bluuebunny/crossref_metadata_2025 huggingface dataset:
THE ACTIVITY OF SODIUM CROMOGLYCATE ANALOGUES IN HUMAN LUNG in vitro: A COMPARISON WITH RAT PASSIVE CUTANEOUS ANAPHYLAXIS AND CLINICAL EFFICACY
Authors: CHURCH MARTIN K. , GRADIDGE CAROLYN F.
Published: July 2012

Eleven analogues of sodium cromoglycate have been tested for their ability to suppress histamine release induced by anti‐IgE from passively sensitized human lung fragments in vitro.

With the exception of WY 16922, which released histamine at high concentrations, all inhibited histamine release in a linear dose‐related manner.

The analogues were 30 to 1500 times more potent than sodium cromoglycate. However, their regression slopes of activity upon log‐concentration were only one‐third as steep as that for sodium cromoglycate, indicating a possible difference in their mechanism of action.

In comparison with sodium cromoglycate, the analogues were more potent in human lung than in rat passive cutaneous anaphylaxis (PCA); there was no quantitative correlation between potencies in the two tests.

The human lung model is not predictive of anti‐asthmatic activity in man as the six analogues tested clinically are less effective than sodium cromoglycate.

These results throw doubt on the use of models of mast cell degranulation in the search for Antiallergic drugs and, possibly, on the relative importance of mast cell degranulation in the pathogenesis of asthma.
SOME STUDIES ON THE RELEASE OF HISTAMINE FROM MAST CELLS STIMULATED WITH POLYLYSINE
Authors: ENNIS MADELEINE , PEARCE FREDERICK L. , WESTON PETER M.
Published: July 2012

Polylysine is an extremely potent releaser of histamine from rat peritoneal mast cells. Isolated mesenteric mast cells of the rat also respond to the secretagogue but guinea‐pig mesenteric cells are unreactive.

The release does not require the presence of extracellular calcium ions but shows some dependence on internal stores of the cation.

The effect of polylysine is blocked by extremes of temperature and by metabolic inhibitors.

The release is very rapid and is virtually complete within 10 s of adding the inducer.

The release is unaffected by the Antiallergic drug, doxantrazole, but is inhibited by theophylline and disodium cromoglycate. The latter compounds are effective in both the presence and absence of added calcium. This result is discussed in terms of the postulated effect of the drugs on calcium transport.
ACEBUTOLOL, METOPROLOL AND PROPRANOLOL IN CONSCIOUS DOGS WITH CHRONIC HEART‐BLOCK: CHRONOTROPIC EFFECTS AND RELATION BETWEEN DEPRESSION OF VENTRICULAR ACTIVITY AND β‐ADRENOCEPTOR BLOCKING POTENCY
Authors: BOUCHER M. , DUCHENE‐MARULLAZ P.
Published: July 2012

Atrial and ventricular chronotropic effects of acebutolol, metoprolol and propranolol were studied in conscious dogs with chronic heart‐block. Ventricular β‐adrenoceptor blocking activity was assessed for the three drugs against isoprenaline (1 μg/kg) under the same experimental conditions.

Acebutolol and metoprolol significantly increased atrial rate. The effect was proportional to the dose for acebutolol, independent for metoprolol. Propranolol had no significant effect on atrial rate. All three drugs significantly lowered ventricular rate in proportion to the dose.

Ventricular β‐blocking potencies of metoprolol and acebutolol were respectively 2 and 3 times weaker than that of propranolol as indicated by ED50 values.

The ventricular depressor effect observed was proportional to the degree of ventricular β‐blockade present, although this may not be the only factor involved.
HYDROCORTISONE‐INDUCED INHIBITOR OF PROSTAGLANDIN BIOSYNTHESIS IN RAT LEUCOCYTES
Authors: CARNUCCIO ROSA , DI ROSA M. , PERSICO PAOLA
Published: July 2012

Rat peritoneal leucocytes incubated with hydrocortisone (10 μg/ml) release a factor which inhibits prostaglandin generation. The steroid‐induced inhibitor, which mediates the anti‐phospholipase effect of anti‐inflammatory steroids, may be a protein or a polypeptide since its formation is blocked by cycloheximide, a known inhibitor of protein synthesis.
ENHANCEMENT OF RAT BRAIN METABOLISM OF A TRYPTOPHAN LOAD BY CHRONIC ETHANOL ADMINISTRATION
Authors: BADAWY A.A.‐B. , EVANS M. , PUNJANI N.F.
Published: July 2012

We have previously shown that chronic ethanol administration enhances brain 5‐hydroxytryptamine synthesis by increasing the availability of circulating tryptophan to the brain secondary to the decreased liver tryptophan pyrrolase activity. We now find that ethanol enhances the brain metabolism of a tryptophan load by the same mechanism. The results are discussed in relation to ethanol preference and the need for further clinical work on the effects of alcoholism on tryptophan metabolism.
COMPARATIVE ELECTROPHYSIOLOGICAL EFFECTS OF Org 6001, A NEW ORALLY ACTIVE ANTIDYSRHYTHMIC AGENT, AND LIGNOCAINE ON HUMAN VENTRICULAR MUSCLE
Authors: KANE KATHLEEN A.
Published: July 2012

The electrophysiological effects of Org 6001, a new orally active antidysrhythmic agent, have been compared with those of lignocaine on the human ventricular action potential in vitro.

Org 6001 (4 to 16 mg/l) greatly reduced the maximum rate of depolarization (MRD) of the human ventricular action potential but had no effect on resting membrane potential or action potential amplitude.

The action potential duration at the 50% repolarization level, but not at the 90% repolarization level, was significantly reduced by Org 6001. The absolute refractory period was unchanged.

Lignocaine, at a concentration (4 mg/l) within the therapeutic range, had no significant effect on any measured parameter, either in muscle exposed to a normal (4.0 mm) or high (5.4 mm) extracellular potassium concentration ([K+]0).

