bluuebunny/crossref_metadata_2025 huggingface dataset:
A STUDY OF THE INTERACTIONS BETWEEN GLUTAMATE AND ASPARTATE AT THE LOBSTER NEUROMUSCULAR JUNCTION
Authors: NISTRI A. , CONSTANI A.
Published: July 2012

The depolarizations produced by bath‐applied or iontophoretically applied glutamate and aspartate were recorded from lobster muscle fibres by means of intracellular microelectrodes.

Bath‐applied glutamate or aspartate evoked reversible, membrane depolarizations; however, responses to repeated applications of aspartate decreased progressively in amplitude until a plateau level was attained. Repeated applications of glutamate, kainate, domoate or quisqualate did not produce a similar effect.

After a dose of glutamate, responses to bath‐applied aspartate were enhanced. Responses to other depolarizing agonists were little affected by previous administration of glutamate. Aspartate dose‐depolarization curves were therefore constructed after initial aspartate responses had stabilized. The log‐log transforms of the aspartate and glutamate curves had limiting slopes of 0.8 and 2.1 respectively.

Iontophoretic application of aspartate to single glutamate‐sensitive sites produced small depolarizations with slow time course, compared with the glutamate potentials. When aspartate and glutamate were pulsed simultaneously from a twin‐barrelled pipette, the resultant glutamate potential was enhanced. It is suggested that this potentiation was due to summation of agonist concentrations in the receptor region interacting with a second‐order dose‐response relationship.

Bath‐applied aspartate increased the amplitude and prolonged the half‐decay time of the glutamate potential. This effect was particularly noticeable when the glutamate potential was of slow time course.

It is proposed that bath‐applied aspartate has an agonist effect whose magnitude is possibly exaggerated by concomitant release of glutamate and/or inhibition by glutamate of aspartate uptake. This agonist action of aspartate is thought to be exerted mainly on extrajunctional areas of the glutamate‐sensitive sites.
THE ACUTE EFFECTS OF NICOTINE, TOBACCO SMOKE AND CARBON MONOXIDE ON MYOCARDIAL OXYGEN TENSION IN THE ANAESTHETIZED CAT
Authors: RINK RICHARD D.
Published: July 2012

The acute effects of nicotine, tobacco smoke, and carbon monoxide on myocardial oxygen tension (MPo2) were estimated amperometrically in 33 anaesthetized open‐chest cats with a glass‐insulated 25 gtm platinum cathode within a 22‐gauge needle implanted in the left ventricular wall.

MPo2 was 1.6–60 mmHg (mean 23.5 mmHg) when arterial P02 was >80 mmHg. Sequential intravenous infusions of nicotine (2–3 gg/kg every 45 s) or intracheal puffs (3–5 ml) of tobacco smoke commonly produced transitory increases (25–35 mmHg) of arterial pressure and 4–6 mmHg increments of MPo2. Intratracheal puffs (5 ml) of 5% carbon monoxide sufficient to increase carboxyhaemoglobin from 0.8 to 1.5% to 4–7% had no effect on arterial Po2 or blood pressure but typically decreased MPo2 by approximately 1–4 mmHg. Augmentation of MPo2 often succeeded carbon monoxide administration.

Arterial hypoxia (arterial Po2 < 60 mmHg) reduced mean MPo2 to 14.4 mmHg but anoxic levels were not observed. Pressor responses to nicotine and tobacco smoke were accompanied by small increases (usually 1–3 mmHg) of MPo2. Puffs of 5% carbon monoxide had less effect than during normoxia. Locations of low MPo2 (<10 mmHg) were unaffected as carboxyhaemoglobin was raised to 7–11% during hypoxaemia.

It is concluded that nicotine and tobacco smoke cause augmentation of myocardial oxygen supply, even during moderate hypoxaemia. By contrast, smoking dosages of carbon monoxide have the potential of producing a small reduction of MPo2 during normoxia, but the effect is negligible during moderate hypoxaemia.
ACTION OF GUANETHIDINE ON RABBIT ATRIAL MEMBRANES
Authors: MISU Y. , NISHIO H.
Published: July 2012

Intracellular potentials were recorded in driven left atria from reserpine‐treated rabbits. Guanethidine 2 × 10−5m slightly increased Vmax and shortened the total duration (TD) of the action potential (AP) without causing hyperpolarization. For the first 30 min after 4 × 10−4m, Vmax increased without hyperpolarization and AP height increased slightly. Thereafter, Vmax and height decreased with a slight and gradual depolarization. This depolarization was irreversible. TD was increased after 15 minutes. Guanethidine 2 × 10−3 M initially decreased Vmax and height before causing depolarization.

Pretreatment with tetrodotoxin (TTX) 1.6 × 10−7m prevented or reversed the initial increases in Vmax, height and TD induced by guanethidine (4 × 10 −4m).

TTX 3.1 to 6.2 × 10−6m, added 15 or 30 min after guanethidine 4 × 10−4m, delayed or prevented depolarization by guanethidine.

Ouabain 10−5m incubated for 20 and 90 min greatly inhibited Na+, K+‐adenosine triphosphatase and K+‐phosphatase activities; guanethidine was without effect.

Guanethidine probably increases resting sodium permeability after the promotion of increases in sodium permeability during the AP. High doses of the drug decrease sodium permeability during the AP.
THE EFFECT OF DIPHENIDOL ON OUABAIN CARDIOTOXICITY IN THE CAT
Authors: BOUNOUS H. , CAGIN N. , LEVITT B. , SOMBERG J.
Published: July 2012

The capacity of diphenidol to influence ouabain‐induced cardiotoxicity was studied in anaesthetized cats with and without spinal cord transection.

Diphenidol pretreatment increased the lethal dose of ouabain in both intact cats and cats in which the spinal cords had been transected. Diphenidol pretreatment increased the myocardial content of ouabain associated with death in the intact animals, but failed to influence the lethal ventricular concentration in cats with transected spinal cords.

The failure of diphenidol to influence tissue thresholds for toxicity in the spinal cat and the equivalence of tissue ouabain requirements for death in spinal cats and diphenidol‐treated intact animals, suggest a neural mechanism for the protective effect in intact animals.

