bluuebunny/crossref_metadata_2025 huggingface dataset:
EFFECT OF LANTHANIDE IONS ON HISTAMINE SECRETION FROM RAT PERITONEAL MAST CELLS
Authors: PEARCE F.L. , WHITE J.R.
Published: July 2012

Ions of the lanthanide series (lanthanum‐lutetium) inhibit histamine release induced by allergen and anti‐IgE in the presence of extracellular calcium. The inhibition is dose‐dependent in the range 10−6 to 10−9 m and there is no marked difference in potency between the lanthanides.

The response to lanthanum is biphasic and higher concentrations (10−4 m) potentiate the release. Maximal concentrations (10−3 m) again abolish secretion.

The effect of concanavalin A is weakly antagonized by lanthanum but strongly inhibited by higher lanthanides.

Inhibition of histamine release evoked by basic agents is markedly dependent on the ionic radius of the lanthanide. In the presence of extracellular calcium, dysprosium is the most effective inhibitor. Similar results are observed with dextran. In the absence of calcium, there is a regular increase in inhibition with decreasing ionic radius.

Inhibition of release in the presence of calcium is immediate and does not require preincubation with the lanthanide. The antagonism due to lanthanum is competitive and the pA2 values vary with the secretagogue. In contrast, the inhibitory effect in the absence of extracellular calcium increases progressively with time.

These results are discussed in terms of the calcium‐pools important in histamine release and the mode of action of different secretagogues.
COMPARATIVE ANTIDYSRHYTHMIC AND HAEMODYNAMIC EFFECTS OF ORALLY OR INTRAVENOUSLY ADMINISTERED MEXILETINE AND ORG 6001 IN THE ANAESTHETIZED RAT
Authors: MARSHALL R.J. , MUIR A.W. , WINSLOW E.
Published: July 2012

The antidysrhythmic and haemodynamic effects of the aminosteroid, Org 6001, were studied in the rat anaesthetized with pentobarbitone. Mexiletine was used for comparison

Both Org 6001 (2–10 mg/kg) and mexiletine (1 mg/kg) given intravenously antagonized the development of dysrhythmias evoked by acute coronary artery ligation in rats

In antidysrhythmic doses, Org 6001 and mexiletine exerted only moderate and transient hypotension and depression of cardiac contractility (assessed from LV dP/dtmax). Org 6001 did, however, induce a more sustained bradycardia

Effective oral doses of Org 6001 (20–100 mg/kg) were similar to those of mexiletine, disopyramide and propafenone

Oral Org 6001 (100 mg/kg) was effective for 18 h whereas mexiletine (100 mg/kg) failed to protect against evoked dysrhythmias 3 h after dosing

Org 6001 and mexiletine differed in their actions on ventricular fibrillation threshold (VFT). Org 6001 (100 mg/kg orally 12 h before ligation) prevented the decrease in VFT produced by coronary ligation whereas mexiletine (100 mg/kg orally) had no effect. When administered intravenously, mexiletine (but not Org 6001) increased VFT in normal ventricular muscle.
INHIBITION BY APOMORPHINE OF THE POTASSIUM‐EVOKED RELEASE OF [3H]‐γ‐AMINOBUTYRIC ACID FROM THE RAT SUBSTANTIA NIGRA in vitro
Authors: ARBILLA SONIA , KAMAL LINDA A. , LANGER S.Z.
Published: July 2012

The spontaneous and potassium‐evoked release of tritium from the rat substantia nigra prelabelled with [3H]‐γ‐aminobutyric acid [3H]‐GABA were assessed in vitro under conditions of supervision

Kainic acid lesions performed in the right caudate nucleus resulted in a 70% reduction in the ability of the homolateral nigral cells to take up and retain [3H]‐GABA when compared with the unlesioned side. The potassium‐evoked release of [3H]‐GABA remained proportional to the radioactivity retained in the tissue suggesting that the nigral GABA neurones that survived kainic acid treatment were still functional

The spontaneous outflow of [3H]‐GABA was significantly increased by exposure to different concentrations of exogenous GABA (10 to 1000 μM) when amino‐oxyacetic acid was present in the incubation medium

Apomorphine in concentrations ranging from 1 to 30 μM inhibited the calcium‐dependent release of [3H]‐GABA induced by 1 min exposure to 30 mM K+. These concentrations of apomorphine did not affect the spontaneous outflow of radioactivity. In vivo administration of haloperidol 0.2 mg/kg antagonized the in vitro inhibition by apomorphine of the K+‐evoked release of [3H]‐GABA

The results obtained with apomorphine and haloperidol suggest the presence of presynaptic dopamine‐like inhibitory receptors in gabaergic nerve terminals

Dopamine in concentrations ranging up to 300 μM did not modify either the spontaneous or the K+‐evoked release of [3H]‐GABA from the substantia nigra. These concentrations of dopamine effectively displaced [3H]‐dopamine recently taken up into the substantia nigra

Our results do not support the view that dendritic release of dopamine from the substantia nigra might be involved in the physiological modulation of the spontaneous or the stimulation‐evoked release of GABA.
THE EFFECT OF HARMINE ON THE ACTION POTENTIAL OF THE GUINEA‐PIG ATRIAL MUSCLE DEPENDS ON THE EXTERNAL CALCIUM CONCENTRATION
Authors: CARPENTIER ROBERT G.
Published: July 2012

The influence of the external calcium concentration on the effect of harmine 2 × 10−5 M upon the guinea‐pig atrial muscle was analysed. Transmembrane potentials of contractile fibres were measured during exposure to the drug at 30°C

In preparations superfused with 1.35 mM Ca2+‐Tyrode solution and driven at 60/min (1Hz) harmine depressed the amplitude of the action potential (AP) and the maximum velocity of the upstroke (d V/dt). The resting potential was not affected. Harmine depressed similarly the d V/dt of fibres superfused with 2.7 mM Ca2+‐Tyrode solution but the AP was slightly enhanced

Harmine diminished both the AP and the d V/dt of fibres superfused with 2.7 mM Ca2+‐Tyrode solution and driven at a fast rate (180/min, 3 Hz). Increased external calcium concentration (5.4 mM) annulled the depressant effect on AP while the action on dV/dt persisted

