bluuebunny/crossref_metadata_2025 huggingface dataset:
THE EFFECTS OF PARAOXON ON BLOOD PRESSURE IN THE ANAESTHETIZED AND IN THE CONSCIOUS RAT
Authors: DE NEEF J.H. , JORDAAN K.M. , PORSIUS A.J.
Published: July 2012

Intravenous administration of paraoxon (150–825 μg/kg) to anaesthetized rats induced long‐lasting, dose‐dependent pressor effects. Only after injection of 825 μg/kg paraoxon was the pressor response followed by a depressor effect and a bradycardia that could be blocked by N‐methylatropine. Intracerebroventricular injection of paraoxon into anaesthetized rats also induced pressor effects.

In order to elucidate the mechanism of the pressor action rats were given dexetimide, N‐methylatropine, mecamylamine, phentolamine, prazosin, yohimbine, atenolol and metoprolol. If treatment with these drugs resulted in a low initial blood pressure, vasopressin was infused to elevate blood pressure to normal levels. The influence of adrenalectomy, pretreatment with reserpine and midcollicular transection was also examined.

The pressor effect of paraoxon was not influenced by N‐methylatropine or mecamylamine. However, a combination of these drugs as well as dexetimide, phentolamine or prazosin combined with yohimbine, reduced or prevented the pressor effect.

In conscious rats the effects of paraoxon and the action of antimuscarinic drugs upon the pressor response were similar to those observed in anaesthetized animals.

Acetylcholinesterase activities were measured in various brain regions and in whole blood. Paraoxon concentrations within the CNS were also measured.

It is concluded that the pressor effect of paraoxon in anaesthetized and conscious rats is mediated by a central mechanism, although a contribution of peripheral acetylcholinesterase inhibition in sympathetic ganglia to this pressor effect cannot be ruled out.
THE PRESSOR EFFECTS OF PARAOXON IN THE PITHED RAT
Authors: DE NEEF J.H. , PORSIUS A.J.
Published: July 2012

In pithed rats paraoxon 825 μg/kg induced a short‐lasting pressor effect. Lower doses of the drug were ineffective.

The pressor effect was prevented by N‐methylatropine, dexetimide and α‐receptor blocking agents but not by mecamylamine.

When blood pressure of pithed rats was elevated either by the continuous infusion of vasopressin or by electrical stimulation of the pithing rod, both 275 and 825 μg/kg paraoxon induced further pressor effects. The effectiveness of various receptor blocking agents was similar to that observed in pithed rats without vasopressin.

It is concluded that the pressor effect of paraoxon is mediated by ganglionic muscarinic receptors. Stimulation of these receptors by accumulated acetylcholine results in an increase in postganglionic sympathetic activity and causes pressor effects.

The peripheral action of paraoxon is compared with its action in intact anaesthetized animals.
MODULATION OF BRONCHOCONSTRICTOR RESPONSES TO HISTAMINE IN PITHED GUINEA‐PIGS BY SYMPATHETIC NERVE STIMULATION
Authors: AINSWORTH GILLIAN A. , GARLAND L.G. , PAYNE A.N.
Published: July 2012

Electrical stimulation (40V, 0.5–8 Hz, pulse width 0.5 ms) of the thoracic spinal outflow for between 10 and 120 s inhibited histamine‐induced bronchoconstriction in pithed guinea‐pigs.

The degree of this bronchodilatation varied with the position of the stimulating electrode within the spinal canal. Two maxima were identified. The first, at the level of the 9th and 10th thoracic vertebrae, was abolished by adrenalectomy. The second, at the level of the 3rd and 4th thoracic vertebrae, was associated with tachycardia and was unchanged by adrenalectomy.

The magnitude of this second bronchodilator effect varied with the frequency of stimulation. It was abolished by pretreatment with reserpine (5 mg/kg i.p. 48 and 24 h beforehand) and was competitively blocked by propranolol (0.01–1.0 mg/kg).

