bluuebunny/crossref_metadata_2025_split huggingface dataset:
SITES OF ACTION OF MOJAVE TOXIN ISOLATED FROM THE VENOM OF THE MOJAVE RATTLESNAKE
Authors: GOPALAKRISHNAKONE P. , HAWGOOD B.J. , HOLBROOKE S.E. , MARSH N.A. , DE SA S. SANTANA , TU A.T. 
Published: July 2012

Mojave toxin isolated from the venom of the Mojave rattlesnake (Crotalus scutulatus scutulatus) produced an irreversible blockade of the contractile response of the mouse hemidiaphragm to stimulation of the phrenic nerve in vitro, at concentrations of 0.16 to 20 μg/ml; the response to direct stimulation was not affected over a testing period of several hours.
Mojave toxin (1 to 4 μg/g) was injected into the tail vein of mice and the intoxicated hemidiaphragm preparation was removed either for testing the contractile response or for intracellular recording.
In fully intoxicated hemidiaphragms the contractile response to indirect stimulation was either small and transient or absent, whilst the response to direct stimulation was well maintained.
Intracellular recording showed that resting membrane potentials of the muscle fibres were within the normal range. Endplates were difficult to locate but miniature endplate potentials (m.e.p.ps) were recorded at sites at which neurally evoked responses either could not be detected or did not exceed 2 mV which corresponds to transmitter release of a few quanta only.
The mean frequency of m.e.p.ps at fully intoxicated endplates was not significantly different from controls but potassium depolarization produced only a small increase in m.e.p.p. frequency relative to the control response. A 50 Hz tetanus had no effect on m.e.p.p. frequency.
When a sub‐lethal dose (3 μg) of Mojave toxin was injected into one hindlimb of mice and the tissues examined at 72 h, there was histological evidence of myonecrosis.
The isolated perfused heart of the rat was exposed to recycled Mojave toxin (50 and 100 μg/ml) but showed no change in rate or force of ventricular contraction.
Post‐mortem examination of intoxicated mice showed a frequent incidence of localized areas of interstitial and intra‐alveolar haemorrhage in the lungs. Other organs including skin and muscle were not affected.
Mojave toxin showed antigenic similarities to crotoxin, the lethal neurotoxin in the venom of the South American rattlesnake, as determined by the ability of antiserum raised against crotoxin to neutralize Mojave toxin.
With systemic Mojave intoxication of rapid onset, the cause of death was respiratory paralysis. However, the toxin acts at multiple sites at differing rates of action. With a slower rate of intoxication, impaired respiration may act synergistically with cardiovascular changes to produce circulatory failure. The desirability of using an antivenin with a high titre against Mojave toxin is indicated.
THE EFFECTS OF SOME ANTIRHEUMATIC DRUGS ON AN in vitro MODEL OF HUMAN POLYMORPHONUCLEAR LEUCOCYTE CHEMOKINESIS
Authors: SMITH M.J.H. , WALKER J.R. 
Published: July 2012

A rapid, reproducible in vitro assay for studying the chemokinetic movement of human polymorphonuclear leucocytes (PMNs) is described. Two synthetic peptides, formyl methionyl‐leucylphenylalanine (FMLP) and formyl methionyl‐phenylalanine (FMP), were used as standard chemokinesins.
Maximal chemokinetic movement was observed with peptide concentrations of 2.5 nm (FMLP) and 100 μm (FMP). EC50 values of 650.0 ± 60.0 pm and 27.0 ± 3.5 μm respectively are similar to those reported for chemotactic activity of the peptides in micropore filter assays.
The PMN chemokinetic response to FMLP was enhanced by histamine (100 nm) and vitamin C (2.5 μm).
Human serum albumin was shown to induce chemokinesis but to antagonize the response to FMLP in a dose‐related fashion. Fibrinogen similarly antagonized the cell response to peptide.
Levamisole (250 nm to 2.5 μm) significantly potentiated the chemokinetic responses to FMLP and FMP in a dose‐related manner. The chemokinetic response to FMLP was unaffected by d‐penicillamine (250 μm to 10 mm) while alclofenac (500 μm to 1 mm), salicylic acid (250 μm to 10 mm) and indomethacin (100 μm to 1 mm) caused dose‐related inhibition.
A CLASSIFICATION OF OPIATE RECEPTORS THAT MEDIATE ANTINOCICEPTION IN ANIMALS
Authors: TYERS M.B. 
Published: July 2012