Ouabain administration prolonged atrio‐ventricular conduction time in all animals and diphenidol attenuated this effect. Thus, the influence of both drugs on atrioventricular conduction may not be entirely mediated by central neurones.
STIMULATION OF PRESYNAPTIC β‐ADRENOCEPTORS ENHANCES [3H]‐N0RADRENALINE RELEASE DURING NERVE STIMULATION IN THE PERFUSED CAT SPLEEN
Authors: CELUCH STELLA M. , DUBOCOVICH MARGARITA L. , LANGER S.Z.
Published: July 2012

The effects of isoprenaline, propranolol and phosphodiesterase inhibitors on 3H‐transmitter overflow elicited by low frequency nerve stimulation were determined in the isolated perfused spleen of the cat.

(‐)‐Isoprenaline (0.14, 1.4, and 14 nm) produced a concentration‐dependent increase in [3H]‐transmitter overflow evoked by nerve stimulation at 1 Hz and was more effective at 1 Hz than at 2 hertz.

A concentration of propranolol (0.1 μm), devoid of neurone blocking activity, blocked this effect of (—)‐isoprenaline. These results are compatible with the presence of β‐adrenoceptors in the noradrenergic nerve endings of the cat spleen.

(‐l‐)‐Isoprenaline (140 nm) failed to increase the release of radioactivity induced by nerve stimulation, indicating that the β‐adrenoceptor mediating the facilitation of transmitter release was stereo‐specific.

The increase in 3H‐transmitter overflow induced by nerve stimulation during exposure to the phosphodiesterase inhibitor, papaverine (27 μm) was more pronounced than that obtained in the presence of 3‐isobutyl‐l‐methyl xanthine (IBMX) 0.5 mm. The facilitation in transmitter release induced by papaverine was not correlated with the granular effect produced by this drug.

In the presence of papaverine, the concentration‐effect curve for (—)‐isoprenaline on transmitter release was shifted to the left and its maximum was increased. In addition, propranolol significantly reduced the enhancement in noradrenaline release obtained by exposure to papaverine under conditions in which the granular effect produced by the phosphodiesterase inhibitor was even greater than in the absence of the P‐blocker.

It is concluded that activation of presynaptic p‐adrenoceptors in the perfused cat spleen leads to an enhancement in transmitter release which appears to be linked to an increase in cyclic adenosine 3′, 5′‐monophosphate levels in noradrenergic nerve endings.
THE EFFECTS OF d‐PENICILLAMINE AND LEVAMISOLE ON LEUCOCYTE CHEMOTAXIS IN THE RAT
Authors: CUNNINGHAM F.M. , FORD‐HUTCHINSON A.W. , OLIVER A.M. , SMITH M.J.H. , WALKER J.R.
Published: July 2012

The administration of D‐penicillamine (25 mg/kg) or levamisole (5 mg/kg) had no effect on leucocyte emigration into the exudates formed in inert sponges implanted in normal rats.

In rats, previously sensitized to Bordetella pertussis and implanted with sponges containing pertussis vaccine, an increased leucocyte migration into the exudates occurred; this was significantly enhanced by the administration of the drugs.

Neither drug in vitro affected the chemotaxis of rat polymorphonuclear leucocytes although random migration was significantly increased by levamisole (2 μg to 1 mg/ml). Neither drug affected the chemotaxis of rat mononuclear cells although levamisole (25 μg/ml) significantly increased that of human monocytes.

It is concluded that both drugs produce similar effects in an animal model of delayed hypersensitivity and that their clinical antirheumatic actions may have common elements.
THE EFFECTS OF AMINO ACIDS AND ANTAGONISTS ON THE ISOLATED HEMISECTED SPINAL CORD OF THE IMMATURE RAT
Authors: EVANS R.H.
Published: July 2012

Records of ventral and dorsal root polarity of the isolated hemisected spinal cord of the 3‐9 day old rat showed that respective dose‐dependent depolarizations of motoneurones (VR responses) and primary afferent terminals (DR responses) were produced by both acidic and neutral amino acids in the presence of procaine (1 mM) or tetrodotoxin (0.1 μM).

Of the four neutral amino acids, γ‐aminobutyrate (GABA), glycine, taurine, and β‐alanine, GABA was the most effective in producing DR responses and glycine the most effective in producing VR responses. Only taurine depressed the electrical activity recorded from ventral roots.

The DR responses produced by GABA, β‐alanine and taurine, were all antagonized by bicuculline (5 μM) and picrotoxin (5 μM). Bicuculline was more selective than picrotoxin in antagonizing VR responses produced by GABA.

Strychnine (1 μM) antagonized VR responses produced by glycine β‐alanine and taurine without affecting responses produced by GABA. DR responses to the neutral amino acids were unaffected by strychnine.
ENHANCEMENT BY OXOTREMORINE OF ACETYLCHOLINE RELEASE FROM THE RAT PHRENIC NERVE
Authors: DAS M. , GANGULY D.K. , VEDASIROMONI J.R.
Published: July 2012

Oxotremorine (10.5 μM) produced a paralytic effect on twitch responses of rat diaphragm in vitro to direct and indirect stimulation.

The paralytic effect of oxotremorine was absent when the diaphragm was stimulated directly in the presence of hemicholinium‐3 (0.42 mM), at a time when twitch responses to indirect stimulation ceased completely.

Oxotremorine, at two different pharmacologically active doses, strikingly increased the resting as well as electrically evoked release of acetylcholine into the bathing fluid from the phrenic nerve‐diaphragm preparation.

This presynaptic effect of oxotremorine may explain its pharmacological effects at the cholinergic synapses studied so far.
RELEASE OF NORADRENALINE FROM CAT SPLEEN SLICES BY POTASSIUM
Authors: GARCÍA A.G. , KIRPEKAR S.M. , PASCUAL R.
Published: July 2012

When cat spleen slices were exposed to a potassium‐enriched (140mM) Krebs solution, 367 ± 31 ng g−1 5 min−1 of noradrenaline (NA) was released into the bathing medium.

Phenylephrine and clonidine (10−7 to 10−3M) did not significantly modify the potassium‐evoked NA release; acetylcholine decreased it in a dose‐dependent manner.