Higher concentrations of lignocaine (8 to 16 mg/l) did, however, reduce MRD at both [K+]0 without changing resting membrane potential or action potential amplitude. The action potential duration was decreased slightly by these higher concentrations of lignocaine whilst the absolute refractory period was lengthened.

Org 6001 was found to be more potent than lignocaine in reducing MRD but, unlike lignocaine, the absolute refractory period was not prolonged. These compounds, therefore, differed in their electrophysiological effects on human ventricular muscle although both are characterized as being class 1 antidysrhythmic drugs.
DISTRIBUTION AND FUNCTION OF β‐ADRENOCEPTORS IN DIFFERENT CHAMBERS OF THE CANINE HEART
Authors: BAKER STEPHEN P. , BOYD HELEN M. , POTTER LINCOLN T.
Published: July 2012

An improved binding assay involving (−)‐[3H]‐dihydroalprenolol (DHA) and KCl‐washed cardiac membranes was developed to study β‐adrenoceptors in the canine heart quantitatively.

Receptor numbers varied from 3.8 to 7.1 pmol/g fresh tissue, showing a steady increase from left atrium → right atrium →right ventricle → interventricular septum → left ventricle. With one minor exception, the same pattern was found for adenylate cyclase activity and Na+, K+ ‐activated ATPase activity.

The binding of DHA was inhibited in the expected manner by β‐adrenoceptor agonists and antagonists, and was stereospecific, in confirmation of previous studies. Dissociation constants determined from Scatchard analyses included DHA: 2.5 nm; (−)adrenaline: 230 nm; (−)noradrenaline: 1167 nm. Kinetic analyses of the binding of DHA yielded a KD of about 4 nm.

The distribution of β‐receptors is closely related to that of blood flow and the arrival plus retention of a circulating catecholamine, but is markedly different from that of endogenous noradrenaline, and thus adrenergic nerve terminals. Most receptors thus appear not at synapses but diffusely localized where they can react with circulating adrenaline.

Evidence is discussed that β‐receptors at synapses respond primarily to neural noradrenaline, less to circulating adrenaline, and hardly at all to circulating noradrenaline; responses mediate increased cardiac output during exercise. In contrast most cardiac β‐receptors appear to respond only to adrenaline, and to be used, except at times of severe circulatory stress, during psychological stress.
PHARMACOLOGICAL ANALYSIS OF SALIVARY AND BLOOD FLOW RESPONSES TO HISTAMINE OF THE SUBMANDIBULAR GLAND OF THE DOG
Authors: SHIMIZU T. , TAIRA N.
Published: July 2012

The submandibular gland in situ was perfused with blood through the glandular artery at constant pressure in anaesthetized dogs. Drugs were administered intra‐arterially.

Histamine produced both salivation and an increase in blood flow, each response having an early and a late component.

Marked tachyphylaxis to histamine developed in both of the salivary responses but only in the late blood flow response to histamine.

The early and late salivary responses were abolished and the late blood flow response was diminished by infusion of tetrodotoxin in doses that abolished the salivary and blood flow responses to electrical stimulation of the chorda‐lingual nerve.

The whole salivary response to histamine was abolished by infusion of (−)‐hyoscyamine in doses that greatly antagonized the salivary and blood flow responses to acetylcholine, whereas the blood flow responses to histamine were scarcely modified. These doses of (−)‐hyoscyamine abolished the salivary response to chorda‐lingual nerve stimulation but left the blood flow response to it unaffected.

The salivary and blood flow responses to histamine were unaffected by infusion of hexamethonium in doses that almost abolished the salivary and blood flow responses to chorda‐lingual nerve stimulation.

The whole salivary response to histamine was abolished and the late blood response to histamine was partially inhibited by the histamine H1‐receptor antagonist, mepyramine, but not, by the histamine H2‐receptor antagonist, metiamide.

The early blood flow response to histamine was antagonized by both mepyramine and metiamide but mepyramine was far more effective than metiamide.

These results led to the following conclusions: (1) the whole salivary response and a part of the late blood flow response to histamine are due entirely to excitation of parasympathetic postganglionic neurones; (2) neuronal histamine receptors involved are exclusively of the H1‐type; (3) histamine has no direct stimulant action on the glandular cells; (4) the early blood flow response and the remaining part of the late blood flow response to histamine result from the direct action on vascular smooth muscle in the glandular vascular bed; (5) vascular histamine receptors consist of H1‐ and H2‐receptors.
COMPARISON OF THE ANTI‐HYPERTENSIVE RESPONSE TO β‐ADRENOCEPTOR BLOCKING DRUGS IN INTACT AND ADRENAL‐DEMEDULLATED SPONTANEOUSLY HYPERTENSIVE RATS
Authors: BUCKINGHAM R.E. , HAMILTON T.C.
Published: July 2012

The β‐adrenoceptor blocking drugs atenolol, metoprolol, practolol, propranolol, timolol and oxprenolol (as racemates) were administered acutely at three dose levels (0.01, 0.03 and 0.1 mmol/kg i.p. or s.c.) to spontaneously hypertensive rats with intact adrenal glands (SH‐rats) and following unilateral adrenalectomy and contralateral adrenal‐demedullation (SHAD‐rats). Changes in mean arterial pressure and heart rate were determined via an indwelling aortic catheter, with the animals placed in a quiet environment.

All drugs significantly lowered the blood pressure of SHAD‐rats, and these responses were not always associated with changes in basal heart rate.

With the exception of metoprolol and atenolol, the β‐adrenoceptor blocking drugs were less effective as anti‐hypertensives in SH‐ than in SHAD‐rats. Notably, timolol and oxprenolol lowered the blood pressure of SH‐rats at low doses only, whereas propranolol evoked a pressor response in this model.

Whilst (+)‐propranolol lowered the blood pressure of SHAD‐rats only at a dose which caused myocardial depression, the anti‐hypertensive response to (−)‐propranolol did not parallel changes in heart rate and was preceded by a pressor response.