To investigate the opiate receptors that mediate antinociception, the activity profiles of opioid analgesic drugs have been determined against different nociceptive stimuli in the mouse and rat.
In tests that employ heat as the nociceptive stimulus, μ‐opiate receptor agonists, such as morphine, pethidine and dextropropoxyphene, had steep and parallel dose‐response curves and were capable of achieving maximum effects. In addition, the antinociceptive potency ratios of these drugs in heat tests were similar to those for analgesia in man.
The κ‐agonists, such as ethylketazocine, nalorphine, Mr2034 and pentazocine, were essentially inactive against heat nociception except at doses that caused sedation and motor incapacitation.
In the writhing and paw pressure tests both μ‐ and κ‐agonists produced steep and parallel dose‐response curves.
It is concluded that both μ‐ and κ‐opiate receptors mediate antinociception in animals and that the interactions of analgesic drugs with these receptors may be classified in terms of their antinociceptive activities against qualitatively different nociceptive stimuli.
EFFECTS OF DIAZEPAM ON ADENOSINE AND ACETYLCHOLINE RELEASE FROM RAT CEREBRAL CORTEX: FURTHER EVIDENCE FOR A PURINERGIC MECHANISM IN ACTION OF DIAZEPAM
Authors: PHILLIS J.W. , SIEMENS R.K. , WU P.H. 
Published: July 2012

Diazepam administered intraperitoneally (0.25 mg/kg) enhanced the rate of efflux of [3H]‐adenosine and its metabolites from rat cerebral cortex. At a lower dose (0.05 mg/kg), this effect could be detected in only one of four rats.
Diazepam (0.05 and 0.25 mg/kg i.p.) depressed acetylcholine release from the rat cerebral cortex. Its effect was reversed by theophylline.
Theophylline (15 and 30 mg/kg) enhanced acetylcholine release from the rat cerebral cortex. Diazepam (0.25 mg/kg) administered after theophylline failed to cause a reduction in the rate of release, rather there appeared to be a further enhancement of release.
Pentobarbitone sodium (5, 10 and 15 mg/kg i.p.) did not elicit any increase in adenosine release.
These results support the proposal that benzodiazepines may exert their pharmacological actions by preventing adenosine uptake, thus enhancing the levels of extracellular adenosine.
ON THE PREPARATION OF HIGHLY PURIFIED SLOW REACTING SUBSTANCE OF ANAPHYLAXIS (SRS‐A) FROM BIOLOGICAL EXTRACTS
Authors: BLACKWELL G.J. , BURKA J.F. , FLOWER R.J. , TORKINGTON P. 
Published: July 2012

Very highly purified (> 100,000 u/mg) slow reacting substance of anaphylaxis (SRS‐A) has been prepared by reversed phase high pressure liquid chromatographic (HPLC) techniques.
High resolution liquid chromatography suggests that SRS‐A may exist in at least three distinct forms which are possible tautomeric.
SRS‐A collected by antigen challenge in vivo and by calcium ionophore‐induced release in vitro are chromatographically indistinguishable.
Treatment of SRS‐A with diazomethane but not sodium borohydride results in a loss of biological activity but treatment of the methyl ester with base results in a partial recovery of activity.
Highly purified SRS‐A was examined by infrared and ultra‐violet spectroscopy, and found to have a benzene‐aromatic and probably an amino acid.
EFFECTS OF ENDORPHINS ON DIFFERENT PARTS OF THE GASTROINTESTINAL TRACT OF RAT AND GUINEA‐PIG in vitro
Authors: NIJKAMP F.P. , VAN REE J.M. 
Published: July 2012