Phenoxybenzamine increased NA release by 50% but phentolamine did not alter it; high concentrations of this drug greatly decreased NA release. Cocaine increased the NA release by about 30%.

It is suggested that the failure of sympathomimetic amines to depress, and of α‐adrenoceptor blocking agents to enhance the release of NA by high potassium concentrations may be related to prolonged depolarization of the nerve terminals, which may desensitize presynaptic α‐receptors. The fact that the same drugs are able to modify NA release during electrical nerve stimulation may be ascribed to the much shorter periods of depolarization occurring under these conditions.
SODIUM‐DEPENDENT CARDIAC GLYCOSIDE BINDING: EXPERIMENTAL EVIDENCE AND HYPOTHESIS
Authors: FRICKE U. , KLAUS W.
Published: July 2012

The influence of increasing Na+ concentrations on the binding of digitoxin, digoxin and ouabain was examined in a Na+‐K+‐ATPase preparation of guinea‐pig hearts

Two distinct processes seem to be involved in this interaction: one binding process was activated at low Na+ concentrations. The maximum binding capacities were different and the K0.5 values were nearly identical for the cardiac glycosides studied.

In contrast, the second binding process was activated at appreciably higher Na+ concentrations, the maximum binding capacities were almost identical and the K0.5 values were different for the cardiac glycosides studied.

On the basis of these results attempts are made to explain the well known differences in the myocardial accumulation of cardiac glycosides.
EFFECTS OF END‐TIDAL CONCENTRATIONS OF CYCLOPROPANE, HALOTHANE AND DIETHYL ETHER ON PERIPHERAL AUTONOMIC NEUROEFFECTOR SYSTEMS IN THE RAT
Authors: CLANACHAN A.S. , MUIR T.C.
Published: July 2012

The effects of the inhalation anaesthetics, cyclopropane, halothane and diethyl ether were examined on peripheral neuroeffector systems in the pithed and in the conscious rat.

In the absence of a suitable means of accurately quantifying doses of inhalation anaesthetics given to small animals, an apparatus was constructed whereby end‐tidal gas samples were collected semi‐automatically from the mechanically ventilated rat.

Cyclopropane (15.3 and 29.3% end‐tidal), halothane (0.20, 0.52 and 0.83% end‐tidal) and diethyl ether (2% and 4% end‐tidal) lowered the arterial pressure of the pithed rat. Heart rate was increased by diethyl ether 4%, decreased by halothane and unchanged by cyclopropane.

While each anaesthetic depressed the pressor responses to sympathetic nerve stimulation, cyclopropane increased and halothane and diethyl ether depressed the pressor responses to exogenous noradrenaline.

Each anaesthetic reduced the motor responses of the smooth muscle of the colon to parasympathetic stimulation.

The significance of the effects on peripheral neuroeffector systems is discussed in relation to the overall circulatory changes produced by these anaesthetics in the whole animal.
REPEATED EXPOSURE OF RATS TO THE CONVULSANT AGENT FLUROTHYL ENHANCES 5‐HYDROXYTRYPTAMINE‐ AND DOPAMINE‐MEDIATED BEHAVIOURAL RESPONSES
Authors: GREEN A.R.
Published: July 2012

Rats were convulsed once daily for 7 days by exposure to the inhalant convulsant agent, flurothyl (Indoklon, bis (2,2,2‐trifluouroethyl)ether). Twenty four hours after the final convulsion the rats were injected with tranylcypromine (20 mg/kg) followed 30 min later by L‐DOPA (50 mg/kg), a procedure which increases brain dopamine concentrations. The flurothyl‐treated rats showed a greater locomotor activity response than rats that had not been convulsed.

This enhanced response appears to be due to increased postsynaptic dopamine receptor sensitivity since flurothyl‐treated rats also showed enhanced locomotor responses to methamphetamine (2 mg/kg) and apomorphine (2 mg/kg).

Enhanced 5‐hydroxytryptamine‐induced activity responses following administration of tranylcypromine (20 mg/kg) and L‐tryptophan (50 mg/kg) were also seen 24 h after the last of 10 daily flurothyl‐induced convulsions.

The increased 5‐hydroxytryptamine response also appears to be due to increased postsynaptic sensitivity since the flurothyl‐treated rats showed increased hyperactivity following administration of tranylcypromine (20 mg/kg) and the suggested 5‐hydroxytryptamine agonist, 5‐methoxy N,N‐dimethyltryptamine (2 mg/kg).

No change in the brain concentration of 5‐hydroxytryptamine, 5‐hydroxyindoleacetic acid, tryptophan, dopamine or noradrenaline was observed 24 h after the last of 10 daily flurothyl‐induced convulsions, compared to untreated rats. The rate of 5‐hydroxytryptamine accumulation after tranylcypromine/L‐tryptophan treatment and of dopamine and noradrenaline accumulation after tranylcypromine/L‐DOPA treatment was similar in both groups.

Repeated flurothyl convulsion has the same effects on these behavioural tests as repeated electro‐convulsive shock. Since both treatments have been used successfully to treat depression, it is suggested that the mechanism of action of electroconvulsive therapy may be by increasing postsynaptic responses to the monoamine neurotransmitters.
H1‐ AND H2‐RECEPTORS IN THE SMOOTH MUSCLE OF THE RUMINANT STOMACH
Authors: OHGA A. , TANEIKE T.
Published: July 2012

The effects of histamine on the longitudinal and circular smooth muscle from the rumen and reticulum of the bovine stomach have been analyzed by the use of H1‐ and H2‐receptor antagonists.

Histamine caused three different types of response of the smooth muscle preparations: a contraction, contraction followed by relaxation, and a relaxation. These responses were resistant to the effect of tetrodotoxin, atropine, combined treatment with α‐ and β‐ adrenoceptor blocking agents, hexamethonium and also to guanethidine.

Mepyramine antagonized the contractile responses and metiamide antagonized the relaxation responses in a highly selective and competitive manner.