The results imply that adrenal catecholamine release contributes towards masking the anti‐hypertensive effects of some β‐adrenoceptor antagonists in SH‐rats.
EFFECTS OF SULPHASALAZINE AND ITS METABOLITES ON PROSTAGLANDIN SYNTHESIS, INACTIVATION AND ACTIONS ON SMOOTH MUSCLE
Authors: HOULT J.R.S. , MOORE P.K.
Published: July 2012

We have investigated the effects of sulphasalazine and of its principal colonic metabolites (5‐aminosalicylic acid and sulphapyridine) on prostaglandin inactivation, synthesis and actions on gastrointestinal smooth muscle.

Sulphasalazine inhibits prostaglandin F2α breakdown in 100,000 g supernatants in all organs so far tested from 7 species with an ID50 of approx. 50 μm; it has a selective action on prostaglandin 15‐hydroxydehydrogenase and does not inhibit prostaglandin Δ‐13 reductase, prostaglandin 9‐hydroxydehydrogenase or ‘enzyme X’ at millimolar concentrations. Enzyme activities were measured radiochemically or by bioassay.

Sulphapyridine and 5‐aminosalicylic acid do not inhibit prostaglandin inactivation in vitro (4 species tested). A methyl analogue of sulphasalazine is a more potent inhibitor than the parent compound. Rabbit colon prostaglandin F2α metabolism in vitro was inhibited by the following drugs with ID50 values (μm) of: diphloretin phosphate 20, sulphasalazine 50, indomethacin 220, frusemide 1000 and aspirin 10,000. A similar rank order of potencies was obtained with rabbit kidney.

Sulphasalazine at 50 to 100 μm inhibited inactivation of prostaglandin E2 in the perfused rat and guinea‐pig lung by 3 to 40% (rat) and 32 to 100% (guinea‐pig) when measured by superfusion cascade bioassay and of prostaglandin F2α by 43.6 ± 6.5% in rat lung perfused with 50 μm sulphasalazine and assayed radiochemically.

Prostaglandins E1 and E2 were 97.0 ± 8.2% and 92.3 ± 6.8% inactivated in the lungs after intravenous injection in the anaesthetized rat as measured by reference to their vasodepressor potencies when injected intra‐arterially. Prostaglandin A2 was not similarly inactivated. Pulmonary inactivation was prevented in the presence of an intravenous infusion of 16.3 μg kg−1 min−1 sulphasalazine and partially inhibited at a lower infusion rate.

Prostaglandin biosynthesis from arachidonic acid was measured in microsomal preparations from four sources by bioassay and radiochemical methods. Indomethacin was a potent inhibitor (ID50 0.8 to 4.1 μm) but sulphasalazine and its methyl analogue were very weak inhibitors (ID50 1500 to > 5000 μm), 5‐aminosalicylic acid was weaker still and sulphapyridine inactive.

Sulphasalazine at 50 μm did not affect the actions of prostaglandins on five smooth muscle preparations; at 500 μm there was a rapidly reversible and probably non‐specific antagonism of responses to low doses of prostaglandins.

The specificity and selectivity of the interaction of sulphasalazine and its metabolites with the formation, breakdown and actions of prostaglandins are discussed.
THE INTERACTION OF HUMAN HAEMOGLOBIN WITH ALLOSTERIC EFFECTORS AS A MODEL FOR DRUG‐RECEPTOR INTERACTIONS
Authors: GOODFORD P.J. , ST‐LOUIS J. , WOOTTON R.
Published: July 2012

The release of bound oxygen from oxyhaemoglobin by allosteric effectors is considered as a model for those drug‐receptor interactions where the primary response to agonist binding is the release of a second messenger species.

A theory of haemoglobin oxygenation, based on the two‐state model of Monod, Wyman & Changeux (1965) is used to predict the relationship between ‘pharmacological’ response and dose of agonist. This relationship is the same as that derived from classical pharmacological occupancy theory.

The potency of an agonist is a weighted average of its affinities for the two conformational states of the receptor.

The efficacy of an agonist depends not only upon its preferential binding to one of the two conformational states, but also on its ability to alter the functional properties of that state by lowering the affinity of the state for the second messenger.

2,3‐Diphosphoglycerate and adenosine triphosphate are approximately equipotent and of similar efficacy, but inositol hexaphosphate is about 500 times more potent and has a higher efficacy.
STUDY OF CENTRAL NEUROTRANSMITTERS IN STRESS‐INDUCED GASTRIC ULCERATION IN ALBINO RATS
Authors: BHARGAVA K.P. , DAAS M. , GUPTA G.P. , GUPTA M.B.
Published: July 2012

Restraint when combined with cold (4°C) consistently induces gastric ulceration in rats at 2 h. The cold‐restraint ulcer (CRU) technique provides a suitable model for acute studies.

The peripheral mechanisms in CRU seem to be increased sympathetic and parasympathetic outflow since CRU was significantly reduced by prior spinal transection or vagotomy or by appropriate blocking agents. Since metiamide significantly reduced CRU, H2‐histamine receptors are also involved.

Central catecholaminergic as well as cholinergic mechanisms seem to be responsible for the activation of peripheral sympathetic and parasympathetic outflow in CRU, since central administration of dibenamine, propranolol, 6‐hydroxydopamine and atropine prevented the CRU.

Exogenous administration of putative neurotransmitters (adrenaline, noradrenaline and acetylcholine) into the cerebroventricular system produced gastric ulceration similar to CRU. However, dopamine, histamine and 5‐hydroxytryptamine failed to induce gastric ulceration.

The results with intracerebroventricular adrenaline and acetylcholine indicate a central cholinergic link distal to adrenergic activation in the ulcerogenesis.

Intracerebroventricular adrenaline‐induced gastric ulceration appears to be most akin to CRU. However, other central neurotransmitter mechanisms may also be involved.
INFERIOR CARDIAC NERVE ACTIVITY IN THE CAT DURING SUPER‐FUSION OF THE VASCULARLY ISOLATED CAROTID SINUS WITH PROPRANOLOL
Authors: McCLEARY M. , TUTTLE R.S.
Published: July 2012

Inferior cardiac nerve activity in 9 cats was in inverse relationship to the pressure maintained in the systemically isolated and perfused carotid sinus.