The spasmogenic and spasmolytic effects of β‐lipotropin (LPH) fragments and one analogue were investigated on different parts of the gastro‐intestinal tract of guinea‐pig and rat in vitro.
Changes in muscle tone were observed in colon and rectum and to a lesser extent in jejunum and ileum of both species. Rat colon and rectum contracted to the peptides. Guinea‐pig colon and rectum relaxed after an initial short‐lasting contraction.
On the rat rectum (d‐ala2)met‐enkephalin, leu‐enkephalin, γ‐endorphin, α‐endorphin and β‐LPH 80–91 caused dose‐dependent contractions, their ED50 values being 0.96 × 10−12 mol, 1.05 × 10−11 mol, 1.22 × 10−11 mol, 1.08 × 10−10 mol, 2.65 × 10−10 mol and 6.5 × 10−9 mol, respectively.
Naloxone dose‐dependently shifted the dose‐response curve of met‐enkephalin to the right. Atropine, hexamethonium, burimamide, mepyramine, propranolol and indomethacin did not influence the response to met‐enkephalin.
In the presence of tetrodotoxin, the ED50 for met‐enkephalin and the maximal contractor response induced by met‐enkephalin, appeared to be increased.
The 5‐hydroxytryptamine (5‐HT) antagonists, methysergide and cyproheptadine, reduced the contractor response in a non‐competitive manner. The α‐adrenoceptor antagonist phentolamine, in contrast, caused an increase of the maximal response to met‐enkephalin of up to 200%. Noradrenergic and tryptaminergic systems, therefore, might be involved in the changes in muscle tone induced by met‐enkephalin.
These results demonstrate that rectum and colon of guinea‐pig and rat are very sensitive to opioid‐like peptides.
EVIDENCE FOR ANTITHROMBIN III INVOLVEMENT IN THE ANTI‐COAGULANT ACTIVITY OF CELLULOSE SULPHATE
Authors: KINDNESS G. , LONG W.F. , WILLIAMSON F.B. 
Published: July 2012

Cellulose sulphate, like heparin, prolonged the clotting time in partial thromboplastin time (PTT) assays, inhibited the amidolytic activity of thrombin, was without effect on amidolysis catalysed by activated coagulation factor X(Xa), and potentiated the inhibition of both thrombin and Xa by antithrombin III (AT).
The anticoagulant activity of cellulose sulphate in PTT assays was, like that of heparin and heparan sulphate, but unlike that of dermatan sulphate, reduced by prior incubation of plasma with antiserum specific for AT.
These results, which suggest that the anticoagulant activity of cellulose sulphate is at least partially mediated through AT, are discussed in terms of the structural features of polysaccharides required for AT activation.
HISTAMINE H1‐RECEPTORS IN THE BRAIN OF THE GUINEA‐PIG AND THE RAT: DIFFERENCES IN LIGAND BINDING PROPERTIES AND REGIONAL DISTRIBUTION
Authors: HILL S.J. , YOUNG J.M. 
Published: July 2012

The equilibrium dissociation constant, Kd, for mepyramine binding to a particulate fraction from rat brain, 9.1 nm, determined from inhibition of the binding of 1 nm [3H]‐mepyramine, was distinctly higher than that, 0.83 nm, measured on an equivalent preparation from guinea‐pig brain.
In rat brain the dissociation constant for mepyramine, determined from the binding of [3H]‐mepyramine sensitive to inhibition by 2 × 10−6 m promethazine, was higher than the constant obtained from the inhibition of the binding of 1 nm [3H]‐mepyramine by non‐radioactive mepyramine. This suggests that the promethazine‐sensitive binding of [3H]‐mepyramine includes a lower affinity non‐receptor component, which becomes apparent at higher concentrations of [3H]‐mepyramine.
In the guinea‐pig the dissociation constant for mepyramine determined from inhibition of [3H]‐mepyramine binding was in good agreement with the value obtained from inhibition of the contractile response of intestinal smooth muscle to histamine. No similar comparison was possible in the rat. Rat ileum was much less sensitive to histamine and the contraction produced was not inhibited by 10−6 m mepyramine, indicating that it is not mediated by H1‐receptors.
Low levels of promethazine‐sensitive [3H]‐mepyramine binding were present in membrane fractions prepared from the longitudinal muscle from rat small intestine, but the characteristics of this binding suggest that it may be largely to lower affinity, non‐receptor sites.
Promethazine was practically equipotent as an inhibitor of [3H]‐mepyramine binding in rat and guinea‐pig brain. Chlorpheniramine snowed stereospecificity in the rat as in the guinea‐pig, although the potency of the (+)‐isomer in the rat was only a tenth of that in the guinea‐pig. Histamine had nearly the same IC50 in both species.
The evidence suggests that the high‐affinity [3H]‐mepyramine binding sites in rat brain can be described as H1‐receptors, but that these differ structurally from H1‐receptors in the guinea‐pig.
The regional distribution of [3H]‐mepyramine binding in rat brain was not the same as that in guinea‐pig brain, the most notable difference being the very much lower level in rat cerebellum compared to guinea‐pig cerebellum.
PROSTAGLANDIN ACTION, RELEASE AND INACTIVATION BY RAT ISOLATED PERFUSED MESENTERIC BLOOD VESSELS
Authors: COUPAR I.M. 
Published: July 2012