It is concluded that the effect of harmine on the AP depends on the external calcium concentration. Increase [Ca2+]o reverses the depressant effect of harmine because it annuls the effect of the drug on the slow component of the upstroke. The action on the initial fast component of the rising phase of the action potential persists.
SELECTIVE INHIBITION OF THROMBOXANE BIOSYNTHESIS IN HUMAN BLOOD MONONUCLEAR CELLS AND THE EFFECTS ON MITOGEN‐STIMULATED LYMPHOCYTE PROLIFERATION
Authors: GORDON D. , NOURI A.M.E. , THOMAS R.U.
Published: July 2012

The effects of six imidazole compounds were examined on thromboxane B2 (TxB2) and prostaglandin E2 (PGE2) production and mitogen‐stimulated lymphocyte transformation in human blood mononuclear cells

UK 37248 (4‐(2‐[IH‐imidazol‐l‐yl]ethoxy)benzoic acid), imidazole and 1‐methylimidazole selectively inhibited TxB2 synthesis in a dose‐related manner, with corresponding increases in PGE2 production

Clotrimazole, benzimidazole and 2‐methylimidazole preferentially inhibited TxB synthesis but had little effect on PGE2 production

Clotrimazole and benzimidazole inhibited proliferative responses of the lymphocytes, but UK 37248 and 1‐methylimidazole did not affect transformation at concentrations which inhibited TxB2 synthesis to a similar level (over 90%)

The results do not support involvement of endogenous TxB2 in the process of lymphocyte mitogenesis or in the mechanism of the suppressive effects of some TxB2 synthetase inhibitors.
EFFECTS OF A SALT OF CHOLESTYRAMINE AND 2‐[4‐(p‐CHLOROBENZOYL)PHENOXY]2‐METHYL PROPIONIC ACID (α‐1081) ON BILIARY LIPID SECRETION IN RATS
Authors: ALDINI RITA , BARBARA LUIGI , BENELLI AUGUSTA , BORZATTA VALERIO , GEMINIANI STEFANIA , MASCELLANI GIUSEPPE , MORSELLI ANTONIO , RODA ALDO , RODA ENRICO
Published: July 2012

Hypolipidaemic agents may increase biliary cholesterol in man, inducing a supersaturated bile.

To evaluate this possible side‐effect, we have studied bile lipid secretion over a period of 8 h with intact enterohepatic circulation and 4 h with complete interruption in rats treated for two months with a salt of cholestyramine and 2‐[4‐(p‐chlorobenzoyl)‐phenoxy]2‐methyl propionic acid (α‐1081, 1.150 g/kg body wt., daily), cholestyramine (1.125 g/kgbody wt. daily), procetofenic acid (25 mg/kg body wt. daily) and saline respectively (six rats for each group).

Cholesterol saturation index significantly (P< 0.005) increased (from 0.21 ±0.01 to 0.39±0.09, mean±s.d.), in rats fed with procetofenic acid but it did not in α‐1081‐ and cholestyramine‐treated animals.

Procetofenic acid and, to a lesser extent, cholestyramine increased the bile flow. Procetofenic acid increased cholesterol secretion from 0.45±0.17 to 0.94 ± 0.19 μmol kg−1 body wt. h−1 (mean±s.d.).

Cholestyramine increased both serum cholesterol and bile acid secretion from 0.45±0.17 to 0.68±0.10 and 25.8±9.48 to 39.96 ± 6.68 μol kg−1 body wt. h−1 respectively; α‐1081, on the contrary, had no effect on bile lipid secretion.

These data suggest that α‐1081 may be used as a new hypolipidaemic drug without any risk of increasing cholesterol in bile.
RECEPTOR MECHANISMS FOR 5‐HYDROXYTRYPTAMINE IN RABBIT ARTERIES
Authors: BLACK J.L. , FRENCH R.J. , MYLECHARANE E.J.
Published: July 2012

Previous investigations into the vascular actions of biogenic amines implicated in migraine have shown that the contractile effects of both 5‐hydroxytryptamine (5‐HT) and noradrenaline (NA) in the rabbit ear artery are mediated by a direct sympathomimetic action at α‐adrenoceptors, while in the rabbit aorta, 5‐HT and NA act on pharmacologically distinct receptors. The purpose of the present investigation was to determine whether the absence of 5‐HT receptors in rabbit ear arteries is characteristic of distributing arteries in general, or is confined to particular regional circulations.

Agonist‐antagonist interactions were studied in various rabbit vascular preparations (common carotid, external carotid and femoral arterial strips, and perfused ear arteries) by determining pA2 values for pizotifen and phentolamine against 5‐HT‐ and NA‐induced contractile responses.

In common carotid and femoral arteries, pizotifen was a potent competitive antagonist of 5‐HT, but weak against NA. The converse applied to phentolamine. In external carotid and ear arteries, pizotifen was a weak competitive antagonist of both 5‐HT and NA, whereas phentolamine was a potent competitive antagonist of both. Cocaine did not influence pA2 values against NA.

5‐HT and NA were of similar potency in common carotid and femoral arteries, but 5‐HT was much less potent than NA in external carotid and ear arteries.

The results indicate that rabbit common carotid and femoral arteries contain both D‐type 5‐HT receptors and α‐adrenoceptors, as does the aorta. However, external carotid arteries, like ear arteries, do not contain specific 5‐HT receptors. The action of 5‐HT in the external carotid artery is mediated by α‐adrenoceptors; this is a direct sympathomimetic action since it was not inhibited by cocaine or reserpine‐pretreatment.

6 The absence of 5‐HT receptors in the rabbit extracranial circulation may limit the usefulness of this species as a model for research relating to migraine.
CORRELATION BETWEEN CATECHOLAMINE RELEASE AND SODIUM PUMP INHIBITION IN THE PERFUSED ADRENAL GLAND OF THE CAT
Authors: GARCIA A.G. , GARCIA‐LOPEZ E. , MONTIEL C. , NICOLAS G.P. , SANCHEZ‐GARCIA P.
Published: July 2012

Ca2+ re introduction to retrogradely perfused and ouabain (10−4M)‐treated cat adrenal glands caused a catecholamine secretory response which was greater the longer the time of exposure to the cardiac glycoside. Such a response was proportional to the external Na+ concentration [Na+]0.