Perfusion with propranolol produced no change in this relationship at a concentration of 5.0 μg/ml, but abolished it at 50.0 μg/ml.

The results suggest that concentrations of propranolol which have been reported to enhance the sensitivity of the carotid sinus to pressure do not enhance one neurophysiological component of the reflex depressor response.
INTERACTION BETWEEN SYNTHETIC ANALOGUES OF QUINOXALINE ANTIBIOTICS AND NUCLEIC ACIDS: ROLE OF THE DISULPHIDE CROSS‐BRIDGE AND d‐AMINO ACID CENTRES IN DES‐N‐TETRAMETHYL‐TRIOSTIN A
Authors: FOX K.R. , OLSEN R. K. , WARING M.J. , CHAKRAVARTY P.K. , OLSEN R.K.
Published: July 2012

[Ala3, Ala7] TANDEM is an analogue of des‐N‐tetramethyl‐triostin A (TANDEM) in which both l‐Cys residues of the octapeptide ring are replaced by l‐Ala; accordingly it lacks the disulphide cross‐bridge which limits the conformational flexibility of TANDEM.

In [l‐Ser1] TANDEM the configuration of one of the serine residues is inverted, altering the disposition of one of the quinoxaline chromophores with respect to the peptide ring.

Both compounds interact weakly but detectably with natural DNAs as judged by spectral shifts and increases in the thermal denaturation (‘melting’) temperature Tm. They also raise the Tm of poly rA.poly rU.

Binding isotherms determined by solvent partition analysis with [Ala3, Ala7] TANDEM yield association constants of about 103 m−1 for its interaction with natural DNAs. A Scatchard plot for binding to poly(dA‐dT) determined by solvent partition and spectrophotometric methods shows marked evidence of cooperativity with an intrinsic association constant 1.9 times 104 m−1, 8.7 nucleotides per binding site, and cooperativity parameter 15.

Binding of [Ala3, Ala7] TANDEM to short rod‐like fragments of poly(dA‐dT) increases their contour length by almost the theoretical amount expected for an ideal process of bifunctional intercalation.

No effect of either compound on the winding of the DNA helix could be detected in sedimentation experiments with closed circular duplex PM2 DNA.

It is concluded that the cross‐bridge of TANDEM greatly stabilizes its binding to DNA, most probably via entropic factors, but is not the only structural feature that influences its AT sequence‐selectivity. The consequences of epimerising one of the d‐Ser residues appear as disastrous as epimerising both.

The experimental details for the synthesis of [Ala3, Ala7] TANDEM and [l‐Ser1] TANDEM are given in an appendix to this paper.
HAEMODYNAMIC EFFECTS OF SULPHINPYRAZONE IN EXPERIMENTAL MYOCARDIAL ISCHAEMIA
Authors: RUSSELL D.C.
Published: July 2012

The effect of sulphinpyrazone (30 mg/kg i.v.) on heart rate, blood pressure and ventricular arrhythmias was studied in open‐chested anaesthetized dogs during sequential 10 min occlusions of the left anterior descending coronary artery. An increased duration of occlusion without ventricular fibrillation and reduction in epicardial activation delay in the central ischaemic region were observed after intravenous sulphinpyrazone (n = 7). These effects were associated with a progressive and significant reduction in intrinsic heart rate (up to 15 beats/min) but no change in blood pressure. These findings suggest that heart rate changes alone may account for the observed protective effect of sulphinpyrazone against early ventricular fibrillation during acute experimental myocardial ischaemia.
THE ACTION OF POLYMYXIN B AT THE FROG NEUROMUSCULAR JUNCTION
Authors: DURANT NICHOLAS N. , LAMBERT JEREMY J.
Published: July 2012

The effects of polymyxin B at the neuromuscular junction of the frog were studied by conventional electrophysiological and voltage clamp techniques.

At a concentration of 2.5 μg/ml polymyxin B produced neuromuscular blockade in 10 to 15 min and endplate potentials (e.p.ps) could be recorded. Resting membrane potential was unaffected. The neuromuscular block was characterized by a depressed e.p.p. quantal content (28 ± 7), which was similar to that determined from endplates exposed to 13 mm magnesium (23 ± 3), and a low e.p.p. quantal size, which was similar to that determined from endplates exposed to 3 μm (+)‐tubocurarine.

Polymyxin B (0.25 to 0.75 μg/ml) decreased mean miniature e.p.p. amplitude with little effect on frequency.

At a concentration of 5 μg/ml polymyxin B markedly shortened the duration of endplate currents (e.p.cs) and abolished the relationship between holding potential and the time to half‐decay at negative potentials greater than −;60 mV. This action is consistent with block of open acetylcholine activated ionic channels.

4‐Aminopyridine (20 μm) antagonized the depressed e.p.p. quantal content produced by polymyxin B but did not alter the shortened e.p.c. duration.

It is concluded that polymyxin B decreases quantal release and produces some degree of postjunctional receptor blockade and a marked and persistent blockade of acetylcholine activated channels. The latter action may explain the difficulty of reversal of polymyxin B‐induced neuromuscular blockade and its non‐competitive nature.
INHIBITION OF LYMPHOCYTE CAPPING AND TRANSFORMATION BY PROPRANOLOL AND RELATED COMPOUNDS
Authors: ANDERTON BRIAN H. , AXFORD JOHN S. , COHN PETER , MARSHALL NICHOLAS J. , SHEN LI , SPRAKE SALLY
Published: July 2012

The effects of propranolol on phytohaemagglutinin (PHA)‐induced transformation of murine T lymphocytes and capping of anti‐IgG on the surface of murine B lymphocytes have been examined.

A 50% inhibition of transformation was observed with 10−5m propranolol, whereas a higher concentration, of the order of 10−3m propranolol was required to inhibit capping by 50%. The (+)‐and (−)‐isomers of propranolol proved equipotent in these respects, and the relative potencies of selected analogues of propranolol (alprenolol, oxprenolol, metoprolol, practolol and sotalol) coincided with their potencies as membrane stabilizers; however, lymphocyte transformation was consistently more sensitive than capping.