The following experiments were undertaken to confirm that prostaglandin is necessary for noradrenaline to exert its full vasoconstrictor effect in rat mesenteric blood vessels. Prostaglandin release and inactivation were also studied.
The cyclo‐oxygenase inhibitor, 5, 8, 11, 14‐eicosatetraynoic acid caused a significant depression of the concentration‐effect curve to noradrenaline. As with indomethacin, responses were restored to control levels by prostaglandin E2 (PGE2) but PGE2 did not restore responses to noradrenaline depressed by papaverine.
PGE2‐like activity was released from tissues at rest, equivalent to 50 ± 20 pg PGE2/min. The substance was probably a stable prostaglandin since activity remained on acidifying and extracting into chloroform. The increase in release stimulated by noradrenaline was reduced below resting values by indomethacin.
There was a net loss of 7 ± 1 and 1 ± 0.2 ng PGE2/min from tissues perfused with 40 and 4 ng/min PGE2 respectively. No uptake occurred at lower PGE2 perfusion rates.
When indomethacin was used to depress responses to noradrenaline 15(S)‐15‐methyl PGE2 methyl ester was 12 times more potent than PGE2 in restoring responses to control values. The cyclic endoperoxide analogue U‐46619 caused only partial restoration of indomethacin‐depressed responses to noradrenaline but increased perfusion pressure at 2 ng/ml and above.
The results confirm that endogenous prostaglandin release, possibly of PGE2, is obligatory to the full vasoconstrictor effect of noradrenaline. Noradrenaline increases the amount of prostaglandin released which may then be taken up and inactivated by 15‐hydroxy prostaglandin dehydrogenase or β‐oxidase. U‐46619 may mimic both PGE2 and thromboxane A2.
THE EFFECTS OF NONIDET P40 ON THE FUNCTION OF RAT PERITONEAL MAST CELLS in vitro
Authors: BATCHELOR K.W. , STANWORTH D.R. 
Published: July 2012

Treatment of purified rat peritoneal mast cells at 37°C with concentrations of the non‐ionic detergent nonidet P40 (NP40) up to 0.005% (v/v) failed to reduce their viability.
There was a marked reduction in the histamine releasing capacity of NP40‐treated mast cells upon challenge with a variety of selective (adrenocorticotrophic hormone 1–24 (Synacthen), rabbit anti‐rat IgE antiserum, adenosine triphosphate (ATP) and the calcium ionophore, A 23187) and non‐selective (rabbit anti‐rat mast cell antiserum plus complement) histamine liberators.
Nonidet P40 (0.005%) was found to reduce the activity of a mast cell membrane ‘ecto‐enzyme’, calcium‐activated ATPase, by about 45% when present at the time of its assay.
DISSOCIATION CONSTANTS OF ISOPRENALINE AND ORCIPRENALINE AND THEIR RELATIVE EFFICACIES ON GUINEA‐PIG ISOLATED ATRIA DETERMINED BY USE OF AN IRREVERSIBLE β‐ADRENOCEPTOR ANTAGONIST
Authors: BROADLEY KENNETH J. , NICHOLSON C. DAVID 
Published: July 2012

