bluuebunny/crossref_metadata_2025_split huggingface dataset:
INTERACTIONS OF DRUGS ACTIVE AT OPIATE RECEPTORS AND DRUGS ACTIVE AT α2‐RECEPTORS ON VARIOUS TEST SYSTEMS
Authors: BROWNING S. , LAWRENCE D. , LIVINGSTON A. , MORRIS B. 
Published: July 2012

The actions of the opiate receptor drugs, morphine, methionine‐enkephalin (Met‐enkephalin) and naloxone were compared with the actions of the α2‐receptor drugs, clonidine, xylazine and yohimbine on analgesic tests, in vitro bioassay (guinea‐pig ileum and mouse vas deferens), and radioligand displacement studies on rat brain membrane preparations.
Both opiate and α2‐agonist drugs showed analgesic activity but whilst the α2‐agonist analgesic activity was antagonized by only α2‐antagonists, the analgesic activity of morphine was antagonized by both naloxone and yohimbine. In the in vitro tests, both groups of agonists inhibited electrically evoked activity; however in these experiments only antagonism of opiates by naloxone and α2‐agonists by yohimbine could be shown and it is concluded that in these systems the activity of the α2‐agonists is mediated via the presynaptic α2‐receptors only.
In the radioligand studies the drugs acting at α2‐receptors were active in the micromolar range at displacing labelled opioid ligands but opiates did not displace labelled α2‐ligands.
It is concluded that drugs which act on α2‐receptors interfere with the in vivo analgesic effects of opiates and weakly displace opioid radioligand binding, but opioids do not affect α2 agonist analgesia and do not appear to displace α2‐agonist radioligand binding.
THE EFFECT OF CHEMICAL SYMPATHECTOMY ON MITOCHONDRIAL FUNCTION IN THE ISCHAEMIC AND REPERFUSED MYOCARDIUM
Authors: NAYLER WINIFRED G. , SCOTT ELIZABETH M. 
Published: July 2012

Isolated rabbit hearts were perfused aerobically for 120 min, made ischaemic for 90 min, or made ischaemic for 90 min and then reperfused for 30 min.Some rabbits were pretreated with 6‐hydroxydopamine (6‐OHDA), given as three separate intravenous doses of 30, 20 and 20 mg/kg, 20 to 48 h before they were killed; others (controls) received saline according to the same regime.Mitochondria were harvested from left ventricular homogenates and their function assessed by measuring state 3 O2consumption (state 3QO2), respiratory control index (RCI), phosphate: oxygen ratio (ADP:O), Ca2+content, and ATP‐producing activity. In other experiments peak left ventricular developed tension was recorded.In hearts from saline‐treated animals, mitochondrial state 3QO2, RCI and ATP producing activities were reduced after global ischaemia, with or without reperfusion. There was a small gain in mitochondrial Ca2+after ischaemia, and a large gain upon reperfusion.6‐OHDA pretreatment provided some protection against the effects of ischaemia and reperfusion on mitochondrial function and on peak developed tension.It was concluded that chemical sympathectomy with 6‐OHDA does not duplicate the effect of prolonged β‐adrenoceptor blockade in protecting mitochondrial function against the deleterious effects of ischaemia and reperfusion.
GABAA and GABAB receptor‐mediated effects in guinea‐pig ileum
Authors: Giotti A. , Luzzi S. , Spagnesi S. , Zilletti Lucilla 
Published: July 2012

