine intestinal circular and longitudinal muscles to field stimulation (20 Hz, 1 ms, 30 V/cm, for 5 s) were inhibited by treatment with atropine (0.1 μg/ml), indicating that the response to field stimulation was mediated by acetylcholine (ACh).

Prostaglandins E1 (PGE1), PGE2 and PGF2α inhibited the response of circular but not longitudinal muscle to field stimulation, althouth PGF2α was less effective than PGE1 and E2.

PGE1 was much less active in inhibiting the response of circular muscle to ACh than to field stimulation, suggesting that prostaglandins might act predominantly at prejunctional sites to prevent the release of ACh.

Indomethacin (1 μg/ml) potentiated the response of circular muscle but not longitudinal muscle to field stimulation.

Release of PGE‐like compounds from circular muscle only, was increased by field stimulation at 20 Hz (total of 1000 pulses) and ACh (10 μg/ml), but not by a lower frequency (2 Hz, total of 2400 pulses) which produced only a slight contraction. This finding may indicate that prostaglandins were released predominantly from the muscle.

Prostaglandins may exert a negative feedback mechanism of excitatory transmission in circular muscle but not in longitudinal muscle of canine small intestine.
INHIBITION BY MORPHINE OF PROSTAGLANDIN E1‐STIMULATED SECRETION AND CYCLIC ADENOSINE 3′,5′‐MONOPHOSPHATE FORMATION IN THE RAT JEJUNUM in vivo
Authors: BEUBLER E. , LEMBECK F.
Published: July 2012

The effects were studied of prostaglandin E1 (PGE1), theophylline and morphine on net water flux and mucosal cyclic adenosine 3′,5′‐monophosphate (cyclic AMP) levels in the jejunum of anaesthetized rats in vivo.

Infusion of PGE1 (3.2 μg/min, i.a.) caused a reversal from net water absorption to net secretion and enhanced the mucosal cyclic AMP content by 54%.

Theophylline (5 mg/ml, intraluminal) similarly produced a reversal from net water absorption to net secretion and increased mucosal cyclic AMP content by 54%. Additional intra‐arterial infusion of PGE1 resulted in a massive increase in net water secretion and an increase in mucosal cyclic AMP content by about 200%.

Pretreatment with morphine (10 mg/kg, s.c.) reduced the effect of PGE1 on net water flux and completely inhibited its effect on the mucosal cyclic AMP content. Naloxone (10 mg/kg, s.c.) abolished both effects of morphine.

A good correlation (r = 0.99) was demonstrated between mucosal cyclic AMP levels and net water flux.

The present results demonstrate that PGE1 stimulates intestinal fluid secretion by increasing mucosal cyclic AMP levels. The antidiarrhoeal effect of morphine can be explained by its inhibition of the PGE‐mediated increase in cyclic AMP levels, which, in turn, leads to a reduction in intestinal secretion.
CONTRACTILE AND RELAXANT ACTIONS OF PROSTAGLANDINS ON GUINEA‐PIG ISOLATED TRACHEA
Authors: COLEMAN R.A. , KENNEDY I.
Published: July 2012

The effects of 12 prostaglandins on guinea‐pig isolated trachea have been examined in the presence of indomethacin. Two series of experiments were carried out, the first on preparations without tone (‘zero tone’), and the second on preparations with tone induced with acetylcholine (‘high tone’).

The compounds tested fell into two groups. The first, comprising prostaglandins F1α, F2α F2α acetal, I2 and Wy 17186, contracted both zero and high tone preparations. The second, comprising prostaglandins A1, A2, B1, B2, E1 E2 and F2β, contracted zero, but relaxed high tone preparations. Responses to the second group of compounds are probably the resultant of their contractile and relaxant actions.

The order of potency for contracting zero tone preparations was prostaglandin E (PGE) > F = I = Wy 17186 > B > A, 2‐series compounds being 5 to 18 times more potent than 1‐series compounds.

The order of potency for relaxing high tone preparations was PGE > Fβ > B > A > Wy 17186 > Fα = I = 0. There was little difference between the potency of 1‐ and 2‐series compounds.