Dissociation constants (Ka) of isoprenaline and orciprenaline were determined for the positive inotropic and chronotropic responses of guinea‐pig isolated atria. Cumulative dose‐response curves to the agonists were constructed before and after incubation with and washout of the irreversible β‐adrenoceptor antagonist, Ro 03–7894 1‐(5‐chloracetylaminobenzfuran‐2‐yl)‐2‐isopropylaminoethanol).
After 20 min washout, the curves were displaced to the right with depression of the maxima. After 3 h washout, there was only depression of the maxima.
Dissociation constants were determined by plotting reciprocals of molar concentrations before Ro 03–7894 (1/A) against reciprocals of the equiactive concentrations after Ro 03–7894 (1/A'). Ka = (slope‐1)/intercept.
Isoprenaline had a greater affinity (Ka) than orciprenaline on both rate and tension. The affinity for rate and tension was identical for both agonists, indicating that the β‐adrenoceptors were identical.
Isoprenaline and orciprenaline produced identical rate response maxima when compared in the same preparation but the orciprenaline tension maximum was only 92.0 ± 0.3% that of isoprenaline.
These dose‐response curves were replotted as response against ‐log RA/Rt (fraction of receptors occupied) for each agonist concentration, calculated from the equation RA/Rt = (A)/(Ka + (A)). The antilogarithm of the distance along the ‐log RA/Rt axis gave the efficacy of orciprenaline relative to isoprenaline. It had a greater efficacy (2.24) for rate responses but a lower efficacy for tension responses (0.5).
EFFECTS OF 6‐[p‐(4‐PHENYLACETYLPIPERAZIN‐1‐YL)PHENYL]‐4,5‐DIHYDRO‐3(2H)PYRIDAZINONE (CCI 17810) AND ASPIRIN ON PLATELET AGGREGATION AND ADHESIVENESS
Authors: GRIFFETT ELIZABETH M. , KINNON SUSAN M. , KUMAR A. , LECKER DOROTHY , SMITH GILLIAN M. , TOMICH THE LATE E.G. 
Published: July 2012

The effects of 6‐[p‐(4‐phenylacetylpiperazin‐1‐yl)‐phenyl]‐4,5‐dihydro‐3(2H)pyridazinone (CCI 17810) on platelet aggregation and adhesiveness have been investigated and compared with those of aspirin.
In vitro, CCI 17810 was a potent inhibitor of the aggregation of human platelets induced by collagen, adenosine 5′‐diphosphate (ADP) (primary response), thrombin and arachidonic acid, with EC50 values in the range 0.5 to 10 μg/ml. The second phase of the response to adrenaline was blocked by concentrations in the range 15 to 25 μg/ml. Platelets from rats, rabbits and dogs were as sensitive as human platelets to the effects of CCI 17810. Aspirin was nearly as effective as CCI 17810 against collagen, and adrenaline but about 10 times less active against arachidonic acid; it did not inhibit the primary response to ADP and was only a weak inhibitor of thrombin‐induced aggregation.
In mice, single oral doses of CCI 17810 in the range 12.5 to 100 mg/kg inhibited collagen‐induced thrombocytopenia. Arachidonic acid‐induced mortality was markedly reduced by 10 mg/kg and possibly slightly reduced by 1 mg/kg. Aspirin was considerably less active than CCI 17810 in inhibiting collagen‐induced thrombocytopenia but was almost as active as CCI 17810 in reducing arachidonic acid‐induced mortality.
In vitro, CCI 17810 reduced the adhesiveness of human platelets to glass beads (retention of platelets in glass bead columns). Single oral doses of CCI 17810 in the range 25 to 200 mg/kg reduced mouse platelet adhesiveness; rat platelet adhesiveness was reduced by doses in the range 12.5 to 100 mg/kg. Aspirin (20 or 200 mg/kg) slightly increased mouse platelet adhesiveness.
ONTOGENESIS OF UPTAKE AND DEAMINATION OF 5‐HYDROXYTRYPTAMINE, DOPAMINE AND β‐PHENYLETHYLAMINE IN ISOLATED PERFUSED LUNG AND LUNG HOMOGENATES FROM RATS
Authors: BEN‐HARARI R.R. , YOUDIM M.B.H. 
Published: July 2012