It is concluded that histamine‐induced excitatory and inhibitory responses of the smooth muscles from the bovine forestomach are mediated by histamine H1‐ and H2‐receptors, respectively.
IS ACETYLCHOLINE INVOLVED IN A DOPAMINE RECEPTOR MEDIATED HYPOTHERMIA IN MICE AND RATS?
Authors: COX B. , LEE T. F.
Published: July 2012

Apomorphine and oxotremorine caused a dose‐related fall in core temperature in the mouse and a fall in core temperature preceded by an increase in tail‐skin temperature in the rat.

In both species the slope of the dose‐response curve was greater for oxotremorine (8.2 ± 0.6 mice, 0.9 ± 0.1 rats) than it was for apomorphine (1.7 ± 0.3 mice, 0.5 ± 0.07 rats).

The mouse was more sensitive than the rat to the effects of both agonists.

Atropine (0.625 to 5 mg/kg) and hyoscine (0.5 and 1 mg/kg) caused a dose‐related rightward shift of the dose‐response curve to oxotremorine in mice, but pimozide (0.25 to 1 mg/kg) was ineffective. Similar results were obtained in the rat.

Pimozide (0.125 to 1 mg/kg) caused a dose‐related rightward shift of the dose‐response curve to apomorphine in mice, but atropine (1.25 to 1 mg/kg) and hyoscine (0.5 and 1 mg/kg) were ineffective. Similar results were obtained in the rat.

Intrahypothalamic injection of apomorphine (10 μg) and oxotremorine (1.25 μg) caused a fall in core temperature in rats. Pimozide (0.5 mg/kg i.p.) caused reversal of the effect of apomorphine but did not significantly change the response to oxotremorine. Atropine (2.5 mg/kg i.p.) blocked the effect of oxotremorine, but not that of apomorphine.

These results suggest that there are both central dopamine and central muscarinic acetylcholine receptors which mediate a fall in core temperature in rodents, but do not support the hypothesis that any connection exists between these two receptor populations.
PHARMACOLOGICAL EVIDENCE FOR THE INVOLVEMENT OF Na+ CHANNELS IN THE RELEASE OF CATECHOLAMINES FROM PERFUSED ADRENAL GLANDS
Authors: ITO S. , NAKAZATO Y. , OHGA A.
Published: July 2012

Veratridine (0.1 mM) was found to be effective in producing an increase in the catecholamine output from perfused guinea‐pig adrenal glands in the presence of high concentrations of hexamethonium (1.83 mM) and atropine (28.8 μM). The response to veratridine was abolished by removal of either Na+ or Ca2+ from perfusion media and by the addition of tetrodotoxin (0.1 μM). It is suggested that the response to veratridine may be due to an increase in the tetrodotoxin‐sensitive Na+ permeability of chromaffin cell membranes.
EFFECTS OF A NEW SELECTIVE β1‐ADRENOCEPTOR AGONIST ON AMYLASE SECRETION FROM THE RAT PAROTID GLAND
Authors: CARLSÖÖ BENGT , DANIELSSON AKE , HENRIKSSON ROGER
Published: July 2012

The effects of a new selective β1‐adrenoceptor agonist, (−)‐1‐(4‐hydroxyphenoxy)‐3‐isopropyl‐amino‐pro‐panol‐2‐hydrochloride (H 133/22), on amylase secretion from the rat parotid gland were investigated in an in vitro system. The results were compared to the secretory responses obtained with noradrenaline, adrenaline, methoxyamine and terbutaline. H 133/22 was found to be a potent enzyme secretagogue and appeared even more effective than noradrenaline and adrenaline, particularly at low concentrations. The β2‐adrenoceptor agonist, terbutaline, also stimulated amylase discharge from the parotid gland but was much less potent than H 133/22. Methoxyamine had no effect on enzyme secretion. We suggest that the adrenergic stimulation of amylase secretion from the rat parotid gland is mainly mediated by β1‐receptors.
CHARACTERIZATION OF ADRENOCEPTORS MEDIATING POSITIVE INOTROPIC RESPONSES IN THE VENTRICULAR MYOCARDIUM OF THE DOG
Authors: ENDOH M. , SHIMIZU T. , YANAGISAWA T.
Published: July 2012

The pharmacological characteristics of adrenoceptors mediating the positive inotropic action in the dog heart were assessed by the use of blood‐perfused papillary muscles and isolated strips of ventricular myocardium.

On the blood‐perfused papillary muscle driven at 2 Hz and in sinus node preparations, phenylephrine induced positive inotropic and chronotropic responses in the same dose range and was much less potent than isoprenaline. The dose‐response curve for the chronotropic action of phenylephrine was parallel to that of isoprenaline, whilst the dose‐response curve for the inotropic action of phenylephrine was less steep than that of isoprenaline.

The infusion of pindolol, a β‐adrenoceptor blocking agent, at a rate of 1 μg/min, shifted the isoprenaline dose‐response curves to the right, and to the same extent, in both papillary muscle and sinus node preparations. In contrast to isoprenaline, the antagonism of phenylephrine by pindolol was noncompetitive. Phentolamine did not affect the positive inotropic and chronotropic actions of phenylephrine.

On isolated ventricular strips α‐adrenoceptor blockade by 10−6m phentolamine did not affect dose‐response curves to phenylephrine or dopamine. Pindolol shifted the dopamine dose‐response curves to the right in a competitive manner and those of phenylephrine in a noncompetitive manner.

On ventricular strips from reserpine‐pretreated dogs phenylephrine and tyramine dose‐response curves were shifted markedly to the right and downwards. Desipramine (10−5m) which enhanced the action of noradrenaline considerably reduced the myocardial responses of phenylephrine.

Papaverine (10−5m) decreased the threshold concentration of phenylephrine required to stimulate the myocardium and shifted phenylephrine dose‐response curves to the left.

Raising the temperature from 32°C to 37°C shifted phenylephrine dose‐response curves to the right; when the temperature was raised from 37°C to 42°C the affinity of the drug was not changed.

Other α‐adrenoceptor stimulants, methoxamine and clonidine, decreased the active tension of ventricular strips. The responses to noradrenaline and adrenaline (in the presence of pindolol; 3 × 10−8m) were not affected by phentolamine (10−6m).