A qualitatively similar, yet smaller response was observed when glands were perfused with Krebs solution lacking K+ ions; thus, K+ deprivation mimicked the secretory effects of ouabain. Catecholamine secretion evoked by Ca2+ reintroduction in K+‐free solution (0‐K+) was also proportional to [Na+]0 and greater the longer the time of exposure of the gland to 0‐K+ solution.

The ionophore X537A also mimicked the ouabain effects, since Ca2+ reintroduction to glands treated with this agent (25 μm) caused a sharp secretory response. When added together with X537A, ouabain (10−4m) did not modify the response to the ionophore.

N‐ethylmaleimide (NEM), another Na+, K+‐ATPase inhibitor, did not evoke the release of catecholamines; on the contrary, NEM (10−4m) inhibited the catecholamine secretory response to high [K+]0, acetylcholine, Ca2+ reintroduction and ouabain.

Ouabain (10−4 m) inhibited the uptake of 86Rb into adreno‐medullary tissue by 60%. Maximal inhibition had already occurred 2 min after adding the drug, indicating a lack of temporal correlation between ATPase inhibition and the ouabain secretory response, which took longer (about 30–40 min) to reach its peak. NEM (10−4 m) blocked 86Rb uptake in a similar manner.

The results are further evidence in favour of the presence of a Na+‐Ca2+ exchange system in the chromaffin cell membrane, probably involved in the control of [Ca2+]i, and in the modulation of catecholamine secretion. This system is activated by increasing [Na+]i, either directly (ionophore X537A, increased [Na+]0) or indirectly (Na+ pump inhibition). However, the simple inhibition of Na+ pumping does not always lead to a catecholamine secretory response; such is the case for NEM.
POTENTIATION OF K+‐EVOKED CATECHOLAMINE RELEASE IN THE CAT ADRENAL GLAND TREATED WITH OUABAIN
Authors: GARCIA A.G. , GARCIA‐LOPEZ E. , HORGA J.F. , KIRPEKAR S.M. , MONTIEL C. , SANCHEZ‐GARCIA P.
Published: July 2012

A vigorous catecholamine secretory response was evoked by small increments (2–10 mM) of the extracellular concentration of K+ ([K+])0) in cat adrenal glands treated with ouabain (10−4m), and perfused with Krebs‐bicarbonate solution at room temperature.

The secretory response depends on [K+]0; increments of [K+]0 as small as 2 mM for 2 min evoked a clear secretory response; at 10–17.7 mM K+, the maximal secretory response was observed. In normal glands, not treated with ouabain, no increase of the rate of catecholamine output was observed by raising [K+]0 up to 17.7 mM for 2 min.

The K+ secretory response was time‐dependent, requiring at least 1 min to be initiated; on continued exposure to 10 mM [K+]0, the enhanced response remained for at least 1 h.

In low [Na+]0, the K+‐secretory response was unchanged. However, in 0‐Ca2+, high‐Mg2+ solutions, or in the presence of D600, an organic Ca2+ antagonist, it was abolished.

The K+‐induced secretory response was not altered in the presence of tetrodotoxin or tetraethylammonium.

It is concluded that ouabain potentiated the catecholamine secretory response to raised [K+]D by increasing the amount of Ca2+ available to the secretory machinery through (a) mobilization of an enhanced pool of membrane‐bound Ca2+, (b) activation of membrane Ca2+ inward current; or (c) decrease of intracellular Ca2+ buffering systems. The activation by ouabain of a membrane Na+‐Ca2+ exchange system is not involved in this K+‐secretory response. It is suggested that the plasma membrane ATPase enzyme system, by changing the affinity of its Ca2+ binding sites, might control the availability of this cation to the secretory machinery and, therefore, modulate catecholamine secretion in the adrenal gland.
STIMULATION OF RAT CEREBELLAR GUANOSINE 3‘,5’‐CYCLIC MONOPHOSPHATE (CYCLIC GMP) LEVELS: EFFECTS OF AMINO ACID ANTAGONISTS
Authors: FOSTER GEORGE A. , ROBERTS PETER J.
Published: July 2012

The ability of glutamate, aspartate and related neuroexcitants to produce large calcium‐dependent increases in the levels of guanosine 3′,5′‐cyclic monophosphate (cyclic GMP) in immature rat cerebellar slices has been demonstrated.

These effects were inhibited by selective antagonist compounds, indicating the presence of at least two types of excitatory amino acid receptor mediating the cyclic GMP response.

Protoveratrine also produced large increases in cyclic GMP, and this action was antagonized by L‐glutamate diethylester suggesting that released endogenous glutamate, subsequently interacting with its postsynaptic receptors, is the predominant mechanism.

The kinetic characteristics of several of the inhibitor compounds were investigated.
MECHANISMS OF FORSSMAN‐INDUCED BRONCHOSPASM AND THEIR INHIBITION
Authors: BUTLER K.D. , SMITH J.R.
Published: July 2012

The bronchospasm induced in the guinea‐pig by the injection of Forssman antiserum was biphasic in nature in both the sublethal and the lethal reaction.

The development of both phases of the bronchospasm in the sublethal reaction was dependent upon the presence of the intact complement system and circulating platelets. In the lethal reaction the phase II bronchospasm did not appear to depend on these factors.

The compounds used in this study inhibited phase I bronchospasm of the sublethal reaction in the order, methysergide > indomethacin > aspirin = sulphinpyrazone and phase II in the order, indo‐methacin > sulphinpyrazone > aspirin. Methysergide was inactive.

Aspirin, indomethacin and sodium salicylate all prevented the inhibitory action of sulphinpyrazone in reducing the phase II bronchospasm of the sublethal reaction in the order, indomethacin > sodium salicylate > aspirin, when the drugs were administered prior to sulphinpyrazone.

The inhibitory action of aspirin on the sulphinpyrazone effect could be prevented by administering sulphinpyrazone before aspirin. All drug‐induced inhibitions of sulphinpyrazone by aspirin, indomethacin and sodium salicylate were dose‐dependent.
COMPARISON OF THE EFFECTS OF METHOXAMINE WITH THOSE OF NORADRENALINE AND PHENYLEPHRINE ON SINGLE CEREBRAL CORTICAL NEURONES
Authors: BRADSHAW C.M. , PUN R.Y.K. , SLATER N.T. , SZABADI E.
Published: July 2012

The technique of microelectrophoresis was used to compare the actions of methoxamine, noradrenaline and phenylephrine on single neurones in the somatosensory cerebral cortex of the rat.