These observations are consistent with the view that bronchodilator tone is derived from neuronally‐released noradrenaline within the lung. The noradrenaline probably overflows from well‐innervated vasculature adjacent to sparsely innervated airways.
THE EFFECTS OF MONOVALENT AND DIVALENT CATIONS ON THE α‐ADRENOCEPTOR OF INTACT HUMAN PLATELETS
Authors: ELLIOTT J.M. , GRAHAME‐SMITH D.G.
Published: July 2012

We have examined the effects of smonovalent and divalent cations and purine nucleotides on the binding of agonists and antagonists to the α‐adrenoceptor of intact human platelets.

Replacement of Na+ (150 mm) by NH4+ (150 mm) in the incubation medium significantly reduced the binding affinity of [3H]‐dihydroergocryptine (P<0.05) but did not alter the binding capacity. The competitive binding affinity of adrenaline and noradrenaline was unaltered.

The addition of Ca2+ (1 mm) or Mg2+ (1 mm) to the platelet suspension significantly reduced the platelet α‐adrenoceptor capacity as indicated by either [3H]‐dihydroergocryptine (P<0.05) or [3H]‐yohimbine (P<0.01; Ca2+ only).

The addition of Ca2+ (1 mm) or Mg2+ (1 mm) had no effect on the binding affinity of [3H]‐dihydroergocryptine but significantly reduced that of [3H]‐yohimbine (P<0.05). The competitive affinity of adrenaline and noradrenaline determined by inhibition of [3H]‐dihydroergocryptine binding, was unchanged in the presence of either cation.

Addition of the purine nucleotides ADP, ATP, GDP or GTP (final concentration 10 μm), either alone or in the presence of 1 mm Ca2+ or 1 mm Mg2+, had no effect on the binding of [3H]‐dihydroergocryptine or on the competitive affinity of adrenaline or noradrenaline.

We conclude that the α‐adrenoceptor of intact human platelet displays the binding characteristics of the α2L form of the receptor previously identified in the platelet lysate preparation.
THE USE OF LOW CONCENTRATIONS OF DIVALENT CATIONS TO DEMONSTRATE A ROLE FOR N‐METHYL‐D‐ASPARTATE RECEPTORS IN SYNAPTIC TRANSMISSION IN AMPHIBIAN SPINAL CORD
Authors: SMITH PETER A.
Published: July 2012

Synaptic potentials and the responses of frog spinal cord to various acidic amino acids were examined by means of the sucrose gap recording technique.

Divalent cations (50–250 μm) specifically antagonized responses evoked at N‐methyl‐d‐aspartate (NMDA) receptors by N‐methyl d,l aspartic acid (NMDLA). The rank order of potency was Ni2+ > Co≫2+ > Mg2+ > Mn2+. Responses to glutamate and aspartate were relatively insensitive to these concentrations of divalent cations.

The rank order of potency for divalent ions (1 mm) for antagonism of synaptic transmission in bullfrog sympathetic ganglia was Mn2+ ≫ Co2+ > Ni2+ ≫ Mg2+. Thus synaptic transmission in ganglia was especially sensitive to Mn2+ whereas NMDLA responses were especially sensitive to Co2+ and Mg2+.

It was possible to depress selectively the dorsal root‐dorsal root potential (DR‐DRP) and dorsal root‐ventral root potential (DR‐VRP) of frog spinal cord using low doses of Co2+ or Mg2+ which did not affect VR‐DRP (ventral root‐dorsal root potential). It was not possible to produce this selective depression of DR‐DRP and DR‐VRP with Mn2+, as this cation non‐selectively depressed all responses.

These results suggest that: (i) divalent cations do not antagonize NMDLA responses by blocking Ca2+ channels which may mediate the response; (ii) postsynaptic NMD A receptors are activated by a neurotransmitter involved in the DR‐DRP and DR‐VRP pathways but not by any neurotransmitters involved in the VR‐DRP pathway; (iii) the neurotransmitter activating NMDA receptors in amphibian spinal cord may be an aspartate‐like substance rather than aspartate itself or glutamate.
HISTAMINE H2‐ANTAGONISTS MODIFY GASTRIC EMPTYING IN THE RAT
Authors: BERTACCINI G. , SCARPIGNATO C.
Published: July 2012

Histamine H2‐receptor antagonists were tested for their effect on gastric emptying in the rat.