Similar effects were also seen with quinidine, chlorpromazine and lignocaine, and it was concluded that the inhibition of both lymphocyte functions was due to the membrane stabilizing actions of propranolol.
THE EFFECTS OF TRIMETHADIONE ON PENTETRAZOL‐INDUCED DISCHARGES OF PRIMARY MUSCLE SPINDLE AFFERENTS FROM THE HIND LIMB OF THE RAT
Authors: ANGEL A. , CLARKE K.A.
Published: July 2012

Recordings have been made from primary muscle spindle afferents in split dorsal root filaments of rats anaesthetized with urethane.

Injection of pentetrazol (PTZ, 10 mg/kg) produced elevated discharge in the afferents with intact efferents without any changes in tension or electrical activity of the muscle of origin.

This elevated discharge was found to contain elements of both γd and γs activation.

Trimethadione (100 mg/kg), itself produced a transient increase in discharge and effectively suppressed PTZ‐induced discharges of the afferents for at least 2 h.

These results are discussed in the context of established effects on sensory and motor systems.
ORAL HYOSCINE BUTYLBROMIDE DOES NOT ALTER THE PATTERN OF SMALL INTESTINAL MOTOR ACTIVITY
Authors: THOMPSON D.G. , WINGATE D.L.
Published: July 2012

Continuous recording of proximal jejunal motility in conscious healthy subjects was made following ingestion of 200 mg hyoscine butylbromide (ten times the recommended therapeutic dosage).

There was no detectable modification of fasting or postprandial motor activity, although the therapeutic potency of the standard intravenous dose was confirmed.
INHIBITION BY CLINICALLY USED DYES OF PROSTAGLANDIN INACTIVATION IN RAT AND HUMAN LUNG
Authors: BAKHLE Y.S.
Published: July 2012

The effect of several clinically used dyes on prostaglandin E2 (PGE2) inactivation was studied in rat and human isolated lung.

All the dyes, given as infusions through the pulmonary circulation, inhibited the inactivation of PGE2 as measured by bioassay. The action of the dyes was readily reversible on stopping the infusion.

The concentration producing 30% inhibition varied from 0.6 μm for indocyanine green to over 100 μm for methylene blue.

Inhibition of PGE2 inactivation was also observed when the dyes were given as bolus injections during PGE2 infusions through the lung.

These dyes are therefore not physiologically inert as they had previously been thought to be and their interaction with prostaglandins may affect the variables they are used to measure.
DRUG‐RECEPTOR RECOGNITION: ELECTROSTATIC FIELD LINES AT THE RECEPTOR AND DIELECTRIC EFFECTS
Authors: DEAN P.M.
Published: July 2012

In this paper the directional component of the vector electrostatic field emanating from a drug receptor is analysed in the three orthogonal planes

B‐DNA with an alternating guanine‐cytosine sequence was chosen for a receptor model and the lines of force constructed for two dielectric conditions, namely the cases where firstly the dielectric is homogeneous and a constant throughout the space surrounding the receptor, and secondly where the dielectric is inhomogeneous and is treated as a vector quantity

Electric field line maps indicate marked differences in the local fields situated in the helical wide and narrow grooves for the different sequences of cytosine and guanine; these variations are enhanced when the dielectric is handled as a vector

The significance of electric field lines in interpreting receptor‐induced ligand orientation effects is discussed since the direction of the lines is related to the torque that a receptor would impose on an attacking drug molecule.
ACTIONS OF VERAPAMIL, DILTIAZEM AND OTHER DIVALENT CATIONS ON THE CALCIUM‐CURRENT OF Helix NEURONES
Authors: AKAIKE N. , BROWN A.M. , NISHI K. , TSUDA Y.
Published: July 2012

Effects of organic Ca2+‐antagonists, verapamil and diltiazem, and cations, Ni2+, Mn2+, Co2+ and La3+ on Ca2+ current (ICa) separated from other ionic currents in a Helix neurone were studied. A suction pipette technique which allows internal perfusion of the cell body and voltage clamp was used

Verapamil and diltiazem (10−6‐10−4m) increased the threshold, and decreased both the amplitude and rate of rise of the soma Ca2+‐spike. Both agents inhibited ICa over the entire range of the current‐voltage (I‐V) relationship dose‐dependently, without shifting the threshold of the I‐V relationship. Increases in external Ca2+ overcame the inhibitory action of the agents

Divalent cations, Ni2+, Mn2+, Co2+ and the trivalent cation, La3+ inhibited ICa dose‐dependently, but induced shifts of the I‐V relationship to more positive voltages. The order of potency of inhibition of ICa among these cations was as follows; Ni2+ > La3+ > Mn2+ > Co2+

Double reciprocal plots for peak ICa versus external Ca2+ concentrations in the presence or absence of both organic and inorganic Ca2+‐antagonists intersect at the ordinate. Results indicate that both organic and inorganic Ca2+‐antagonists compete for Ca2+ at the common binding site for Ca2+

Internal application of the organic Ca2+‐antagonists (10−4m) inhibited ICa in a time‐dependent manner to about 40–60% of the control. Ni2+, when applied internally, also depressed ICa

The results provide evidence that organic Ca2+‐antagonists occupy the binding site for Ca2+ in a competitive manner at the surface of the soma membrane of the Helix neurone, while divalent and trivalent cations, in addition to inhibiting ICa in a similar manner to the organic Ca2+‐antagonists, change the surface charge of the soma membrane.
DIFFERENT MECHANISMS OF ACTION OF HISTAMINE IN ISOLATED ARTERIES OF THE DOG
Authors: KONISHI MAKOTO , TODA NOBORU , YAMAMOTO MASAKATSU
Published: July 2012

In helically‐cut strips of dog coronary, superior mesenteric, right gastro‐epiploic and renal arteries contracted with prostaglandin F2β (PGF2β), histamine produced a dose‐related relaxation, while, in contrast, the amine caused only a contraction of cerebral arterial strips