The results indicate that adrenoceptors mediating positive inotropic responses in the dog ventricle are of the /J‐type and that post‐synaptic α‐adrenoceptors are not involved. Phenylephrine acts mainly by releasing noradrenaline from adrenergic nerve endings and partly by a weak direct action on β‐adrenoceptors.
EFFECTS OF NARCOTIC ANALGESICS ON THE UPTAKE AND RELEASE OF 5‐HYDROXYTRYPTAMINE IN RAT SYNAPTOSOMAL PREPARATIONS
Authors: MENNINI TIZIANA , PATACCINI R. , SAMANIN R.
Published: July 2012

The effects of various narcotic analgesics on the uptake and release of labelled 5‐hydroxytrypta‐mine (5‐HT) in brain and spinal cord synaptosomes were investigated.

Methadone was most active in inhibiting 5‐HT uptake (IC50 2.5 × 10−7m). Levorphanol also inhibited 5‐HT uptake to a large extent (IC50 8.8 × 10−7m) while dextrorphan, pethidine and pentazocine showed much less activity. Etorphine and morphine had virtually no such activity, with IC50s higher than 10−4 and 10−3m respectively.

The same order of potency as ′5‐HT releasers' was found when radioactivity was measured in [3H]‐5‐HT preloaded synaptosomal pellets incubated for 20min with the various narcotics. Methadone, like chlorimipramine, showed a significant effect at a concentration of 10−7m while morphine, at a concentration of 10−4m, had no effect.

When 5‐HT release was studied by a perfusion technique, which largely prevents reuptake of the released amine, only fenfluramine, an anorectic agent proposed as a 5‐HT releaser, significantly increased spontaneous 5‐HT release. These data suggest that the apparent 5‐HT release induced by various narcotics in traditional incubation techniques may largely depend on their ability to interfere with neurotransmitter reuptake mechanisms.

The effects of the various narcotics on 5‐HT uptake have no relationship to their relative potency as analgesics in the rat. In the light of their poor effectiveness as 5‐HT releasers, it can be concluded that mechanisms other than 5‐HT uptake inhibition and release are probably involved in the analgesic effects of these compounds in intact animals.
CORTICOSTEROID INVOLVEMENT IN THE CHANGES IN NORADRENERGIC RESPONSIVENESS OF TISSUES FROM RATS MADE HYPERTENSIVE BY SHORT‐TERM ISOLATION
Authors: BENNETT T. , GARDINER SHEILA M.
Published: July 2012

The responses to noradrenaline and to noradrenergic nerve stimulation of spontaneously beating right atria, electrically driven left atria and vasa deferentia taken from rats made hypertensive by short‐term isolation have been compared with the responses of tissues from normotensive, group‐housed animals.

Adrenocortical activity of isolated animals was assessed by plasma corticosterone determinations and measurement of adrenal weights.

The hearts of the isolated animals were weighed and the myocardial contents of water, sodium, potassium and calcium were measured.

Spontaneously beating right atria from isolated animals showed a lower resting rate, no difference in the response to nerve stimulation but a greater sensitivity to noradrenaline compared to atria from group‐housed animals.

Vasa deferentia from isolated animals showed a decreased maximal response to noradrenaline, but no change in noradrenaline sensitivity or in the response to transmural stimulation.

There were indications of hyperactivity of the adrenals throughout a 5 week period of isolation, manifest as elevated plasma corticosteroid levels and increased adrenal weights.

Myocardial levels of sodium and calcium were elevated at the same time as the tissue level of potassium was reduced, but heart weights did not significantly change.

It is possible that adrenal steroid action caused the changes in tissue ionic balance. These ionic disturbances may have been responsible for some of the changes in tissue sensitivity found in the isolated hypertensive animals.
THE EFFECTS OF RELEASE AND DEPLETION OF ENDOGENOUS NORADRENALINE ON THE TRANSMISSION OF IMPULSES IN THE MOUSE VAS DEFERENS
Authors: MARSHALL I. , NASMYTH P.A. , SHEPPERSON N.B.
Published: July 2012

The effects of endogenous noradrenaline released by tyramine and the influence of depletion of the tissue noradrenaline with reserpine and/or α‐methyl‐p‐tyrosine on the twitch responses of the field‐stimulated mouse vas deferens have been studied.

Tyramine (10–40 μm) inhibited the twitch responses to field stimulation and failed to produce a contraction. The inhibition decreased as the rate of stimulation increased.

The inhibition produced by tyramine was antagonized by cocaine (10 μm) and by yohimbine (10 nm), which indicated that it was produced by released noradrenaline acting on presynaptic α‐adrenoceptors.

Depletion of the tissue noradrenaline by 39% by blockade of the synthesis of noradrenaline with α‐methyl‐p‐tyrosine, was without effect on the twitch response but it reduced the inhibitory effect of tyramine.

Depletion of the tissue noradrenaline by 96.5% with reserpine alone and by 99.4%, with a combination of reserpine and α‐methyl‐p‐tyrosine, reduced the twitch responses by approximately 66% and virtually abolished the inhibition produced by tyramine. It also increased the rate of decline of the responses when the tissue was continuously stimulated. The remaining twitch was not antagonized by phenoxybenzamine (15 μm).

Residual twitches were bigger in tissues depleted by 99.4% than in those depleted by only 96.5%. This difference was eliminated in the presence of yohimbine (128 nm).

It is concluded that inhibition of the twitch responses by tyramine is produced by stimulation of presynaptic α‐adrenoceptors and that the twitch response is associated with stimulation of the sympathetic neurone, but that it is not mediated by postsynaptic α‐adrenoceptors.
THE ROLE OF β1 ‐ AND β2‐ADRENOCEPTORS IN THE INHIBITION OF GASTRIC ACID SECRETION IN THE DOG
Authors: DALY M.J. , LONG JANET M. , STABLES R.
Published: July 2012

Characterization of the β‐adrenoceptors mediating inhibition of gastric acid secretion in the conscious Heidenhain pouch dog has been investigated by determination of the effects of propranolol, (+)‐propranolol, practolol and H 35/25 on salbutamol and isoprenaline‐induced inhibition of gastric acid secretion.