Methoxamine evoked only excitatory responses on cortical neurones. The methoxamine‐sensitive cells were also excited by phenylephrine; cells excited by methoxamine could either be excited or depressed by noradrenaline.

Methoxamine appeared to be less potent than either noradrenaline or phenylephrine in evoking excitatory responses.

Responses to methoxamine had a slower time course than responses to either noradrenaline or phenylephrine, both the latencies to onset and the recovery times being longer for responses to methoxamine than for responses to noradrenaline or phenylephrine.

When the absolute mobilities of methoxamine, noradrenaline and phenylephrine were compared using an in vitro method, no significant differences were found between the mobilities of the three ionic species, suggesting that the three drugs have similar transport numbers. Thus the differences in potency between methoxamine and the other two drugs, and the difference between the time courses of responses to methoxamine and the other two drugs, are presumably of biological origin.

The α‐adrenoceptor antagonist, phenoxybenzamine, antagonized equally excitatory responses to methoxamine and noradrenaline, and responses to methoxamine and phenylephrine, without affecting responses to acetylcholine.

When responses to methoxamine and noradrenaline and responses to methoxamine and acetylcholine were summated on the same cells, the net responses were smaller than those expected on the basis of additive effects; the deviation from additivity was greater in the case of the summation of responses to methoxamine and noradrenaline than in the case of summation of responses to methoxamine and acetylcholine. This observation is consistent with the hypothesis that the interaction between methoxamine and noradrenaline follows the model of competitive dualism, whereas the interaction between methoxamine and acetylcholine follows the model of functional synergism.

The results suggest that methoxamine may act as a partial agonist at excitatory α‐adrenoceptors on cerebral cortical neurones.
EFFECTS OF PHOSPHATE‐MODIFIED ADENINE NUCLEOTIDE ANALOGUES ON INSULIN SECRETION FROM PERFUSED RAT PANCREAS
Authors: CHAPAL JEANNIE , LOUBATIERES‐MARIANI MARIE‐MADELEINE
Published: July 2012

The effects of three methylene analogues of adenosine 5′‐triphosphate (ATP) or 5′‐diphosphate (ADP) have been studied on insulin secretion from the isolated perfused pancreas of the rat: 5′‐adenylmethylene diposphonate or β, γ‐methylene ATP, adenosine 5′‐α, β‐methylene triphosphate or α, β‐methylene ATP and adenosine 5′‐α, β‐methylene diphosphonate or α, β‐methylene ADP.

β.γ‐Methylene ATP did not elicit any increase of insulin release; α, β‐methylene ATP and α, β‐methylene ADP induced a biphasic stimulation of insulin secretion; this effect was dose‐related between 1.65 and 165 μmol/1. Relative potency ATP/α, β‐methylene ATP was 1.2 and ATP/α, β‐methylene ADP was 0.31.

Our results point to the importance of the steric and electronic characteristics of the polyphosphate chain of the analogues of ATP and ADP in inducing an insulin secretory effect. They support the hypothesis of a purine receptor for ATP and ADP.
A CYTOCHEMICAL BIOASSAY METHOD FOR THE DETERMINATION OF LUTEINIZING HORMONE IN BIOLOGICAL FLUIDS AND TISSUES
Authors: BUCKINGHAM JULIA C. , HODGES J.R.
Published: July 2012

The ability of luteinizing hormone (LH) to alter the reducing activity of corpora lutea in rat ovarian sections has been exploited to develop a new cytochemical bioassay for the hormone.

Sections of ovaries, removed from mature rats during the second day of dioestrus, were incubated with either standard LH or samples diluted for assay, stained immediately for reducing potential and the intensity of the stain measured by scanning and integrating microdensitometry.

An inverse linear relationship existed between the density of the stain and the logarithm of the concentration of standard LH (68/40) and the dose‐response lines of serial dilutions of rat or human plasma were parallel with those of the standard.

The method was found to be accurate, specific, sensitive, precise and suitable for the determination of LH in the rat and in man.
CHARACTERISTICS OF (±)‐[14C]‐OXPRENOLOL AND (±)‐[14C]‐PROPRANOLOL INCORPORATION BY RAT LUNG SLICES
Authors: HEMSWORTH BRIAN A. , STREET JAMES A.
Published: July 2012

The uptake of (±)‐[14C]‐oxprenolol and (±)‐[14C]‐propranolol has been studied in rat lung slices. The loss of these two radiolabelled β‐adrenoceptor antagonists from pre‐loaded lung slices has also been studied.

Over the concentration range studied (3.3 × 10−7m to 1.7 × 10−3m) a biphasic uptake of both compounds was observed. At concentrations below 1.5 × 10−4m approximately, there was some evidence of saturability, but at higher concentrations uptake appeared to be a linear function of drug concentration.

At concentrations of 6.6 × 10−7m and 1.7 × 10−6m respectively, the uptake of oxprenolol and propranolol was significantly reduced by low temperature, anaerobic conditions, incubation in Na+‐free medium, and by the metabolic inhibitors potassium cyanide and 2, 4‐dinitrophenol. Ouabain had little or no effect.

At the same concentration, oxprenolol uptake was also inhibited in a concentration‐dependent manner by propranolol, amphetamine, chlorpromazine and imipramine. Noradrenaline was without effect.

The loss of oxprenolol and propranolol from lung slices preloaded with the two compounds was fairly slow, with 60 to 70% of the drug originally taken up still remaining in the tissue after 30 min in fresh medium.

Possible mechanisms underlying the pulmonary accumulation of oxprenolol and propranolol are discussed.
A TEST OF THE NULL EQUATION FOR FUNCTIONAL ANTAGONISM
Authors: EMMERSON JANE , MACKAY DENNIS
Published: July 2012

The quantitative model for functional antagonism and synergism has been tested by studying its ability to fit data obtained from the functional antagonism of (−)‐isoprenaline by muscarinic agonists on guinea‐pig isolated atria.