The contractile response of cerebral arteries to histamine was attenuated by chlorpheniramine (10−6M)but was unaffected by cimetidine (10−5m). Relaxant responses to histamine of coronary and renal arteries were significantly attenuated by treatment with cimetidine and to a similar extent by combined treatment with cimetidine and chlorpheniramine. Chlorpheniramine alone was ineffective

In mesenteric and gastro‐epiploic arteries, relaxant responses to histamine were attenuated only slightly by cimetidine. Chlorpheniramine slowed the development of histamine‐induced relaxations but did not alter the magnitude of the relaxations. Combined treatment with these H1‐ and H2‐ antagonists attenuated the histamine‐induced relaxations to an appreciably greater extent than treatment with cimetidine alone

It may be concluded that the cerebroarterial contraction induced by histamine is mediated through H1‐receptors and the relaxations of coronary and renal arteries induced by histamine are mediated through H2‐receptors. It appears that H1‐ and H2‐receptors interact with each other to produce potentiation of histamine‐induced relaxations of mesenteric and gastro‐epiploic arteries.
DOPAMINE‐LIKE PROPERTIES OF EPHEDRINE IN RAT BRAIN
Authors: ZARRINDAST M.R.
Published: July 2012

Ephedrine (3.1–50 mg/kg) was given intraperitoneally to rats and was found to cause a marked increase in spontaneous locomotor activity

In rats with a unilateral lesion in the substantia nigra made by stereotaxic injection of 6‐hydroxydopamine, ephedrine (12.5–150 mg/kg i.p.) caused a dose‐dependent turning towards the lesioned side

Turning behaviour and increase in locomotion produced by ephedrine were antagonized by pretreatment of the animals with pimozide, amino‐oxyacetic acid or reserpine plus α‐methyl‐ρ‐tyrosine, but not by pretreatment with phenoxybenzamine, propranolol or methergoline

In in vitro studies with synaptosomes prepared from rat brain, ephedrine blocked the uptake and caused the release of [3H]‐dopamine

Similar results with regard to locomotion and turning behaviour were obtained with (+)‐amphetamine

It is concluded that the increase in locomotion and turning behaviour produced by ephedrine is mediated through an indirect dopaminergic mechanism.
EFFECT OF ADENOSINE ON CAROTID CHEMORECEPTOR ACTIVITY IN THE CAT
Authors: McQueen D.S. , Ribeiro J.A.
Published: July 2012

The effects of intracarotid (i.e.) injections or infusions of adenosine on chemoreceptor activity recorded from the peripheral end of a sectioned carotid sinus nerve have been studied in cats anaesthetized with pentobarbitone

Adenosine injections (0.1–100 μg) caused a rapid and marked increase of spontaneous chemoreceptor discharge, the intensity, duration and onset of which was dose‐dependent. Infusion of adenosine, 50 μg/min, also evoked an increase in discharge which persisted for the duration of the infusion

Both theophylline (1 mg i.e.) and aminophylline (1 mg i.e.) caused short‐lasting decreases in spontaneous discharge but did not prevent the excitatory effect of adenosine. Theophylline increased the excitatory action of adenosine

Naloxone (400 μg i.e.) antagonized the depressant effect of morphine on chemoreceptor discharge but not the excitatory action of adenosine

It is concluded that exogenous adenosine can excite the cat carotid chemoreceptors, an effect which is not prevented by theophylline in the doses studied. The physiological significance of the findings is discussed.
EFFECTS OF MIANSERIN, DESIPRAMINE AND MAPROTILINE ON BLOOD PRESSURE RESPONSES EVOKED BY ACETYLCHOLINE, HISTAMINE AND 5‐HYDROXYTRYPTAMINE IN RATS
Authors: CAVERO ICILIO , LEFÈVRE‐BORG FRANÇOISE , ROACH ALAN G.
Published: July 2012

In rats anaesthetized with pentobarbitone, intravenous administration of desipramine (0.1 mg/kg), maprotiline (0.5 mg/kg) or mianserin (0.3‐3.0 mg/kg) did not modify the blood pressure lowering effects of acetylcholine (0.25‐1.0 μg/kg, i‐v.) which were significantly reduced by atropine (3.0 μg/kg, i.v.)

Maprotiline and mianserin, like promethazine (0.1 mg/kg, i.v.), inhibited the vasodepressor responses evoked by histamine (2.5‐ 10.0 μg/kg, i.v.). However, desipramine was inactive against histamine

In pithed rats, the pressor effects of intravenous 5‐hydroxytryptamine (5‐HT: 5.0–20.0 μg/kg) were antagonized by mianserin (0.01‐0.3 mg/kg, i.v.) and cyproheptadine (0.01 mg/kg) but were unaffected by maprotiline and desipramine

In syrosingopine pretreated rats given mianserin 0.1 mg/kg, intravenously, 5‐HT (20.0 μg/kg, i.v.) produced a significant fall in blood pressure which could be reduced by a large dose of mianserin (10.0 mg/kg, i.v.)

In conclusion, desipramine, maptrotiline and mianserin, in doses previously found to inhibit noradrenaline neuronal reuptake in the rat cardiovascular system, lack muscarinic receptor antagonist properties. Whilst maprotiline and mianserin blocked vascular histamine receptors, only mianserin, like cyproheptadine, was a potent antagonist of the 5‐HT receptors that mediate increases in blood pressure in rats. Finally, the vasodepressor effects of 5‐HT in syrosingopine pretreated rats given a small dose of mianserin were antagonized by a large dose of mianserin, suggesting that 5‐HT may activate two distinct types of receptors in the rat.
ADDITIVE AND NON‐ADDITIVE EFFECTS OF MIXTURES OF SHORT‐ACTING INTRAVENOUS ANAESTHETIC AGENTS AND THEIR SIGNIFICANCE FOR THEORIES OF ANAESTHESIA
Authors: RICHARDS C.D. , WHITE ANN E.
Published: July 2012