The gastric antisecretory effect of salbutamol was significantly blocked by propranolol and H35/25 but not by practolol or (+)‐propranolol. The effect of isoprenaline was significantly blocked by propranolol and practolol but not by H35/25 or (+)‐propranolol.

It is concluded that both β1‐ and β2‐adrenoceptors can mediate inhibition of pentagastrin‐induced gastric secretion in conscious dogs with a Heidenhain pouch. Salbutamol exerts its antisecretory effect through β2‐adrenoceptors, whereas isoprenaline mediates its effects primarily through β1‐adrenoceptors.

The results are discussed with regard to the sub‐classification of β‐adrenoceptors and to the possible role of adrenoceptors in the physiological control of gastric secretion.

In this study it is concluded that the tachycardia induced by isoprenaline or salbutamol is mediated primarily through reflexes activated by β2‐adrenoceptor mediated vasodilatation.
RAT VAS DEFERENS: A SPECIFIC BIOASSAY FOR ENDOGENOUS OPIOID PEPTIDES
Authors: LEMAIRE SIMON , MAGNAN JACQUES , REGOLI DOMENICO
Published: July 2012

The electrically‐evoked contractions of the rat vas deferens were selectively inhibited by β‐endorphin, the preparation being much less sensitive to enkephalins and narcotic analgesic drugs. However, introduction of D‐Ala in position 2 of [Leu]‐enkephalin enhanced the activity of the opioid peptide to the order of that of β‐endorphin. It is concluded that the rat vas deferens preparation constitutes a specific bioassay for endogenous opioid peptides and related compounds.
DIGOXIN TOXICITY COMPARED WITH MYOCARDIAL DIGOXIN AND POTASSIUM CONCENTRATION
Authors: STEINESS EVA
Published: July 2012

Twenty‐nine dogs were given digoxin (0.25 mg) by mouth twice daily for eight days. Some of them (group 1) also received diuretics and others (group 2) a mineralocorticoid. The dogs were then given an intravenous bolus injection of digoxin and plasma and cardiac muscle were analysed for digoxin and potassium.

In the digitalized dogs, myocardial potassium concentration decreased following the intravenous injection of either 0.05 or 0.15 mg/kg digoxin; in contrast, in those dogs given diuretics or mineralocorticoid the potassium concentration increased.

Ventricular arrhythmias occurred after digoxin injection (0.05 mg/kg) in the hypokalemic dogs, in those given a mineralocortocoid and in those dogs which received a toxic digoxin dose (0.15 mg/kg). No arrhythmias where seen in the control (digitalized) group.

Myocardial digoxin concentrations were similar in the control digitalized group and in the mineralocorticoid‐treated dogs after the intravenous administration of the lower digoxin dose (0.05 mg/kg). The myocardial digoxin concentration was significantly higher in the hypokalemic group and in the group receiving the higher digoxin dose (0.15 mg/kg).

There was no obvious relationship between the occurrence of arrhythmias and the myocardial concentration of digoxin or potassium.
MORPHINE ANALGESIA AND CEREBRAL OPIATE RECEPTORS: A DEVELOPMENTAL STUDY
Authors: AUGUY‐VALETTE A. , CROS J. , GOUARDERES Ch. , GOUT R. , PONTONNIER G.
Published: July 2012

Development of the analgesic response to morphine and ontogenesis of central opiate receptors were analyzed in rats 5 to 120 days old.

The analgesic effect of morphine increased until day 15, after which it decreased to reach a plateau at about day 30. With phenoperidine, on the other hand, the analgesic effect increased until day 15, remained constant between day 15 and day 30 after which it decreased slowly.

The ratio of the amounts of morphine in blood over those in brain increased about 3 fold between day 15 and day 30.

Opiate receptors were detected in the brain of newborn rats: stereospecific binding of [3H]‐naloxone at 10 and 50 nM indicated the presence of low and high affinity binding sites.

The number of [3H]‐naloxone binding sites increased rapidly during the second and third week after birth. Their affinity for several opiates remained constant throughout development.

These results indicate that the analgesic activity of opiates varies with age: until day 15, the analgesic effect of opiates increases in parallel with the number of opiate brain receptors. Then, the formation of the blood brain barrier introduces an additional step in the regulation of opiate activity.
ANTAGONISM OF THE INHIBITORY EFFECTS OF ADENOSINE 5′‐TRIPHOSPHATE ON THE ISOLATED TAENIA OF THE GUINEA‐PIG CAECUM: STRUCTURE‐ACTIVITY RELATIONSHIPS WITHIN A SERIES OF ISATOGEN DERIVATIVES
Authors: FOSTER H.E. , HOOPER M. , SPEDDING M. , SWEETMAN A.J. , WEETMAN D.F.
Published: July 2012

A series of eight isatogen derivatives was studied on isolated tissues taken from guinea‐pigs. The ability of the compounds to relax the taenia, to inhibit adenosine 5′‐diphosphate (ADP)‐stimulated respiration in mitochondria and to antagonize the inhibitory effects of adenosine 5′‐triphosphate (ATP) on smooth muscle was measured.

All the derivatives inhibited ADP‐stimulated respiration in mitochondria and relaxed the smooth muscle. These two effects were found to be significantly correlated.

Only half the compounds blocked the inhibitory effects of ATP, and all of these had a chemically reactive group (nitro, methoxy or pyridyl) in the 2–2′‐position. 2–2′‐Pyridylisatogen was the most effective blocking agent.

The blockade of the inhibitory effects of ATP is not related to the other actions of the derivatives.
POTENTIATION OF VASOCONSTRICTOR RESPONSES BY 3‐ AND 4‐AMINOPYRIDINE
Authors: GLOVER W. E.
Published: July 2012

In concentrations that are known to reduce potassium conductance in many excitable membranes, 3 and 4‐aminopyridine (3‐AP, 4‐AP) potentiate vasoconstrictor responses of the isolated ear artery of the rabbit to noradrenaline and histamine.

3‐ and 4‐AP have no effect on the responses of potassium‐depolarized arteries to noradrenaline, histamine or calcium.