The general form of the null equation has been shown to fit the experimental curves satisfactorily.

Functional interaction between (–)‐soprenaline and muscarinic agonists on atria has been shown to be type I although there does seem to be a discrepancy between values of the functional affinity constants. KA1F and KA2F estimated in two different ways.

The affinity constants, KA. of the muscarinic agonists for their receptors have been estimated by use of the selective irreversible antagonist propylbenzilylcholine mustard. The discrepancy between KAF (i.e. both KA1F and KA2F) and KA is small for pentyltrimethylammonium which is an agonist of low intrinsic efficacy. By contrast the discrepancy between KAF and KA is much greater for methyl‐furmethide and oxotremorine both of which have much higher intrinsic efficacies. These results are as predicted by the model.

It is suggested that the discrepancy between KA1F and KA2F may be due to the limited ability of the equation

to describe quantitatively the relation between sequential stimuli. However, it is concluded that this complication need not interfere with the use of the model to study mechanisms and possible sites of functional interaction.
THE SPONTANEOUS AND EVOKED RELEASE OF SPERMINE FROM RAT BRAIN in vitro
Authors: HARMAN R.J. , SHAW G.G.
Published: July 2012

The efflux of previously accumulated [3H]‐spermine from brain slices was measured using a continuous perfusion system. The spontaneous efflux was biphasic, consisting of an initial rapid efflux followed by a much slower release.

The slices were depolarized by the addition to the medium of high potassium concentrations, ouabain or veratrine.

At concentrations greater than 30 mM, potassium evoked a striking increase in the release of [3H]‐spermine. Following uptake in the presence of 5.7 × 10−9M[3H]‐spermine, K+‐evoked release was dependent on the presence of calcium ions. Release of spermine after uptake at 5.6 × 10−8m or 5.0 × 10−7m was not calcium‐dependent.

The calcium‐dependent, K+‐stimulated release of spermine was inhibited in the presence of diphenylhydantoin (5 × 10−3m) or ruthenium red (10−3 m).

Following uptake of 5.7 × 10−9m [3H]‐spermine in a sodium‐free medium, the calcium‐dependent, K+‐stimulated release was significantly inhibited.

Ouabain (10−4m) caused a large but calcium‐independent increase in the efflux of [3H]‐spermine.

Veratrine‐induced release was less substantial but was increased in a calcium‐free medium. Release evoked by veratrine was abolished in the absence of sodium.

These results are discussed with respect to a possible ‘neurotransmitter’ or ‘neuromodulator’ role for spermine.
A COMPARISON OF THE CARDIOVASCULAR AND SEDATIVE ACTIONS OF THE α‐ADRENOCEPTOR AGONISTS, FLA‐136 AND CLONIDINE, IN THE RAT
Authors: HAMILTON T.C. , LONGMAN SUSAN D.
Published: July 2012

The cardiovascular and sedative effects of FLA‐136 have been compared with those of clonidine after intracerebroventricular (i.c.v.) administration in the rat. The effects of both drugs on pre‐ and postsynaptic α‐adrenoceptors in the periphery have been investigated after intravenous (i.v.) administration in the pithed rat.

In the anaesthetized rat, i.c.v. FLA‐136 and clonidine produced dose‐related hypotension, FLA‐136 having three to 30 times less activity than clonidine; both drugs caused concomitant bradycardia. In the conscious rat i.c.v. FLA‐136 had less sedative potential than clonidine, in terms of overt sedation assessed visually.

Yohimbine reduced the hypotension and bradycardia produced by i.c.v. FLA‐136 and clonidine; prazosin and mianserin also antagonized the cardiovascular responses to clonidine, but not those to FLA‐136.

Chemical sympathectomy by 6‐hydroxydopamine (6‐OHDA) markedly reduced the cardiovascular effects of FLA‐136 but only slightly reduced those of clonidine.

Naloxone antagonized the cardiovascular responses to clonidine, but not FLA‐136, suggesting a direct or indirect involvement of central opiate receptors in the responses induced by clonidine.

Metiamide attenuated the cardiovascular responses to FLA‐136 and clonidine, implying a direct or indirect involvement of central histamine (H2)‐receptors in such responses.

FLA‐136, unlike clonidine, did not stimulate peripheral pre‐ or postsynaptic α‐adrenoceptors in the pithed rat.

FLA‐136 is a novel centrally‐acting hypotensive compound which, unlike clonidine, selectively stimulates central α‐autoreceptors (yohimbine‐sensitive) in the rat; these autoreceptors may be different from peripheral pre‐ and postsynaptic α‐adrenoceptors. The results suggest that clonidine lowers blood pressure by stimulation of two types of central postsynaptic α‐adrenoceptors in the rat, ‐one type being sensitive to yohimbine and the other to prazosin.
DIFFERENTIAL ACTIONS ON RABBIT NODAL, ATRIAL, PURKINJE CELL AND VENTRICULAR POTENTIALS OF MELPERONE, A BRADYCARDIC AGENT DELAYING REPOLARIZATION: EFFECTS OF HYPOXIA
Authors: MILLAR J.S. , WILLIAMS E.M. VAUGHAN
Published: July 2012

Melperone, a butyrophenone tranquillizer, caused bradycardia in vivo and in vitro.

Although Melperone had α‐adrenoceptor antagonist activity in the pithed rat, it was not a β‐adrenoceptor antagonist, nor was it a cholinoceptor agonist.

The bradycardic action could be attributed almost entirely to a prolongation by Melperone of action potential duration (APD) in sinus node cells, with little effect on the slow diastolic depolarization.

APD was prolonged by Melperone in atrial and ventricular muscle, and most of all in the bundle of His, but only moderately in the terminal Purkinje cells.

In all cardiac tissues depolarized by fast inward current, Melperone caused a dose‐related reduction in the maximum rate of depolarization and conduction velocity. On desheathed frog nerve Melperone had a local anaesthetic potency equal to that of procaine.

There was no negative inotropic effect in cardiac muscle, nor interference with A‐V nodal conduction, from which it was inferred that Melperone did not restrict slow inward current.

Melperone did not reduce hypoxic shortening of APD relative to the initial value at the start of hypoxia, but because APD was already lengthened by Melperone in normoxic conditions, APD90 during hypoxia remained close to normal values. There was no protection against hypoxic depression of contractions.