At low doses all the compounds were inactive except for burimamide which delayed and ranitidine which accelerated gastric emptying.

At high doses burimamide, metiamide, Cimetidine and oxmetidine delayed, whereas ranitidine accelerated gastric emptying; tiotidine remained ineffective.

Changes in emptying rate were not accompanied by changes in emptying pattern which, with all the compounds examined, proceeded, as in the controls, by apparent first order kinetics.

The mechanism of the ranitidine‐induced acceleration of gastric emptying seemed to be connected with an interference with the cholinergic system, whereas the mechanism of cimetidine‐ and oxmetidine‐induced slowing of gastric emptying was apparently related to cholinolytic and possibly also relaxant effects of the compounds.

These different effects of the various H2‐blockers are consistent with the idea that changes in emptying rate are independent of H2‐receptor blockade.
SPECTRUM OF THE μ‐, δ‐ AND κ‐BINDING SITES IN HOMOGENATES OF RAT BRAIN
Authors: GILLAN M.G.C. , KOSTERLITZ H.W.
Published: July 2012

In homogenates of rat brain, the binding characteristics of tritiated opiates and opioid peptides were examined and the relative capacities of μ‐, δ‐ and κ‐binding sites of the opiate receptor determined by saturation analysis.

In competition experiments, binding of the selective μ‐ligand [3H]‐[d‐Ala2,MePhe4,Gly‐ol5]enkephalin at the μ‐site was displaced by [d‐Ala2,d‐Leu5]enkephalin with rather low affinity (KI = 12.6 nm) and more readily by the ketazocine‐like compounds (−)‐ethylketazocine (KI = 3.1 nm) and (−)‐bremazocine (KI = 0.32 nm), which also displaced the binding of [3H]‐[d‐Ala2,d‐Leu5]enkephalin from the δ‐site. In contrast, the binding to the κ‐site was easily displaced by ethylketazocine (1.0 nm) and bremazocine (0.37 nm) but not by the μ‐ligand [d‐Ala2,MePhe4,Gly‐ol5]enkephalin (KI = 2000–3000 nm) or the δ‐ligand [d‐Ala2,d‐Leu5]enkephalin (KI > 20,000 nm).

The dissociation equilibrium constant (KD) and the binding capacity (pmol/g) of the μ‐binding site were determined with the selective μ‐ligand [3H]‐[d‐Ala2,MePhe4,Gly‐ol5]enkephalin. For the δ‐site, [3H]‐[d‐Ala2,d‐Leu5]enkephalin was used in the presence of unlabelled [d‐Ala2,MePhe4,Gly‐ol5]enkephalin in order to suppress cross‐reactivity to the μ‐binding site. For the estimation of κ‐binding, [3H]‐(±)‐ethylketazocine or [3H]‐(−)‐bremazocine were used in the presence of unlabelled μ‐ and δ‐ligands for the suppression of cross‐reactivities to the μ‐ and δ‐binding sites.

In rat brain the capacity of the μ‐binding site was 7.3 pmol/g brain, that of the δ‐binding site 6.7 pmol/g brain and that of the κ‐binding site 2.0 pmol/g brain. Thus, the κ‐binding site had the lowest value whereas in the guinea‐pig brain the capacity of the μ‐binding site was lower than that of the δ‐ or κ‐binding site.
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.
Direct effect of lithium on active and inactive renin secretion
Authors: Ginesi Laura M. , Munday K.A. , Noble A.R.
Published: July 2012

Rabbit kidney cortex slices were used to investigate the effect of lithium chloride (0 to 20 mm) on renin release. Secretion of active renin was increased in the presence of lithium but inactive (acid‐activatable) renin secretion was unchanged. Increased plasma renin activity in patients receiving lithium therapy may be the result of direct effects of lithium on renin secretion mechanisms rather than being secondary to altered renal sodium handling.
A comparison of some of the properties of the [3H]‐sulpiride binding site in soluble and native membrane preparations of dog striatum
Authors: Templeton Wilma W. , Woodruff G.N.
Published: July 2012