The results suggest that the aminopyridines have no direct effect on the contractile machinery or on pharmacomechanical coupling, but cause potentiation by influencing electrical events at the cell membrane.

4‐AP causes a greater potentiation of the response to electrical stimulation than of the response to noradrenaline. This suggests that the aminopyridines may also cause an increase in the amount of noradrenaline released in response to sympathetic nerve stimulation.
DIFFERENCES IN DIHYDROERGOTAMINE ANTAGONISM OF GLUCOSE RELEASE BY CATECHOLAMINES, GLUCAGON AND ADENOSINE 3′,5′‐MONOPHOSPHATE IN RABBIT LIVER SLICES
Authors: CHAN PETER S. , ELLIS SYDNEY , MUHLBACHOVA ELFA
Published: July 2012

Quantitative studies were made on the glucose release from rabbit liver slices in vitro induced by a range of concentrations of (—)‐adrenaline (Ad), (—)‐isoprenaline (Iso), glucagon and adenosine 3′,5′‐monophosphate (cyclic AMP) in the presence and absence of several concentrations of dihy‐droergotamine (DHE).

DHE (3.16 × 10−6m) shifted the Ad log concentration‐response (LCR) curve to the right and also reduced the maximum response; at a higher concentration (3.16 × 10−5m) it produced a greater shift to the right of the LCR curve and caused a reduction in the slope and a larger depression of the maximal responses. The LCR curve to Iso was similarly affected by this higher concentration of DHE.

DHE (1 × 10−5m) produced no significant effect on the LCR curves of glucagon or cyclic AMP and even at 1 × 10−4m DHE caused only a slight depression of the maximal responses to both agonists without any modification of the lower major portions of the curves.

These data indicate a selective antagonism by DHE at the rabbit liver adrenoceptor and, since the maximal responses to catecholamines were depressed by a lower concentration of DHE than was required to produce a slight depression of the responses to glucagon and cyclic AMP, the antagonism of DHE against catecholamines does not appear to be at a site beyond the formation of cyclic AMP, but rather at a site more intimately related to the adrenoceptor.
COMPARISON OF THE ELECTROCORTICAL CHANGES INDUCED BY (+)‐AMPHETAMINE AND CHLORPROMAZINE WHEN PERFUSED DIRECTLY INTO THE DORSAL RAPHE NUCLEUS OF THE CAT
Authors: KEY B.J. , KRZYWOSINSKI L.
Published: July 2012

(+)‐Amphetamine mimicked the intermittent and sustained electrocortical desynchronization produced by (—)‐noradrenaline (NA) when perfused directly into the dorsal raphe nucleus of cat ence‐phale isole preparations.

The effects of amphetamine or NA were abolished or significantly attenuated by prior application of (—)‐propranolol.

The effect of amphetamine, but not that of NA, was blocked by prior applications of guanethidine or chlorpromazine (CPZ).

Desmethylimipramine (DMI) produced dose‐related changes in electrocortical activity which were similar to those induced by NA when applied to the same sites within the dorsal raphe nucleus.

DMI potentiated the effects of both amphetamine and NA, but guanethidine only abolished the DMI‐induced potentiation of the amphetamine response.

(—)‐Propranolol, guanethidine and CPZ produced a short period of electrocortical desynchronization at the beginning of the perfusion period before antagonism of the amphetamine response was apparent.

The results suggest that CPZ and amphetamine have an action within the dorsal raphe nucleus possibly related to noradrenergic terminals.
THE RESPONSE OF THE CIRCULAR MUSCLE LAYER OF THE GUINEA‐PIG ISOLATED VAS DEFERENS TO TRANSMURAL ELECTRICAL STIMULATION
Authors: ANSTEY MARY D. , BIRMINGHAM A.T.
Published: July 2012

Four preparations are described for the isolation of the response of the circular muscle of the guinea‐pig vas deferens. These are the 'Furchgotf strip, the ‘Vane’ strip, the chain preparation and the perfused preparation.

The four preparations were stimulated transmurally with pulses of supramaximal voltage. The threshold pulse width to which the strips and the perfused preparation responded was 0.025 ms and the maximum responses occurred at 0.1ms. The threshold frequency was 2 Hz for strip and perfused preparations, the maxima being 20 or 50 Hz for strip preparations and 100 Hz for perfused preparations. The effect of varying the number of pulses per train was also investigated on the perfused vas. Responses occurred to train lengths of 8, 16, 32, 128 pulses, the maximum response being given at 128 pulses at 100 Hz; 256 pulses per train did not produce a further increase in response. The perfused preparation exhibited an after‐response at certain frequencies and train lengths.

Tetrodotoxin and the local anaesthetics, procaine and lignocaine, reversibly abolished the responses of strip and perfused preparations to transmural stimulation.

The response to intramural nerve fibre stimulation was abolished by guanethidine or bethanidine; this abolition was reversed by dexamphetamine. Noradrenaline contracted strip preparations of circular muscle and raised the pressure in perfused preparations; noradrenaline was competitively antagonized by thymoxamine. The major part of the motor innervation of the circular layer seems to be noradrenergic.
5‐HYDROXYTRYPTAMINE: THE EFFECTS OF IMPAIRED SYNTHESIS ON ITS METABOLISM AND RELEASE IN RAT
Authors: CURZON G. , FERNANDO J.C.R. , MARSDEN C.A.
Published: July 2012

Control rats given L‐tryptophan (100 mg/kg) showed a smaller increase of brain 5‐hydroxytryptamine (5‐HT) than its metabolite 5‐hydroxyindoleacetic acid (5‐HIAA). However, when brain 5‐HT oncentrations were depleted by 40–50% after treatment with the synthesis inhibitor p‐chlorophenylalanine (PCPA) (150 mg/kg) L‐tryptophan caused a considerable increase in 5‐HT but no change in 5‐HIAA. Similar results were obtained following depletion of brain 5‐HT by pretreatment with p‐chloroamphetamine (10 mg/kg).

Electrical stimulation of the median raphe nucleus of control rats significantly increased 5‐HIAA in the hypothalamus, hippocampus and striatum. However, stimulation of PCPA (200mg/kg) pretreated animals did not significantly increase 5‐HlAA either 24 or 72 h after administration of the drug.