The effects of γ‐aminobutyric acid (GABA) and related substances were examined in guinea‐pig ileum longitudinal muscle.
GABA at doses ranging from 10−7 m to 3 m 10−6 m elicited a relaxation while at higher doses (3 × 10−6 m — 10−4 m), as previously described, it caused a contraction followed by relaxation.
GABA‐induced relaxation was bicuculline‐insensitive, was mimicked by (—)‐baclofen but not by homotaurine and muscimol. The effect of baclofen was stereospecific. GABA‐ and (—)‐baclofen‐induced relaxations were dose‐dependent and their ED50 values were similar. A specific cross‐desensitization occurred between GABA and (—)‐baclofen.
The bicuculline‐insensitive relaxation induced by GABA and (—)‐baclofen was prevented by tetrodotoxin and hyoscine but not by phentolamine plus propranolol, naloxone or theophylline.
In preparations in which the muscle tone was raised by histamine or prostaglandin F2α, GABA and (—)‐baclofen induced relaxation to the same extent as before increasing the tone. If the tone was raised by DMPP, a greater bicuculline‐insensitive relaxation occurred.
Contraction caused by GABA was bicuculline‐sensitive and was mimicked by homotaurine and muscimol. Contraction was dose‐dependent and muscimol was about three times more potent than GABA or homotaurine. A specific cross‐desensitization occurred between the contractile effects of GABA and those of homotaurine or muscimol.
Bicuculline competitively antagonized the contractile effects of GABA, homotaurine and muscimol and gave closely similar pA2 values. The slope of the Schild plot for the above drugs was near 1, confirming the competitive nature of the antagonism.
The bicuculline‐sensitive contraction induced by GABA, homotaurine and muscimol was abolished by tetrodotoxin and was non‐competitively antagonized by hyoscine, while it was unaffected by hexamethonium, mepyramine and methysergide.
It is concluded that two receptors mediate the GABA effects in guinea‐pig ileum: a bicuculline‐sensitive GABAA receptor, which elicits contraction through an excitatory action on cholinergic post‐ganglionic neurones; and a bicuculline‐insensitive GABAB receptor which causes relaxation through an inhibitory presynaptic action on cholinergic post‐ganglionic neurones. We confirm that GABA, homotaurine and muscimol are GABAA agonists, while GABA and (—)‐baclofen are GABAB agonists.
Hypotensive and α‐adrenergic activities of 2‐(2,3,6‐trichlorophenylimino) and 2‐(2,3‐dichloro‐6‐methylphenylimino) imidazolidine, two potent derivatives of clonidine
Authors: DE Jonge A. , Timmermans P.B.M.W.M. , van Zwieten P.A. 
Published: July 2012

α‐Adrenergic activities (hypotension, bradycardia, sedation) and affinities of clonidine and two newly substituted derivatives, 2‐(2,3,6‐trichlorophenylimino)imidazolidine (I) and 2‐(2,3‐dichloro‐6‐methylphenylimino)imidazolidine (II), were determined in various in vivo and in vitro models.
In anaesthetized normotensive rats, the intravenous —log doses (mol/kg) of clonidine, compound I and II required to decrease mean arterial pressure by 20% were 7.96, 8.39 and 7.79, respectively, and to reduce heart rate by 20% were 7.85, 8.23 and 7.91, respectively. Comparable potencies were obtained in vagotomized rats. Following vertebral arterial infusion of clonidine, compound I and II into anaesthetized cats, the —log doses for 20% diminution in mean arterial pressure were 8.72, 9.17 and 7.92, respectively.
In pithed normotensive rats, the intravenous —log doses (mol/kg) of clonidine, compound I and II required to elevate diastolic pressure by 50 mmHg were 7.49, 7.80 and 8.04, respectively, whereas 50% of the maximal inhibition of electrical stimulation‐induced tachycardia was obtained at —log doses of 8.20, 8.25 and 8.34, respectively.
In mice, the intraperitoneal ‐log doses (mol/kg) needed for a prolongation of the hexobarbitone‐induced loss of the righting reflex by 100% were 6.51, 6.55 and 6.60 for clonidine, compound I and II, respectively.
Compounds I and II displayed a higher affinity for α1‐ and α2‐adrenoceptors than clonidine, identified in rat cerebral membranes by [3H]‐prazosin and [3H]‐clonidine.
The results show that 2,3,6‐trisubstituted derivatives of clonidine are potent α‐adrenoceptor stimulants. This new class of congeners may have potential for pronounced hypotensive activity following systemic application. It is not likely that among members of this series, hypotensive potency can be separated from sedative activity.
Comparison of the effects of the hypolipidaemic agents ICI 53072 and clofibrate with those of phenobarbitone on liver size, blood flow and DNA content in the rat
Authors: Berman J. S. , Hiley C. R. , Wilson A. C. 
Published: July 2012