It was concluded that Melperone had class 1 and class 3 antiarrythmic actions and merited trial as an antiarrhythmic drug.
ANALYSIS OF HISTAMINE RECEPTORS IN THE CENTRAL THERMOREGULATORY MECHANISM OF Mastomys natalensis
Authors: DHAWAN B.N. , SHUKLA R. , SRIMAL R.C.
Published: July 2012

The effect of intracerebroventricular (i.c.v.) injection of histamine on the rectal temperature of Mastomys natalensis at ambient temperatures of 10, 24 and 33°C has been studied.

Low doses (0.1–1.0 μg) of histamine produced hypothermia while larger doses (5–20 μg) produced dose‐dependent hyperthermia. The hypothermic effect was significantly antagonized by mepyramine while the hyperthermia was blocked by cimetidine.

Histamine H1‐receptor agonists, 2‐methyl‐histamine and 2‐pyridyl‐ethylamine, also produced hypothermia which could be blocked by mepyramine.

Histamine H2‐receptor agonists, impromidine and dimaprit, produced hyperthermia which was antagonized by cimetidine.

Pretreatment of the animals with a β‐adrenoceptor antagonist, MJ1999, did not affect the response to histamine.

The hyperthermic effect of histamine (10 μg) was most marked at 10°C and was attenuated at 33°C.

It is concluded that both H1‐ and H2‐histamine receptors are present in the brain of Mastomys. The H1‐receptors mediate hypothermia and H2‐receptors hyperthermia.
TWO ACTIONS OF γ‐AMINOBUTYRIC ACID ON THE RESPONSES OF THE ISOLATED BASILAR ARTERY FROM THE RABBIT
Authors: ANWAR N. , MASON D.F.J.
Published: July 2012

In the isolated basilar artery of the rabbit, γ‐aminobutyric acid (GABA) (ED50±s.e.mean, 2.4 ± 1.1 × 10−5 m) produced a relaxation, if the tone had been increased with 5‐hydroxytryptamine (5‐HT).

3‐Aminoproprane sulphonic acid (3‐APS) produced a similar, but smaller relaxation, while baclofen had no effect. The relaxation produced by GABA was inhibited by bicuculline.

Transmural electrical stimulation produced a reproducible contraction of the isolated basilar artery. In 9 out of 14 preparations GABA (ED50± s.e.mean, 5.6 ± 2.1 × 10−7 m) caused a reduction of the response, with a maximum of 49.2 ±4.3%. Bicuculline did not inhibit these responses to GABA.

Baclofen (ED50±s.e.mean, 6.8± 1.4 × 10−7 m) produced a similar inhibition (47.4±3.2% maximum) but 3‐APS had no effect.

GABA (10−4 m) had no effect on the tone of isolated mesenteric or internal carotid arteries from the rabbit, whether or not the tone was increased with 5‐HT. Similarly, GABA (10−4 m) did not produce any change in the responses to transmural stimulation in isolated mesenteric or internal carotid arteries.

These findings are consistent with the presence of two types of GABA receptor on the rabbit basilar artery.
THE EFFECT OF ETHANOL ON INHIBITORY AND MOTOR RESPONSES IN THE RAT AND RABBIT ANOCOCCYGEUS AND THE BOVINE RETRACTOR PENIS MUSCLES
Authors: GILLESPIE J.S. , HUNTER J.C. , McKNIGHT A.T.
Published: July 2012

Ethanol (200 mm) reduced the response to inhibitory nerve stimulation in the rat and rabbit anococcygeus and the bovine retractor penis (BRP) muscles. Ethanol also reduced the response to the inhibitory extract from the BRP consistent with the inhibitory factor in these extracts playing some part in the response to inhibitory nerve stimulation.

Ethanol's effect on the response to other inhibitory stimuli was examined in the rabbit anococcygeus and the BRP. In the anococcygeus the response to carbachol was reduced, to bradykinin and isobutylmethylxanthine (IBMX) unaltered, and to isoprenaline and adenosine 5′‐triphosphate (ATP) potentiated. In the BRP responses to IBMX and sodium nitroprusside were unaltered but in this tissue the response to isoprenaline was reduced. Ethanol's ability to reduce inhibitory responses is, therefore, selective and confined to inhibitory nerve stimulation, inhibitory extract, carbachol and, in the BRP, isoprenaline.

Ethanol reduced the rate of development of inhibition even where the magnitude of the inhibitory response was unaltered.

In the rat anococcygeus, ethanol (200 mm) potentiated the response to motor nerve stimulation and to noradrenaline (NA) at low frequencies and low concentrations respectively. Higher ethanol concentrations (400 mm) reduced the response to both motor nerve stimulation and NA. The motor response to carbachol was also reduced.

Ethanol (200 mm) itself caused an easily reversible contraction in all three tissues. This was not due to the release of NA but was highly sensitive to the removal of external calcium from the medium.

A unified explanation of these varied effects of ethanol based on a reduction in membrane binding of calcium and a reduced efficiency of receptor coupling is suggested.
EFFECTS OF OPIOIDS ON NONCHOLINERGIC EXCITATORY RESPONSES OF THE GUINEA‐PIG ISOLATED ILEUM: INHIBITION OF RELEASE OF ENTERIC SUBSTANCE P
Authors: GINTZLER ALAN R. , SCALISI JENNIE A.
Published: July 2012

Experiments were carried out to determine whether opiates and opioid peptides could affect noncholinergic excitatory responses of the isolated guinea‐pig ileum.

Transmural field stimulation (10–20 Hz) of an atropine pretreated, intact segment of gut produced a contracture that could be elicited repeatedly without significant variation in magnitude.

This noncholinergic contracture was significantly reduced 75.3 ±8.3% (mean±s.e.mean) by tetrodotoxin (TTX; 1 μg/ml) and by desensitizing the preparation to substance P (76.3 ± 10.1%).

Morphine (5 × 10−6 m) as well as the opioid peptides d‐Ala2, N‐Phe4, Met‐(0)‐01 (FK 33–824; 9 × 10−7 m), d‐Met2‐Pro5 enkephalin (3 × 10−7 m) and d‐Ala2‐d‐Leu5‐enkephalin (5 × 10−6 m) inhibited the magnitude of the noncholinergic contracture but did not alter contractile responses to exogenous substance P (4 × 10−11 m‐4 × 10−10 m).