[3H]‐sulpiride binding sites in dog striatum have been solubilised using CHAPS detergent. Solubilised sites were similar to those in native membrane preparations in terms of Bmax, Kd and sensitivity to dopamine and dopamine receptor antagonists. Binding of [3H]‐sulpiride to the solubilised binding site was dependent upon the presence of sodium ions and was inactivated by the sulphydryl group reagent N‐ethylmaleimide.
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.
The inotropic effect of ouabain and its antagonism by dihydroouabain in rat isolated atria and ventricles in relation to specific binding sites
Authors: Finet M. , Godfraind T. , Noel F.
Published: July 2012

The inotropic effect of ouabain has been studied in rat ventricles and atria.

The concentration‐effect curve of ouabain may be fitted by a model assuming the existence of two saturable components. The component with the higher sensitivity to ouabain accounted for 30% of the maximal increase in systolic tension in ventricles and for only 5% in atria. Increase in diastolic tension was only apparent at ouabain concentrations required to observe the low sensitivity component.

[3H]‐ouabain binding has been examined in microsomes prepared from atria and ventricles. High and low affinity binding sites have been observed. The ratio of high and low affinity ouabain binding sites was 4 fold lower in microsomes from rat atria than from rat ventricles. This could account for the difference in the response of these two tissues to the inotropic action of ouabain.

In ventricular strips the high sensitivity component was much less apparent in the presence of dihydroouabain than with ouabain.

When ventricular strips were preincubated in the presence of dihydroouabain 3 μm, the increase in systolic tension evoked by ouabain 1 μm was significantly reduced. Cumulative concentration‐effect curve studies showed dihydroouabain antagonism to the high sensitivity component.
Antinociceptive action of nicotine and its methiodide derivatives in mice and rats
Authors: Aceto Mario D. , Awaya Hiroyoshi , Martin Billy R. , May Everette L.
Published: July 2012

Three quaternary methiodides of nicotine were prepared and tested for antinociceptive activity in the mouse tail‐flick, mouse phenylquinone and rat tail‐flick tests.

Following peripheral administration, all three methiodides were inactive in the mouse and rat tail‐flick procedures, whereas nicotine was active in both tests, which suggested that nicotine was acting centrally.

Quaternization of nicotine did not eliminate antinociceptive activity as demonstrated by the intraventricular injection of the methiodides in mice. Nicotine pyrrolidine and bis methiodides were somewhat more potent than nicotine, whereas nicotine pyridine methiodide was considerably less potent than nicotine in the tail‐flick procedure.

Systemically administered nicotine pyrrolidine methiodine was approximately one‐third as active as nicotine in the mouse phenylquinone test; nicotine pyridine methiodide and nicotine bis methiodide were 100 and 300 times less active, respectively.

Hexamethonium partially blocked nicotine and nicotine pyrrolidine methiodide, whereas mecamylamine blocked nicotine completely but nicotine pyrrolidine methiodide partially. Nicotine may have both central and peripheral actions in the mouse phenylquinone test, whereas nicotine pyrrolidine methiodide may have both nicotine and non‐nicotine like antinociceptive activity.

The radiolabeled methiodides were synthesized and their disposition in body tissues studied. The methiodides were found to penetrate brain poorly (plasma‐to‐brain ratios > 20).

The methiodides were metabolized to nicotine to a small extent. This metabolism occurred to a greater extent in mice than in rats.
Evidence for a magnesium‐sparing action by amiloride during renal clearance studies in rats
Authors: Devane John , Ryan Michael P.
Published: July 2012

The potassium‐sparing diuretic, amiloride, reduced the fractional excretion of magnesium in anaesthetized rats.

Alterations in glomerular filtration rate (GFR), the filtered load of magnesium, arterial blood pressure, the status of the extracellular fluid volume, plasma aldosterone concentration and acid‐base balance were not involved.

It was concluded that amiloride exerted a magnesium‐sparing effect by a direct renal action.
Evidence that 5‐hydroxytryptamine in the forebrain is involved in naloxone‐precipitated jumping in morphine‐dependent rats
Authors: Cervo L. , Romandini S. , Samanin R.
Published: July 2012

A withdrawal syndrome was precipitated by naloxone in morphine‐dependent rats injected with 5,7‐dihydroxytryptamine (5,7‐DHT) in the ventromedial tegmentum (VMT) at the level of the nucleus interpeduncularis.