The effects of the hypolipidaemic agents ICI 53072 and clofibrate on cardiac output and its distribution to the hepatosplanchnic bed were determined by the use of radioactive microspheres in the rat. The effects of these agents on hepatic DNA content were compared with those of phenobarbitone. Also the effects of ICI 53072 on hepatic microsomal enzymes and bile flow were determined together with the effects of phenobarbitone.
ICI 53072 and clofibrate both increased liver size and liver blood flow. A daily dose of 25 mg kg−1 ICI 53072 for 5 days increased liver weight by 55% and liver blood flow by 43%, the latter by enhancing the proportion of cardiac output passing to the hepatosplanchnic bed. The increased liver blood flow with clofibrate (480 mg kg−1 daily for 5 days) was the result of greater cardiac output but the change (35%) was half the increase in liver weight.
Phenobarbitone (80 mg kg−1 daily for 5 days) produced a fall in DNA content per unit mass of liver but no change in hepatic DNA relative to body weight. ICI 53072 (25 mg kg−1 daily) increased hepatic DNA relative to body weight but by a lesser extent than it increased liver weight as a proportion of body weight; hence DNA content per unit mass of liver decreased. Clofibrate at three dose levels increased hepatic DNA relative to body weight but only one dose significantly decreased DNA content as a proportion of liver weight.
Phenobarbitone (80 mg kg−1 daily) increased bile flow whereas ICI 53072 (25 mg kg−1 daily) had no effect. Both treatments increased hepatic cytochrome P450 content and cytochrome c reductase activity.
It is concluded that phenobarbitone increases liver size by hepatocyte enlargement rather than cellular proliferation but that the hepatomegaly produced by the hypolipidaemic agents, at least at some doses, is due to a mixture of both processes.
It is further concluded that there is no simple relationship between the mechanism of hepatic enlargement resulting from drug treatment and changes in liver blood flow.
Effects of some antiepileptic drugs on the repetitive activity of the node of Ranvier
Authors: Carratú Maria R. , DI Giovanni V. , Mitolo‐Chieppa Delia 
Published: July 2012

Effects of some antiepileptic drugs on the repetitive activity of the node of Ranvier have been tested on frog myelinated nerve fibres.
Nerve fibres were stimulated by supraliminal direct current pulses of long duration. Motor fibres responded with a single action potential; sensory fibres responded with repetitive firing at a frequency of about 300/s. Chlordiazepoxide hydrochloride (0.1 mm), phenobarbitone sodium (0.25 mm) or diphenylhydantoin sodium (0.5 mm) suppressed the repetitive activity.
Sensory and motor nerve fibres stimulated by a 10 kHz alternating current of strength twice the threshold responded with repetitive firing at a frequency of 400–500/s. Superfusion of the node with chlordiazepoxide hydrochloride (0.2 mm), phenobarbitone sodium (0.5 mm) or diphenylhydantoin sodium (1.7 mm) reduced the frequency of firing by 50% either in sensory or in motor fibres activated by a.c. stimulation; at the same concentrations, the drugs altered amplitude of the action potential and threshold for electric excitability by less than 10%.
Unlike local anaesthetics, chlordiazepoxide, phenobarbitone and diphenylhydantoin are more selective in inhibiting repetitive firing than in reducing the amplitude of the action potential or increasing the threshold for electric excitability.
Trimethadione (up to 5 mm) was ineffective on repetitive firing elicited either with direct or with alternating current.
Baclofen blocks postsynaptic inhibition but not the effect of muscimol in the olfactory cortex
Authors: Scholfield C.N. 
Published: July 2012