Pretreatment with the nicotinic receptor blocker, hexamethonium (10−5‐10−4 m) reduced by about 35% the magnitude of the atropine‐resistant contracture but did not affect inhibitory responses to morphine or opioid peptides. Thus the inhibition produced by morphine on the 20 Hz contracture does not involve a nicotinic cholinergic mechanism.

Naloxone pretreatment (10−6 m) in the presence of hexamethonium (10−5‐10−4 m) enhanced the magnitude of the noncholinergic contracture without affecting responses to exogenous substance P (4 × 10−11‐4 × 10−10 m).

These data suggest that substance P is the main, if not the sole, mediator of the atropine‐resistant 20 Hz contracture and indicate further that exogenous as well as endogenous opioids can modulate the release of this enteric peptide.
EFFECTS OF HARMALA ALKALOIDS ON TRANSMEMBRANE POTENTIALS OF GUINEA‐PIG PAPILLARY MUSCLES
Authors: CARPENTIER ROBERT G.
Published: July 2012

The significance of the presence of a methoxy group in the 7 position of the indole nucleus of harmala alkaloids in terms of their effects on the action potential of cardiac muscle was analysed. Guinea‐pig papillary muscles were superfused with Tyrode solution at 30°C and exposed to harmine or its analogue harmane, in which the methoxy group has been removed from the molecule.

Harmine 2 × 10−5 m enhanced the amplitude of the action potential (AAP) of normal fibres and of slow responses elicited by noradrenaline in fibres depolarized by 21.6 mm K+‐Tyrode. The effect of harmine on AAP occurred in the absence of any change in membrane resting potential or maximum velocity of the upstroke and it was abolished by propranol. Harmane 2 × 10−5 m did not have any effect on normal action potentials and slow responses.

Higher concentrations of the two analogues depressed both AAP and the maximum velocity of the upstroke of the action potential, without affecting the duration of the action potential.

It is concluded that: (a) removal of the methoxy group from harmine (1) abolishes the catechol‐mediated stimulatory effect of a low concentration of the drug on the slow component of the upstroke of the action potential, and (2) does not modify the depressant effect of a high concentration of the drug. (b) The two analogues, harmine and harmane, do not affect the duration of the action potential of ventricular muscle.
SYNTHESIS OF NEW HALOPERIDOL ANALOGUES AND CHARACTERIZATION OF THEIR INTERACTIONS WITH α‐ADRENOCEPTORS IN RAT PAROTID SLICES AND HUMAN PLATELET MEMBRANES
Authors: ATLAS DAPHNE , FRIEDMAN ZEEV , LITVIN YAIR , STEER MICHAEL L.
Published: July 2012

The synthesis of several butyrophenone analogues of haloperidol is described.

The effects of these compounds on α‐adrenoceptors were evaluated by examining their ability to reduce α1‐stimulated K+ release from rat parotid slices and to displace [3H]‐phentolamine from human platelet membrane α2‐adrenoceptors.

The affinity of haloperidol and its analogues for α1‐receptors was found to be 1 to 2 orders of magnitude greater than that for α2‐adrenoceptors. These observations suggest that most of the α‐adrenoceptor activity of butyrophenones results from their interaction with α1‐adrenoceptors.

The relatively high affinity of the butyrophenones for α1‐adrenoceptors suggests that they may be useful as probes in studies of α1‐adrenoceptors in these and other tissues.
THE EFFECTS OF ANAESTHETICS ON THE UPTAKE AND RELEASE OF AMINO ACID NEUROTRANSMITTERS IN THALAMIC SLICES
Authors: KENDALL T.J.G. , MINCHIN M.C.W.
Published: July 2012

The effect of thiopentone, methohexitone, urethane and ketamine on the uptake and release of Y‐aminobutyric acid (GABA) and d‐aspartate by rat thalamic slices has been investigated.

A high, supra‐anaesthetic concentration of methohexitone increased the uptake of both d‐aspartate and GABA.

None of the anaesthetics used had any detectable effect upon the spontaneous release of either amino acid.

Urethane and ketamine had no effect upon the K+‐stimulated release of either amino acid.

Methohexitone and thiopentone produced a biphasic dose‐response on the K+‐stimulated release of both amino acids; low concentrations enhanced release, high concentrations depressed release.

Bicuculline hydrochloride and picrotoxin both significantly reduced the barbiturate‐induced enhancement of K+‐stimulated amino acid release, but did not significantly alter the depression of K+‐stimulated release at higher barbiturate concentrations.

Baclofen, either alone (1 μm to 1 mm), or tested against the barbiturates, had no detectable effect.
ACTIONS OF PROSTAGLANDIN F2αAND NORADRENALINE ON CALCIUM EXCHANGE AND CONTRACTION IN RAT MESENTERIC ARTERIES AND THEIR SENSITIVITY TO CALCIUM ENTRY BLOCKERS
Authors: GODFRAIND T. , MILLER R.C.
Published: July 2012

The actions of prostaglandin F2α(PGF2α) and noradrenaline on contraction and45Ca exchange have been studied in rat mesenteric arteries.

PGF2αand noradrenaline contracted rat isolated mesenteric artery preparations to about the same extent. The PGF2α‐stimulated contractions, unlike those produced by noradrenaline, were completely inhibited in calcium‐free physiological solution.

The calcium entry blocking drugs, cinnarizine and flunarizine, had little effect on the resting exchange of calcium in the arterial smooth muscle, but inhibited PGF2α‐stimulated contractions and45Ca uptake to a similar extent.

Flunarizine was about 7 fold more potent as an inhibitor of noradrenaline‐ than of PGF2α‐mediated contraction and45Ca uptake and this ratio was about 50 for cinnarizine.

EGTA (1.25 mm) produced a relaxation of noradrenaline and PGF2α‐induced maximal contractions. Measured over the first 2 min of EGTA contact, the rate of relaxation was much faster in noradrenaline than in PGF2α‐stimulated preparations.

Turnover of cellular calcium (influx plus efflux) during the first 2 min of noradrenaline contact was much greater than that produced by PGF2α, largely due to a greater effect of noradrenaline on calcium efflux.