5,7‐DHT, which markedly depleted 5‐hydroxytryptamine (5‐HT) in the forebrain but not in the brainstem, significantly reduced jumping in abstinent rats with no significant effect on other withdrawal signs.

The effect of morphine 10 mg kg−1 on responses on the hot plate was unchanged in 5,7‐DHT‐treated rats.

The findings suggest that 5‐HT in the forebrain is selectively involved in the jumping of morphine‐abstinent rats.
The effect of indomethacin on the contractile response of the guinea‐pig lung parenchymal strip to leukotrienes B4, C4, D4 and E4
Authors: Austen K.F. , Corey E.J. , Drazen J.M. , Leitch A.G.
Published: July 2012

Indomethacin (1 μg ml−1) almost totally inhibited the dose‐dependent contractile response of isolated lung parenchymal strips of the guinea‐pig (GPLS) to leukotriene B4 (LTB4) over the concentration range 0.18–18 nM.

LTC4 (0.63 pM‐63 nM)‐induced contractions of GPLS were not significantly inhibited by indomethacin (1.0 and 10.0 μg ml−1) except when the highest LTC4 concentration (63 nM) was tested in the presence of indomethacin (10 μg ml−1).

LTD4 (1.3 fM‐13 nM)‐induced contractions of GPLS were not significantly inhibited by indomethacin (0.1–10 μg ml−1) except for contractions induced by concentrations of LTD4 greater than 0.13 nM and 13 nM. Indomethacin 1 μg ml−1 and 10 μg ml−1 inhibited the contractile response to 13 nM LTD4 by 37 and 16% respectively.

LTE4 (2.3 fM‐23 nM)‐induced contractions of GPLS were not significantly inhibited by indomethacin (0.1–10 μg ml−1). Contraction due to LTE4 23 pM was significantly potentiated by indomethacin (1 μg ml−1).

Clotrimazole (10 μM) significantly inhibited LTD4‐induced contractions of GPLS at concentrations greater than 13 pM but had no significant effect on LTC4‐induced contractions.

Cyclo‐oxygenase products, probably principally thromboxane A2, are important secondary mediators of LTB4‐induced contractions of GPLS but make little or no contribution to contractions of GPLS induced by LTC4, LTD4, and LTE4, except at higher concentrations of LTD4 and possibly LTC4. Certain concentrations of LTE4 may generate bronchodilator PGE2 in GPLS.
The effect of exaprolol (MG 8823) on epicardial ST‐segment changes in a feline model of acute myocardial ischaemia
Authors: Parratt J.R. , Udvary Eva
Published: July 2012

A model is described (anaesthetized, open‐chest cats subjected to acute coronary artery occlusion) which allows the effects of drug interventions to be determined on one major electrocardiographic index of myocardial ischaemia. Epicardial ST‐segment changes were continuously recorded from five individual sites on the surface of the left ventricle.

Coronary artery occlusion (left anterior descending branch) resulted in marked and consistent elevations of the ST‐segment in all sites in nearly all experiments. These changes started within 1 min of the onset of ischaemia and reached a peak at between 30 and 60 min; thereafter there was a gradual reduction over the next 4 h. The one significant haemodynamic effect of coronary artery occlusion was an increase in left ventricular (LV) end‐diastolic pressure (LVEDP). Ventricular ectopic activity was not pronounced in this model (about 50 ectopic beats over the initial 30 min post‐occlusion period).

Exaprolol (1.0 mg kg−1, intravenously) a potent β‐adrenoceptor blocking agent with ‘membrane stabilising activity’, when given 1 h after the onset of ischaemia, reduced heart rate and LV dP/dtmax and increased LVEDP. These effects were prolonged (i.e. little recovery in heart rate 3 h after administration).

Exaprolol decreased total ST‐segment elevation immediately after administration; this was significantly different from the effect of intravenous saline and lasted for at least 3 h. The effects appeared to be greater at sites of less pronounced ischaemia.