The olfactory cortex slice preparation from the guinea‐pig brain was used to study the effects of baclofen on inhibition using intracellular recording. Stimulation of the lateral olfactory tract activates sequentially excitatory and inhibitory pathways. Inhibition is manifest as a period of increased membrane conductance (termed postsynaptic inhibitory conductance, IPSC).
Bath application of baclofen (0.2–500 μm) reversibly blocked the IPSC. Baclofen also produced a secondary increase in the amplitude and duration of the initial excitatory postsynaptic potential.
Baclofen (0.5–500 μm) slightly augmented the ability of bath‐applied muscimol to increase the resting membrane conductance. Baclofen had no effect on cell excitability and membrane potential and no effect on the action of γ‐aminobutyric acid (GABA), noradrenaline, glycine, taurine or 5‐hydroxytrypamine.
These results confirm previous suggestions that baclofen at low concentrations acts outside the GABA receptor mediating the IPSC perhaps by reducing the release of the excitatory transmitter activating the inhibitory interneurones.
Characteristics of GABAB receptor binding sites on rat whole brain synaptic membranes
Authors: Bowery N.G. , Hill D.R. , Hudson A.L. 
Published: July 2012

Saturable binding of (±)‐[3H]‐baclofen and [3H]‐γ‐aminobutyric acid ([3H]‐GABA) to rat brain crude synaptic membranes has been examined by means of a centrifugation assay.
The binding of [3H]‐baclofen could be detected in fresh or previously frozen tissue and was dependent on the presence of physiological concentrations of Ca2+ or Mg2+ although a lower affinity Na+‐dependent component could also be observed. Both components probably reflect binding to receptor recognition sites.
The saturable portion of bound [3H]‐baclofen formed 20.3 ± 6.9% of total bound ligand. This could be displaced by GABA (IC50 =.0.04 μm), (−)‐baclofen (0.04 μm) and to a much lesser extent by (+)‐baclofen (33 μm). Isoguvacine, piperidine‐4‐sulphonic acid and bicuculline methobromide were inactive (up to 100 μm) and muscimol was only weakly active (IC50 = 12.3 μm).
Saturable binding of [3H]‐GABA increased on adding CaCl2 or MgSO4 (up to 2.5 mm and 5.0 mm respectively) to the Tris‐HCl incubation solution. This binding (GABAB site binding) was additional to the bicuculline‐sensitive binding of GABA (GABAA site binding) and could be completely displaced by (−)‐baclofen (IC50 = 0.13 μm).
Increasing the Ca2+ concentration (0 to 2.5 mm) increased the binding capacity of the membranes without changing their affinity for the ligand.
The binding of [3H]‐GABA to GABAB sites could be demonstrated in fresh as well as previously frozen membranes with a doubling of the affinity being produced by freezing. Further incubation with the non‐ionic detergent Triton‐X‐100 (0.05% v/v) reduced the binding capacity by 50%.
The pharmacological profile of displacers of [3H]‐GABA from GABAB sites correlated well with that for [3H]‐baclofen displacement. A correlation with data previously obtained in isolated preparations of rat atria and mouse vas deferens was also apparent.
It is concluded that [3H]‐baclofen or [3H]‐GABA are both ligands for the same bicuculline‐insensitive, divalent cation‐dependent binding sites in the rat brain.
Evidence for an Ax‐adenosine receptor in the guinea‐pig atrium
Authors: Collis M.G. 
Published: July 2012

The purpose of this study was to determine whether the adenosine receptor that mediates a decrease in the force of contraction of the guinea‐pig atrium is of the A1‐ or A2‐sub‐type.
Concentration‐response curves to adenosine and a number of 5′‐ and N6‐substituted analogues were constructed and the order of potency of the purines was: 5′‐N‐cyclopropylcarboxamide adenosine (NCPCA) = 5′‐N‐ethylcarboxamide adenosine (NECA) >N6cyclohexyladenosine (CHA) > L‐N6‐phenylisopropyl adenosine (l‐PIA) = 2‐chloroadenosine > adenosine > D‐N6‐phenylisopropyl adenosine (d‐PIA).
The difference in potency between the stereoisomers d‐ and l‐PIA was over 100 fold.
The adenosine transport inhibitor, dipyridamole, potentiated submaximal responses to adenosine but had no significant effect on those evoked by the other purines.
Theophylline antagonized responses evoked by all purines, and with d‐PIA revealed a positive inotropic effect that was abolished by atenolol.
The results indicate the existence of an adenosine Ai‐receptor in the guinea‐pig atrium.
The influence of maternal protein deficiency on the placental transfer of salicylate in rats
Authors: Varma Daya R. , Yue Tian‐Li 
Published: July 2012