The results suggest that PGF2α‐ but not noradrenaline‐induced contractions are entirely dependent on the influx of extracellular calcium and that the agonists may stimulate calcium gating mechanisms differently.
PROSTACYCLIN CAN EITHER INCREASE OR DECREASE HEART RATE DEPENDING ON THE BASAL STATE
Authors: CHIAVARELLI M. , MONCADA S. , MULLANE K.M.
Published: July 2012

The influence of the basal heart rate on the change in rate induced by prostacyclin (PGI2) was investigated in beagles anaesthetized with chloralose.

In male dogs with a low basal heart rate (<100 beats/min) PGI2, in doses up to 0.5 μg/kg intravenously, induced hypotension and tachycardia.

In contrast, PGI2‐induced hypotension was accompanied by bradycardia when either the basal heart rate was increased (> 130 beats/min) with isoprenaline or nitroprusside, or the dose of PGI2 was increased.

Female beagles were less sensitive than males to the stimulation of a reflex bradycardia by PGI2.

The influence of prostaglandin E2 (PGE2) and bradykinin on heart rate was also found to depend upon the basal state in some dogs.

Bilateral vagotomy reversed the bradycardia provoked by PGI2, PGE2 and bradykinin.

Thus, PGI2‐induced bradycardia is dependent on both the dose and the basal heart rate. Similarly the effects of PGE2 and bradykinin on heart rate also depend upon the basal state in some dogs. Moreover, there is a correlation between the ability of all three agonists to induce bradycardia, suggesting a common mechanism of action.
DIFFERENTIAL INHIBITION BY ADENOSINE OR BY PROSTAGLANDIN E1 OF HUMAN PLATELET AGGREGATION INDUCED BY ADENOSINE 5′‐O‐(1‐THIODIPHOSPHATE) AND ADENOSINE 5′‐O‐(2‐THIODIPHOSPHATE)
Authors: CUSACK N.J. , HOURANI S.M.O.
Published: July 2012

Adenosine 5′‐diphosphate (ADP) induces human platelet aggregation and inhibits stimulated adenylate cyclase. Adenosine 5′‐O‐(1‐thiodiphosphate) (ADP‐α‐S) and adenosine 5′‐O‐(2‐thiodiphosphate) (ADP‐β‐S) act at the ADP receptor and achieve the same maximal rate of human platelet aggregation as each other. Adenosine and prostaglandin E1, which noncompetitively inhibit ADP‐induced aggregation by stimulating adenylate cyclase, inhibit aggregation induced by ADP‐α‐S more than aggregation induced by ADP‐β‐S. ADP‐α‐S, unlike ADP‐β‐S and ADP itself, does not inhibit stimulated adenylate cyclase. This suggests that the inhibition of stimulated adenylate cyclase by ADP, although not a cause of aggregation, may be of physiological importance in reducing the effects of endogenous agents such as adenosine and prostaglandins (for example, prostacyclin) to which the platelet may be exposed.

Although the inhibition by ADP of adenylate cyclase cannot be the cause of aggregation, it could limit the inhibitory effects of agents such as PGE1 and adenosine which activate adenylate cyclase. The observation that PGE1 and adenosine are more powerful inhibitors of aggregation induced by vasopressin than by ADP (Haslam & Rosson, 1972), is consistent with this suggestion, although ADP and vasopressin do not act at the same receptor (Macfarlane & Mills, 1975). The differential effects on adenylate cyclase of ADP‐α‐S and ADP‐β‐S, which both act at the ADP receptor (Cusack & Hourani, 1981a,b), provides the first opportunity to investigate whether inhibition of adenylate cyclase by ADP receptor agonists can limit the effects on aggregation of inhibitors such as adenosine and PGE1.
THE ACTION OF GENERAL ANAESTHETICS ON ACETYLCHOLINE‐INDUCED INHIBITION IN THE CENTRAL NERVOUS SYSTEM OF Helix
Authors: JUDGE SUSAN E. , NORMAN J.
Published: July 2012

The effects of general anaesthetics, thiopentone, etomidate, minaxolone and ketamine were studied on identified voltage‐clamped neurones of Helix aspersa.

At concentrations of 0.1–0.5 mm, thiopentone, etomidate and minaxolone had no effect on the resting conductance of identified cells, D1 and D2. Ketamine at a concentration of 0.1–0.5 mm depolarized and excited the cells.

All four anaesthetics tested depressed a chloride‐dependent inhibitory response to acetylcholine (ACh) in cells D1 and D2 at concentrations of 0.1–0.5 mm in a dose‐dependent and reversible manner with no change in the reversal potential of the response.

These results show that general anaesthetics can block the transmitter‐evoked chloride‐mediated increases in membrane conductance in Helix neurones.
CHOLINERGIC ACTION IN THE NUCLEUS ACCUMBENS: MODULATION OF DOPAMINE AND ACETYLCHOLINE RELEASE
Authors: DE BELLEROCHE J.S. , GARDINER I.M.
Published: July 2012

The action of oxotremorine and acetylcholine on the release of dopamine and acetylcholine from tissue slices of the rat nucleus accumbens was studied.

Oxotremorine significantly enhanced the release of [14C]‐dopamine evoked by 34 mmK+ and the EC50 for this action was 1.5 × 10−7 m. A maximal enhancement (30%) for this effect was reached at 2 × 10−7 m oxotremorine. A further enhancement of dopamine release occurred at concentrations of oxotremorine greater than 10−4 m.

The action of oxotremorine on [14C]‐dopamine release was calcium‐dependent and blocked by atropine (10−4 m) but not mecamylamine (up to 10−4 m).

Oxotremorine affected [3H]‐acetylcholine release differentially, inhibiting the K+‐evoked release of [3H]‐acetylcholine at concentrations greater than 10−5m. The IC50 for this process was 4.3×10−5m.

Acetylcholine (8 × 10−4 m) showed a similar pattern of action to oxotremorine: it enhanced the K+‐evoked release of [14C]‐dopamine (50%) and inhibited the K+‐evoked release of [3H]‐acetylcholine (30%).

The mechanism of action of oxotremorine on dopamine release is discussed in terms of a presynaptic receptor‐mediated process.