Intramyocardial temperature records were taken to indicate a reduction in blood flow to the ischaemic region; however the alleviation of epicardial ST‐segment elevation suggests an improved myocardial oxygen demand:supply ratio.

Reperfusion was unsuccessfully attempted after a 4 h occlusion period; reperfusion after a shorter period (30 min) resulted in ventricular ectopic activity but no fibrillation.
Effects of yohimbine, rauwolscine and corynanthine on contractions and calcium fluxes induced by depolarization and prostaglandin F2α in rat aorta
Authors: Godfraind T. , Miller R.C. , Lima J. Socrates
Published: July 2012

The effects of the selective α2‐adrenoceptor antagonists yohimbine and its stereo‐isomer rauwolscine and the selective α1 ‐adrenoceptor antagonist corynanthine (a third yohimbine stereoisomer) on contractions induced in rat aorta by depolarization and prostaglandin F2α (PGF2α) have been compared.

In calcium‐free solution, depolarization with 100 mM K+ failed to produce a contraction of rat aorta but PGF2α (3 μM) stimulated a contraction equal to about 23% of maximal elicited in normal physiological solution.

Yohimbine had no significant effect on depolarization‐induced contractions except at concentrations greater than 30 μM. Rauwolscine and corynanthine (1 to 100 μM) depressed depolarization‐induced contractions in a concentration‐dependent manner, but the characteristics of inhibition were not identical.

Contractions induced by PGF2α (3 μM) were depressed in a concentration‐dependent manner by rauwolscine (3 to 100 μM) but were unaffected by yohimbine or corynanthine.

Depolarization‐stimulated 45Ca influx was depressed by rauwolscine and corynanthine to about the same extent as were the contractions; while rauwolscine (100 μM) completely inhibited PGF2α‐stimulated 45Ca influx, it also depressed part of the PGF2α‐stimulated contraction dependent on intracellular calcium.

Rauwolscine (100 μM) partly inhibited PGF2α‐stimulated release of 45Ca from aortic smooth muscle in calcium‐free solution.

It is concluded that the yohimbine structure possesses a calcium entry blocking action as well as a depressant action on contractions not dependent on calcium entry. The predominant effect depends on the structural configuration and the nature of the stimulating agent.
The effects of p‐chloromercuribenzoate on muscarinic receptors in the cerebral cortex
Authors: Birdsall N.J.M. , Burgen A.S.V. , Hulme E.C. , Wong E.H.F.
Published: July 2012

The action of p‐chloromercuribenzoate (PCMB) on the ligand binding properties of the muscarinic receptors in the rat cerebral cortex has been examined.

At low concentrations, PCMB produces a selective change in the binding of agonists without any effect on the binding of antagonists.

At higher concentrations, the structure‐binding profile for binding antagonists is changed. The affinity of agonists is greatly reduced and the heterogeneity of binding eliminated.

The effects of both high and low concentrations of PCMB can be reversed by dithiothreitol.

Inactivation of receptors proceeds in parallel and is kinetically complex. It can only be partially reversed by dithiothreitol.

Evidence is presented connecting the low affinity agonist binding site with the high affinity pirenzepine binding site.

The changes produced by PCMB have been interpreted in terms of the modification of receptor conformation.
Pharmacological characterization of a substance P antagonist, [D‐Arg1, D‐Pro2, D‐Trp79, Leu11]‐substance P
Authors: Watson Stephen P.
Published: July 2012

The substance P antagonist [D‐Arg1, D‐Pro2, D‐Trp7,9, Leu11]‐substance P produced parallel log dose‐response curve shifts to both substance P and eledoisin on five in vitro smooth muscle preparations.

The slope values of Arunlakshana‐Schild plots were not significantly different from unity suggesting that it acts as a simple competitive antagonist on all five preparations with an association constant (Ka) in the range of 0.3–1.5 × 106M−1.

The Ka value of the antagonist was always slightly greater when tested against eledoisin than against substance P; however, this difference appears too small to suggest that these two agonists are acting on different receptor sub‐types.