The influence of a low protein diet (5% as compared with a control 21% protein diet) on the placental transfer of sodium salicylate was investigated in Sprague‐Dawley rats on day 20 of gestation.
Maternal plasma salicylate concentrations (assayed by high pressure liquid chromatography) were generally lower in protein‐deficient than in control animals at a wide range of times (0.25–12 h) and dose levels (2–250 mg/kg, i.V.); however, foetal plasma salicylate levels in the two groups of animals did not differ.
The placental transfer of salicylate as indicated by the ratio of foetal plasma or foetal liver to maternal plasma salicylic acid concentration was consistently and significantly greater in the protein‐deficient group than in the control group of animals following the administration of the drug to the mother as well as to the foetus.
A decrease in calorie without a concomitant decrease in protein intake (pair‐fed controls) did not alter the placental transfer of salicylate.
The increased placental transfer of salicylate in protein‐deficient animals could not be attributed to changes in serum protein‐salicylate binding.
It is suggested that the pharmacokinetic factors responsible for maintaining a lower level of salicylate in the foetus than in the mother are impaired by maternal malnutrition, and this may increase the foetal effects of maternally ingested salicylate.
In vivo release of [3H]‐purines by quinolinic acid and related compounds
Authors: Perkins M. N. , Stone T. W. 
Published: July 2012

In vivo release of [3H]‐purines from the cortex of anaesthetized rats was measured and the actions of excitatory amino acids and analogues investigated.
High KCl, N‐methyl‐dl‐aspartate (NMDLA) and quinolinic acid produced a large increase in basal release of labelled materials. Glutamate, quisqualate and kainate had less effect.
The N‐methyl‐d‐aspartic acid (NMDA)‐preferring receptor antagonist, 2‐amino‐7‐phosphono‐heptanoic acid, significantly reduced the release evoked by NMDLA and quinolinate but not that produced by the other agonists.
Kynurenic acid, a compound metabolically related to quinolinic acid, reduced the release due to NMDLA and quinolinate but not glutamate.
The results add further support to the suggestion that quinolinic acid acts on the NMDA‐preferring receptor.
Induction of zymosan‐air‐pouch inflammation in rats and its characterization with reference to the effects of anticomplementary and anti‐inflammatory agents
Authors: Konno Satoshi , Tsurufuji Susumu 
Published: July 2012

Induction of an experimental inflammation of the air‐pouch type with the aid of zymosan (known to activate the alternative pathway of the complement system) was carried out in an attempt to induce a reproducible inflammatory model suitable for quantitative studies.
Rats were injected subcutaneously with 8 ml of air on the dorsal surface to make an air‐pouch, followed 24 h later by 4 ml of 1.6% (w/v) zymosan suspension. This induced inflammatory responses.
Treatment with zymosan suspension provoked exudation of fluid, accumulation of polymorphnuclear leukocytes (PMN) in the pouch and the development of granulation tissue as a wall of the pouch. Approximately half of the PMN in the pouch formed a characteristic layer of aggregated cells sticking onto the inner surface of the pouch wall. They were counted after being completely disaggregated by means of incubation with trypsin.
In preliminary experiments with potential anti‐inflammatory drugs, local application of a novel anti‐complementary agent, K‐76COONa, inhibited leukocyte accumulation in the pouch, whereas the potent anti‐inflammatory agent, dexamethasone, was ineffective. By contrast, exudation of the pouch fluid was effectively inhibited by dexamethasone but not by K‐76COONa.
The effect of a selective 5‐HT2 antagonist, ketanserin, on the pulmonary responses to Escherichia coli endotoxin
Authors: Ball H.A. , Parratt J.R. , Rodger I.W. 
Published: July 2012