The potency of a series of short‐acting anaesthetics was established by measuring the duration of the loss of righting reflex following a single bolus injection into the tail vein of male Wistar rats. The agents were, in order of potency, etomidate, alphaxalone, methohexitone, alphadalone acetate and propanidid

The potency of binary mixtures of these agents was also assessed to see whether the anaesthetic effects of different agents were additive as classical theories of anaesthesia suggest. Mixtures of alphaxalone and alphadalone acetate, alphaxalone and propanidid and methohexitone and propanidid all showed simple additive effects. Mixtures of alphaxalone and etomidate and of alphaxalone and methohexitone showed a greater potency than would be expected if their effects were simply additive. Mixtures of etomidate and methohexitone were not examined

Mixtures of alphaxalone and either methohexitone or pentobarbitone produced a greater depression of synaptic transmission in in vitro preparations of guinea‐pig olfactory cortex than would have been expected from the sum of the activities of the individual anaesthetics. Other combinations of anaesthetics did not show similar effects although the interaction between alphaxalone and etomidate was not examined

Neither alphaxalone nor pentobarbitone affected the membrane: buffer partition coefficient of the other for a model membrane system

These results are interpreted as evidence against the classical unitary hypotheses of anaesthetic action based on correlations of anaesthetic potency with lipid solubility and as supporting the view that different anaesthetics act on different structures in the neuronal membranes to produce anaesthesia.
ANTIFIBRILLATORY EFFICACY OF ENCAINIDE, LORCAINIDE AND ORG 6001 COMPARED WITH LIGNOCAINE IN ISOLATED HEARTS OF RABBITS AND GUINEA‐PIGS
Authors: ALMOTREFI A. A. , BAKER J. B.E.
Published: July 2012

In Langendorff‐perfused rabbit hearts, electrical stimulation threshold and ventricular fibrillation threshold (VFT) were measured by applying rectangular impulses of 3 ms duration and increasing current at frequencies of 4 and 20 Hz respectively.

Perfusion with lignocaine or one of three new antiarrhythmic drugs, encainide, lorcainide and ORG 6001, produced significant, dose‐dependent increases in both thresholds.

On a dosage basis, encainide was seven times, lorcainide fourteen times and ORG 6001 twice as potent as lignocaine in raising VFT.

In Langendorff‐perfused guinea‐pig hearts, only lorcainide provided complete protection against ouabain‐induced ventricular fibrillation, while 6 of 6,3 of 6 and 2 of 6 hearts fibrillated in the presence of encainide, lignocaine and ORG 6001 respectively, but with infusion durations significantly higher than control.

These results indicate the potential antifibrillatory activity of these new antiarrhythmic agents.
FURTHER STUDIES ON 5‐HYDROXYTRYPTAMINE TRANSPORT IN PANCREATIC ISLETS AND ISOLATED β‐CELLS
Authors: LINDSTRÖM PER
Published: July 2012

The transport mechanism for 3H‐labelled 5‐hydroxytryptamine (5‐HT) in isolated pancreatic islets of non‐inbred ob/obmice was further characterized.

Isolated β‐cells accumulated 5‐HT to the same degree and with the same Na+‐dependence as whole islets.

Imipramine inhibited the uptake in a concentration‐dependent way.

Reserpine did not affect the uptake or efflux rates.

Glucose stimulation of insulin secretion did not affect the uptake rate.

It is concluded that the observed islet uptake of [3H]‐5‐HT represents an intracellular accumulation by the β‐cells. Mechanisms at the level of the plasma membrane may be rate‐limiting for this process.
DIFFERENTIAL RESPONSES TO CARBACHOL, SODIUM NITRO‐PRUSSIDE AND 8‐BROMO‐GUANOSINE 3‘,5’‐MONOPHOSPHATE OF CANINE ATRIAL AND VENTRICULAR MUSCLE
Authors: ENDOH MASAO , YAMASHITA SHUJI
Published: July 2012

The relation between force of contraction and cyclic nucleotide levels during muscarinic receptor stimulation, and after administration of sodium nitroprusside was assessed in canine isolated atrial and ventricular muscle.

The pD2 value (negative logarithm of ED50) for carbachol to decrease force of atrial contraction was similar to that required to inhibit adenosine 3′,5′‐monophosphate (cyclic AMP)‐mediated positive inotropic responses in ventricular muscle.

The cyclic AMP level of atrial muscle did not significantly change during carbachol‐induced negative inotropic action, whilst the guanosine 3′,5′‐monophosphate (cyclic GMP) level was elevated immediately after administration.

Sodium nitroprusside elevated cyclic GMP levels (without changing cyclic AMP levels) both in atrial and ventricular muscle. The force of atrial contraction was significantly reduced by the drug, whilst ventricular contractile force was unaffected.

8‐Bromo‐cyclic GMP markedly decreased contractile force in atrial muscle. In contrast, similar concentrations of 8‐bromo‐cyclic GMP had no effect on ventricular contractile force. 6 The positive inotropic action of phenylephrine on canine cardiac muscle, which is mediated through β‐adrenoceptors, was unaffected either by sodium nitroprusside or by 8‐bromo‐cyclic GMP.

The present results suggest that the effect of muscarinic receptor stimulation in canine atrial and ventricular muscle is related to different changes in intracellular cyclic nucleotide metabolism. The direct myocardial depressant action on atrial muscle seems to be related to an elevation of cyclic GMP level, whilst a reduction of cyclic AMP may be responsible for the indirect action (‘accentuated antagonism’) in both atrial and ventricular muscle.
INHIBITORY EFFECTS OF PROPRANOLOL ON THE CALCIUM CURRENT OF Helix NEURONES
Authors: AKAIKE N. , NISHI K. , OYAMA Y.
Published: July 2012

Calcium current (ICa) and potassium current (IK) in isolated nerve cell bodies of Helix aspersa were independently separated after suppression of Na+ and K+ currents, and Na+ and Ca2+ currents, respectively. The suction pipette method was used. Under voltage clamp conditions, the effects of propranolol on both the ICa and IK were examined.

Propranolol inhibits the ICa at relatively low concentrations (10−6‐10−5m). The inhibitory action was dose‐dependent.