Pretreatment of rats with PCPA (200 mg/kg) increased striatal synaptosomal uptake of [3H]‐5HT by 30% and reduced 5‐HT concentration in the rest of the brain by 62%.

PCPA (150mg/kg) markedly reduced the acute behavioural response (‐76%) to p‐chloroamphetamine (10 mg/kg) although brain 5‐HT was only moderately reduced (‐36%). L‐Tryptophan (100 mg/kg) given 15 min before p‐chloroamphetamine restored both brain 5‐HT and the behavioural effects of p‐chloroamphetamine in PCPA pretreated rats and enhanced the behavioural response to p‐chloroamphetamine in control rats.

The results suggest that newly synthesized 5‐HT is less rapidly metabolized in rats with low brain 5‐HT. The possible reasons for this and the relevance of the results to the use of L‐tryptophan in the treatment of depressive illness are discussed.
THE MECHANISM OF THE RELAXANT EFFECT OF 2‐2′‐PYRIDYLISATOGEN ON THE ISOLATED TAENIA OF THE GUINEA‐PIG CAECUM
Authors: SPEDDING M. , WEETMAN D.F.
Published: July 2012

2‐2′‐Pyridylisatogen tosylate (PIT) slowly relaxed taenia caeci preparations of the guinea‐pig in a concentration‐dependent manner (threshold 2.5 μm). The relaxant effect did not show tachyphylaxis.

The relaxation was not affected by tetrodotoxin (0.3 μm), guanethidine (17 μm) nor by a combination of phentolamine (36 μm) and propranolol (4 μm)

In taenia caeci preparations suspended in K+‐depolarizing, Ca2+‐free Ringer, addition of Ca2+ (0.1 to 30 mm) resulted in a slow contraction. PIT (50 μm) and papaverine (15 μm) antagonized these contractions, whereas indomethacin (28 μm) was ineffective.

Although PIT (50 μm for 30 min) caused a relaxation of the taenia, and, when the tone of the preparations was restored with carbachol, antagonized adenosine 5′‐triphosphate (ATP)‐induced relaxations, relaxation of the taenia with papaverine (30 μm for 5 min) did not antagonize ATP‐induced relaxations. It is concluded that the relaxant and ATP‐receptor blocking actions of PIT are independent properties of the compound.
THE EFFECTS OF α‐ADRENOCEPTOR ANTAGONISTS ON CONTRACTILE RESPONSES TO 5‐HYDROXYTRYPTAMINE IN DOG SAPHENOUS VEIN
Authors: HUMPHREY P. P. A.
Published: July 2012

5‐Hydroxytryptamine (5‐HT) contracted isolated saphenous vein strips of the dog, producing a biphasic concentration‐effect curve. The first phase occurred with low concentrations of 5‐HT (1.0 × 10−8 to 5.0 × 10−6mol/1) with a plateau between 1.0 × 10−6mol/1 and 1.0 × 10−5mol/1. The second phase occurred with high concentrations of 5‐HT (greater than 1.0 × 10−5 mol/1).

The α‐adrenoceptor antagonists, phentolamine (5.0 × 10−8 to 5.0 × 10−7 mol/1), labetalol (1.0 × 10−6 to 1.0 × 10−5 mol/1) and thymoxamine (1.0 × 10−6 to 1.0 × 10−5 mol/1), antagonized responses to high concentrations of 5‐HT but responses to low concentrations of 5‐HT were not antagonized.

The effects of high concentrations of 5‐HT were antagonized by cocaine (1.0 × 10−6 to 1.0 × 10−5 mol/1) and were not evident in veins removed from dogs pretreated with syrosingopine.

It is concluded that in the saphenous vein, low concentrations of 5‐HT act directly on specific 5‐HT receptors and that high concentrations of 5‐HT also act indirectly on α‐adrenoceptors by displacing noradrenaline from neuronal stores.
ANTIDIURETIC EFFECT OF MORPHINE IN THE RAT: TOLERANCE AND PHYSICAL DEPENDENCE
Authors: HUIDOBRO F.
Published: July 2012

Injection of rats with morphine or methadone, before they received a water load equivalent to 5% of their body weight, produced a dose‐dependent antidiuretic effect. Following the antidiuresis, urine was eliminated with kinetics similar to control untreated rats.

The antidiuretic effect of morphine or methadone was blocked by naloxone administered before the opiate, or reversed when given after the opiate.

Rats implanted with morphine pellets developed a marked degree of tolerance to the antidiuretic effect of morphine. Tolerance was also obtained on injection of three daily doses of morphine or methadone over two days.

Withdrawal symptoms were precipitated by naloxone in rats implanted with pellets of morphine; under these conditions the animals showed a marked reduction in urine production as compared to naive rats.
AGE‐RELATED CHANGES IN THE RESPONSE OF RABBIT ISOLATED AORTAE TO VASOACTIVE AGENTS
Authors: HAYASHI SHIGEHIRO , TODA NOBORU
Published: July 2012

In helically‐cut strips of aortae from rabbits of different ages (2 to 360 days old), responses to vasoconstrictor and vasodilator agents were compared.

The passive tension developed by the same magnitude of stretch was markedly less in aortae from immature rabbits than in aortae from mature rabbits.

Contractile responses to noradrenaline and K+ increased with age in the range from 2 to 90 days. High concentrations of noradrenaline (10−5 and 5 × 10−5m) produced relaxation of aortic strips from immature rabbits (2 to 30 days). The response to histamine was not altered with age. Age‐dependent reductions (90 to 360 days) in the response to 5‐hydroxytryptamine were observed.

Relaxations induced by isoprenaline of aortic strips contracted with prostaglandin F2at increased with age in the range from 2 to 30 days but decreased with age from 30 to 360 days. Similar age‐related alterations in the relaxant response to adenosine were observed.

It is concluded that aortae from immature rabbits are more distensible than those from mature rabbits; α‐adrenoceptors mature during an early postnatal period (2 to 30 days), and 5‐hydroxytryptamine receptor mechanisms deteriorate with age (older than 90 days). The β‐receptor mechanism does not seem to alter greatly with age.