5‐Hydroxytryptamine (5‐HT, 5–160 μg kg−1) injected intravenously in pentobarbitone‐anaesthetized, open‐chest cats caused dose‐dependent increases in pulmonary arterial and intratracheal pressures. There was also a marked systemic hypotension and bradycardia. The pulmonary effects were completely prevented by ketanserin (0.2 mg kg−1), a selective 5‐HT2 blocking drug.
Ketanserin (0.2 mg kg−1) itself lowered arterial pressure (by 30–40 mmHg) but this systemic hypotension was relatively transient.
Endotoxin (E. coli) administration resulted in pulmonary hypertension, increases in intratracheal pressure and airways resistance and reductions in lung compliance and in arterial P. Only the airways resistance response was modified by ketanserin (0.2 mg kg−1), suggesting a relatively unimportant role for 5‐HT in mediating the acute, pulmonary effects of endotoxin in this species.
The reductions in arterial (mixed venous) pH and in P that resulted from endotoxin administration were not affected by pretreatment with ketanserin.
The effects of (+)‐amphetamine, α‐methyltyrosine, and α‐methylphenylalanine on the concentrations of m‐tyramine and α‐methyl‐m‐tyramine in rat striatum
Authors: Dougan D.F.H. , Duffield A.M. , Duffield P.H. , Wade D.N. 
Published: July 2012

The concentration in rat striatum of the meta and para isomers of tyramine and α‐methyltyramine, after the administration of (+)‐amphetamine, α‐methyl‐p‐tyrosine (AMPT) and α‐methylphenylalanine (AMPA) has been determined using chemical ionization gas chromatography mass spectrometry (c.i.g.c.m.s.).
Twenty hours after the last of 7 daily injections of (+)‐amphetamine (5 mg kg−1 i.p.) the concentration of α‐methyl‐p‐tyramine in striatal tissue increased twofold compared to the concentration 20 h after a single injection. In contrast the concentration of α‐methyl‐m‐tyramine did not change.
α‐Methyl‐m‐tyramine and α‐methyldopamine were found in the striatum at concentrations of 42 ng g−1 and 13.5 ng g−1 respectively after treatment of rats 20 h before with AMPA (100 mg kg−1 i.p.). After treatment with AMPT (100 mg kg−1, 20 h before decapitation) only the para isomer of α‐methyltyramine could be detected (13.7 ng g−1) although the striatal concentration of α‐methyldopamine was 274 ng g−1, a level 20 times greater than that observed after AMPA treatment. The combined administration of both AMPT and AMPA (100 mg kg−1 each, 20 h) resulted in a reduction of the striatal concentration of α‐methyl‐m‐tyramine but not α‐methyl‐p‐tyramine.
These data suggest that α‐methyl‐m‐tyramine in rat striatum is formed by the enzyme tyrosine hydroxylase on substrate AMPA, rather than by ring dehydroxylation of α‐methyldopa and ***α‐methyldopamine. Significant reductions in the striatal concentrations of m‐tyramine 2 h after the administration of AMPT, suggest that tyrosine hydroxylase is involved similarly in the production of m‐tyramine.
Effect of hypothermia on β1‐adrenoceptor‐mediated relaxation of pig bronchus
Authors: Foster Paul S. , Goldie Roy G. , Paterson James W. , Spina Domenico 
Published: July 2012

The relaxant potencies of (±)‐isoprenaline and of (−)‐noradrenaline (NA) in the pig isolated bronchus were increased 5.4 and 3.1 fold respectively by lowering the organ bath temperature from 37°C to 27°C, whereas the potencies of the non‐catecholamine β‐adrenoceptor agonists fenoterol and orciprenaline were not significantly changed.
At 37°C, the catechol‐O‐methyl transferase (COMT) inhibitor U‐0521 (30 μm), caused a 7.2 fold increase in the potency of isoprenaline but had no effect on the potency of fenoterol. At 27°C the potency of isoprenaline was similar in the absence or presence of U‐0521 (30 μm). Furthermore, in bronchi where extraneuronal uptake was inhibited by phenoxybenzamine, the potency of NA was not significantly altered by reducing bathing temperature from 37°C to 27°C.
These results suggest that the hypothermic potentiation of isoprenaline in pig bronchus resulted from inhibition of COMT or of access to COMT, rather than from sensitization of β1‐adrenoceptors.