Uptake of 5‐hydroxytryptamine (5‐HT) and β‐phenylethylamine (PEA) was studied in perfused lung from male rats between 10 and 70 days old.
Monoamine oxidase (MAO) activity towards 5‐HT, PEA and dopamine was studied in homogenate preparations of lung from rats aged between 5 and 80 days.
Uptake of 5‐HT (10 μm) decreased throughout the age range studied but uptake of PEA (50 μm) increased for the first 30 days and beyond this age it decreased. Metabolites formed for both amines reflected the changes in uptake.
MAO activity deaminating 5‐HT is well developed by day 10 and reaches its maximum by day 40. For dopamine and PEA, MAO activity remained low until day 20, and then developed rapidly, reaching a maximum by day 40 for dopamine; activity towards PEA did not reach a maximum by day 80.
These results show that uptake and MAO activity changes with age and thus the lung responds like other tissues.
These results also demonstrate the independent development of uptake and MAO activity towards 5‐HT, PEA and dopamine.
EXCITATORY EFFECT OF A NEW POLYPEPTIDE (ANTHOPLEURIN‐B) FROM SEA ANEMONE ON THE GUINEA‐PIG VAS DEFERENS
Authors: NORTON T.R. , OHIZUMI Y. , SHIBATA S. 
Published: July 2012

Anthopleurin‐B (AP‐B, > 3 × 10−9 m), a newly isolated polypeptide from sea anemone (Anthopleura xanthogrammica), caused powerful rhythmic contractions in the guinea‐pig isolated vas deferens. The other polypeptides anthopleurin‐A from A. xanthogrammica and anthopleurin‐C from A. elegantissima, elicited similar effects but in higher concentrations (> 5 × 10−8 m). Toxin II (10−6 m) isolated from the sea anemone, Anemonia sulcata, had no effect
The rhythmic contractions induced by AP‐B were inhibited by phentolamine, bretylium, guanethidine, reserpine, 6‐hydroxydopamine, tetrodotoxin (TTX) and verapamil. Mecamylamine, atropine, methysergide, chlorpheniramine, and indomethacin had no effect
AP‐B (10−8m ∼10−5m) caused a dose‐dependent increase in the amount of endogenous noradrenaline (NA) released from the vas deferens. AP‐B (10−5m) increased the amount of NA released to approximately 310 times (12 μ/g tissue) that of untreated tissues
The AP‐B‐induced release of N A was inhibited or abolished by TTX, verapamil, or incubation in Ca‐free medium
These results suggest that the AP‐B‐induced rhythmic contraction of the vas deferens is mediated through the release of NA from adrenergic nerve endings; AP‐B is one of the most potent substances in stimulating NA release from the vas deferens.
DRUG‐RECEPTOR RECOGNITION: MOLECULAR ORIENTATION AND DIELECTRIC EFFECTS
Authors: DEAN P.M. 
Published: July 2012

The orientation of ethidium and its carboxyphenyl derivative was computed at various positions around one turn of the B‐DNA helical receptor
Dielectric effects of solvent were included using values for the bulk constant and a dielectric vector to simulate dielectric inhomogeneities
From the electrostatic energy values for the orientations, the corresponding Boltzmann distributions were obtained to assess the orientation restriction to the drug imposed by the receptor
A correlation was observed between the direction of the drug molecular dipole and the local line of force generated by the receptor vector field
These findings are discussed with respect to the phenomenon of drug‐receptor recognition.
USE OF POTENTIATION OF THYROTROPHIN RELEASING HORMONE (TRH)‐INDUCED HYPERTHERMIA AS A TEST FOR SCREENING ANTIDEPRESSANTS WHICH ACTIVATE α‐ADRENOCEPTOR SYSTEMS
Authors: DESILES MARGUERITE , RIPS RICHARD 
Published: July 2012

The minimal dose which significantly potentiates the hyperthermia induced by thyrotrophin releasing hormone (TRH, 40mg/kgi.p.) in mice has been established for tricyclic and other antidepressants (imipramine, amitriptyline, clomipramine, nortriptyline, maprotiline, nomifensine, viloxazine) including a specific inhibitor of noradrenaline (NA) uptake (nisoxetine)
The minimal effective dose in this test has been compared with the minimal dose of the same compounds antagonizing reserpine‐induced hypothermia. The ratio of the two doses for each substance indicates that potentiation of TRH‐induced hyperthermia is, in general, the more sensitive test
A correlation seems to exist between the α‐adrenergic effect of antidepressants and the potentiation of TRH‐induced hyperthermia. Those antidepressants which do not act on α‐adrenergic systems (butriptyline, amineptine, trazodone, danitracen, fluoxetine) are inactive in this test
This property may be used to select antidepressants that activate α‐adrenoceptor systems.