The possible relevance of these results to the interpretation of the effects of prostaglandins on human airways is discussed.
ANTAGONISM OF OPIATE MYDRIASIS IN MICE
Authors: KORCZYN AMOS D. , ROCK MEIR
Published: July 2012

Morphine‐induced mydriasis in mice is antagonized by nalorphine, levallorphan and naloxone in a dose‐dependent manner.

The relative potency of the three agents is 10: 56: 134 respectively, thus being in accordance with other tests of narcotic antagonism. Naloxone has the shortest duration of action.

When injected into naive animals, nalorphine (but not levallorphan or naloxone) produces a slight mydriasis.

Measurement of the diameter of the pupil in mice seems to be a precise, simple and rapid test for studying narcotic antagonist as well as agonist action and has several advantages over standard methods used for this purpose.
COCAINE CUE IN PIGEONS: TIME COURSE STUDIES AND GENERALIZATION TO STRUCTURALLY RELATED COMPOUNDS (NORCOCAINE, WIN 35,428 AND 35,065‐2) AND (+)‐AMPHETAMINE
Authors: JÄRBE TORBJÖRN U.C.
Published: July 2012

Pigeons trained to discriminate between the presence or absence of effects induced by cocaine hydrochloride (5.6mg/kg) were tested for generalization with norcocaine and two phenyltropane analogues (WIN 35,428 and WIN 35,065‐2). Separate dose‐effect curves were obtained at different intervals after the injections so that possible changes both in potency and duration of action could be evaluated.

Results showed that all of these drugs fully generalized to cocaine. The order of potency was WIN 35,428 > norcocaine > WIN 35,065‐2 > cocaine when tested either at 15 or 60 min after injection. The cocaine‐like effects were strongest for all drugs when tested 15 min after injection as compared to the tests at the 60 min interval. The decay of the cocaine‐like stimulus effects occurred at about the same rate.

Apomorphine (0.3, 0.56 and 1 mg/kg), morphine (3 and 5.6mg/kg), Δ9‐tetrahydrocannabinôl (0.3 and 0.56 mg/kg), and lysergic acid diethylamide (LSD‐25, 0.056 and 0.1 mg/kg) did not induce more than 30% cocaine appropriate responses. (+)‐Amphetamine produced 73% and 85% cocaine appropriate responses depending on the injection‐test interval used, 15 and 30 min respectively.

The amphetamine homologue, para‐hydroxyamphetamine (3.8 mg/kg) did not generalize to cocaine. Tests with 30 mg/kg of procaine produced 40% cocaine appropriate responses. Cocaine is effective also when administered by gavage into the opening of the proventriculus.

The use of the drug discrimination technique for studying structure activity relationships of drugs is discussed.
PHARMACOLOGICAL CHARACTERIZATION OF OPIATE PHYSICAL DEPENDENCE IN THE ISOLATED ILEUM OF THE GUINEA‐PIG
Authors: LUJÀN MIGUEL , RODRIGUEZ RODOLFO
Published: July 2012

Physical dependence was produced in ilea from naive guinea‐pigs by exposure of the tissues to different opiates for logarithmically‐spaced periods of time (20–320 min). The responsiveness of the tissue to naloxone, as indicated by a strong contracture of the ileum, was enhanced in contrast to that found in intestines not exposed to opiates.

The dose‐response curves to naloxone obtained in tissues individually exposed to different opiates showed that their relative potency in increasing sensitivity to naloxone was as follows: levorphan > morphine > Met‐enkephalin > nalorphine > pentazocine.

The naloxone‐induced response was dose‐dependent and was directly related to the opiate concentration and length of exposure.

Dextrorphan, the inactive isomer of levorphan, did not increase the responsiveness of the tissues to the narcotic antagonist, indicating that the phenomenon is stereospecific.

The naloxone‐induced contraction in ilea exposed for 320 min to morphine (1 × 10−6 m) was not prevented or suppressed by the administration of a large dose of morphine (1 × 10 −5 m) before or immediately after the naloxone challenge.

The evidence presented here shows that a phenomenon resembling in vivo opiate physical dependence can be acutely produced in vitro with pharmacological characteristics similar to other naloxone‐induced abstinence effects.