The IK was moderately suppressed by the drug at high concentrations (10−5‐5 × 10−4m).

Results provide evidence for a new aspect of the pharmacological action of propranolol on the excitable cell membrane.
A RE‐EVALUATION OF ACETYLCHOLINE RECEPTORS ON FELINE RENSHAW CELLS
Authors: KING K.T. , RYALL R.W.
Published: July 2012

The effects of atropine, methylatropine and lachesine administered by ionophoresis were examined on responses of Renshaw cells to acetylcholine, acetyl‐β‐methylcholine, nicotine and DL‐muscarine in cats anaesthetized with pentobarbitone or chloralose.

The antagonists were as effective in antagonizing excitation by nicotine as they were in antagonizing excitation by acetylcholine and were only slightly more effective in antagonizing excitation by acetyl‐β‐methylcholine.

These results are discussed in relation to the characterization of acetylcholine receptors on Renshaw cells.

It is concluded that there are two distinct populations of receptors but that the nicotinic receptors are non‐selective in their activation by agonists and antagonists, whereas the muscarinic receptors display greater selectivity.
EFFECT OF HYPEROXIA ON UPTAKE AND METABOLISM OF 5‐HYDROXYTRYPTAMINE AND β‐PHENYLETHYLAMINE IN RAT LUNG: A SEX DIFFERENCE
Authors: BEN‐HARARI R.R. , LANIR A. , YOUDIM M.B.H.
Published: July 2012

The uptake of 5‐hydroxytryptamine (5‐HT) and β‐phenylethylamine (PEA) and their deamination by monoamine oxidase (MAO) were studied in perfused lung from male and female rats exposed to 100% O2 at 1 ATA for up to 60 h.

The uptake and metabolism of 5‐HT in lungs from both male and female rats was not changed by exposure to O2.

The uptake and metabolism of PEA by lungs from male rats was unchanged. Uptake of PEA by lungs from female rats was inhibited 20% and 62% after 37 h and 50 h exposure respectively.

MAO activity, both in vitro and in perfused lung, was increased towards PEA after 35 h of hyperoxia.

Metabolism of PEA in perfused lung, measured over 30 min, was inhibited 52% after 50 h of O2 hyperoxia.

These results show that exposure to high concentrations of O2 damages lung, resulting in inhibition of uptake of PEA and consequently in inhibition of metabolism of PEA.

These results also indicate that, in lung from female rats, MAO‐type B is more susceptible to changes in O2 tension than MAO type A.
THE BENEFICIAL ACTIONS OF BEPRIDIL IN ACUTE MYOCARDIAL INFARCTION IN ANAESTHETIZED DOGS
Authors: MARSHALL R.J. , MUIR A.W.
Published: July 2012

When administered intravenously shortly before acute coronary ligation in dogs anaesthetized with chloralose, bepridil (5 mg/kg) produced immediate and transient falls in coronary and systemic vascular resistance which were accompanied by marked decreases in myocardial oxygen extraction. These effects were followed by sustained decreases in heart rate and myocardial oxygen consumption.

This dose of bepridil reduced the number of premature ventricular beats and abolished fibrillation induced by coronary artery ligation without modifying the haemodynamic or metabolic consequences (lactate production) of myocardial ischaemia.

When administered 1.5‐2 h after ligation, bepridil did not compromise the critical perfusion of the acutely ischaemic zone but reduced the lactate production and ST‐segment elevation in the ischaemic zone.

These results suggest that bepridil may be a useful drug in the chronic treatment of angina pectoris and in this respect may possess advantages over β‐adrenoceptor antagonists.
In vivo PHARMACOLOGICAL STUDIES ON THE INTERACTIONS BETWEEN TRYPTAMINE AND 5‐HYDROXYTRYPTAMINE
Authors: JONES R.S.G.
Published: July 2012

Three methods have been used in an attempt to study the interactions of tryptamine with central 5‐hydroxytryptamine (5‐HT) systems.

In groups of mice pretreated with tranylcypromine, tryptamine reduced the number of mice showing head twitches following the 5‐HT precursor, 5‐hydroxytryptophan. This effect was not seen in mice pretreated with saline and tryptamine itself did not induce head twitches in either group.

The swallowing reflex induced by 5‐hydroxytryptophan in rats anaesthetized with urethane was substantially reduced by tryptamine injected into the internal carotid artery. This effect was seen in rats pretreated with saline or tranylcypromine, in the latter case the effects being more profound and longer lasting. In addition, swallowing evoked by the 5‐HT uptake blocker, fluoxetine, and the 5‐HT releaser, p‐chloroamphetamine, was also reduced by tryptamine.

5‐HT or noradrenaline injected intravenously into 5 day‐old chicks caused a dose‐dependent behavioural depression resembling sleep. Tryptamine at high doses caused behavioural alerting effects. Tryptamine at low doses had no overt effects but enhanced depression induced by 5‐HT. At behaviourally excitatory doses tryptamine reduced the duration of the 5‐HT depression. Noradrenaline‐induced depression was not affected by high or low doses of tryptamine.

The results show that tryptamine can have complex actions on 5‐HT systems depending on the parameter studied and support the notion that tryptamine may be a controlling factor in 5‐HT‐mediated transmission.
EFFECT OF SULPHATED POLYSACCHARIDES ON THE α1‐ANTITRYPSIN INHIBITION OF AMIDOLYSIS CATALYSED BY COAGULATION CASCADE PROTEINASES
Authors: LONG W.F. , WILLIAMSON F.B.
Published: July 2012

The ability of several sulphated polysaccharide anticoagulants to prevent α1‐antitrypsin inhibition of thrombin paralleled their ability to potentiate antithrombin III inhibition of thrombin. None of the compounds examined altered the ability of α1‐antitrypsin to inhibit activated coagulation factor X (Xa).

These results are consistent with the possibility that a direct polysaccharide‐proteinase interaction may be involved in the sulphated polysaccharide‐modulated inhibition of thrombin by antithrombin III.