bluuebunny/crossref_metadata_2025 huggingface dataset:
PROPHYLACTIC ADMINISTRATION OF ANTIBIOTICS COMPROMISES RETICULOENDOTHELIAL SYSTEM FUNCTION AND EXACERBATES SHOCK MORTALITY IN RATS
Authors: ALTURA BURTON M. , GEBREWOLD ASEFA
Published: July 2012

The effects of short‐term (3 days) administration of three different antimicrobial agents (i.e., kanamycin, cephalothin and polymyxin B) on reticuloendothelial system (RES) phagocytic function and mortality after bowel ischaemic shock was studied in intact rats. All three antibiotics significantly depressed RES phagocytic function and exacerbated mortality after shock. The degree of antibiotic‐induced inhibition of RES function seemed to parallel the antimicrobial effects on shock mortality; the greater the degree of RES inhibition, the greater the degree of exacerbation of shock mortality. In view of such findings, caution should be exercised in administering antibiotics prophylactically to patients and animals.
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.
HISTAMINE RELEASE FROM HUMAN RIGHT ATRIUM
Authors: GRISTWOOD R.W. , LINCOLN J.C.R. , OWEN D.A.A. , SMITH I.R.
Published: July 2012

Histamine release has been detected biologically after exposure of human right atrial biopsy samples to compound 48/80. Human right atrial samples contain large quantities of histamine, 1035±65ng/g fresh weight. Exposure of untreated electrically paced atrial strips to compound 48/80, 300 μg/ml, caused an increase in the force of atrial contraction similar to that caused by histamine. Pretreatment of strips with cimetidine, 3.16×10−5 m, prevented the inotropic response to compound 48/80. It is concluded that mast cell degranulation in human atrial tissue can cause sufficient release of histamine to modify the function of the heart.
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.
INHIBITION OF LYMPHOCYTE PROLIFERATION BY HISTAMINE AND RELATED COMPOUNDS NOT MEDIATED VIA H1‐ OR H2‐ RECEPTORS
Authors: GORDON D. , LEWIS G.P. , NOURI A.M.E.
Published: July 2012

The effects of histamine and chemical analogues were examined on mitogen‐stimulated human lymphocyte proliferation

Compounds with selective agonist activity at either H1‐ or H2‐receptors were found to inhibit proliferative responses, although N‐3‐methyl‐histamine which does not act on either receptor was as inhibitory as histamine itself

The H2‐receptor agonist, dimaprit, had a profound inhibitory effect on proliferation, however nordimaprit, which has little or no H2‐agonist activity, was more active on lymphocytes. Impromidine, although a potent H2‐agonist, failed to produce such inhibition

The effects of dimaprit and nordimaprit were not reversed by H2‐receptor antagonists, cimetidine or metiamide

These results do not support the view that the antiproliferative effects of histamine and related compounds are mediated via conventional H1‐ or H2‐receptors

SKF 93390 was found to be the most active of the dimaprit analogues tested, which could represent a novel series of potential immunosuppressive agents.
A COMPARISON OF THE EFFECTS OF NIFEDIPINE AND VERAPAMIL ON RAT VAS DEFERENS
Authors: FRENCH A.M. , SCOTT N.C.
Published: July 2012

Nifedipine preferentially blocks contractions of the prostatic end of the rat vas deferens to single pulse field stimulation, leaving the epididymal end largely unaffected. This action is not due entirely to antagonism of calcium influx. Verapamil unexpectedly potentiated the responses of the prostatic portion, and antagonized those of the epididymal end. The use of nifedipine may, therefore, allow investigations of adrenergic mechanisms on this tissue to be studied without the complications of non‐adrenergic transmission.
THE ROLE OF CALCIUM IN THE EFFECTS OF NORADRENALINE AND PHENOXYBENZAMINE ON ADRENERGIC TRANSMITTER RELEASE FROM ATRIA: NO SUPPORT FOR NEGATIVE FEEDBACK OF RELEASE
Authors: KALSNER STANLEY
Published: July 2012

The relation of calcium ion influx into nerve terminals to presynaptic adrenoceptor function and the possible masking, by desensitization due to intraneuronal calcium accumulation, of the effects of adrenoceptor agonists and antagonists on presynaptic α‐adrenoceptors was investigated in guinea‐pig atria previously incubated with [3H]‐noradrenahne.

Atria were stimulated with 100 pulses at various frequencies (1 to 15 Hz) in standard (2.3 mm), low (0.26 mm) and high (6.9 mm) calcium‐Krebs solution in the absence and then the presence first of noradrenaline and subsequently phenoxybenzamine.

The per pulse overflow of tritium was directly related to the calcium concentration of the Krebs solution, being much reduced and substantially increased in 0.26 and 6.9 mm calcium‐Krebs solutions respectively.

Noradrenaline inhibited the overflow of tritium in low calcium‐Krebs solution, to a relatively constant extent, independently of frequency. In addition, the agonist had a greater maximal inhibitory effect in standard than in reduced calcium‐Krebs. The catecholamine was as effective an inhibitor of overflow at the lowest and highest frequencies in high as it was in standard calcium‐Krebs solution. Phenoxybenzamine invariably increased the tritium overflow but was generally less effective both in low and in high calcium‐Krebs solution. The patterns of inhibition and enhancement of stimulation‐induced tritium overflow by these two agents do not indicate an intimate relationship between calcium influx and adrenoceptor activation; nor does desensitization appear to be an adequate explanation of the relationship between frequency of stimulation and the intensity of agonist and antagonist effect in the three different calcium concentrations.

It is concluded that the perineuronal levels of adrenergic transmitter do not establish the magnitudes of effect of exogenous adrenoceptor agonists and antagonists on tritium overflow and that a negative feedback regulation of release by transmitter is exceedingly unlikely under ordinary conditions of neurotransmission.
IDENTIFICATION OF A PURINE (P2) RECEPTOR LINKED TO ION TRANSPORT IN A CULTURED RENAL (MDCK) EPITHELIUM
Authors: SIMMONS N.L.
Published: July 2012

Exogenous adenosine triphosphate (ATP) stimulates the short circuit current (SCC) in a cultured renal‐derived epithelium (MDCK). Half‐maximal stimulation is achieved at 1.91 × 10−5m ATP.

It is suggested that ATP interacts with a P2 purine receptor upon the basis of (a) agonist potency (ATP > adenosine diphosphate >> adenosine monophosphate, adenosine; ATP> uridine triphosphate > inosine triphosphate >> cytosine triphosphate, guanosine triphosphate); (b) the inhibition of the ATP response by quinidine (1×10−3m) but not by theophylline (1×10−3m).

Indomethacin (1 × 10−5m) inhibits the response of the cultured epithelium to ATP.

Prostaglandin E1 (PGE1) stimulates SCC but potentiates the effect of ATP on SCC. The divalent cationic ionophore A23187 (1 × 10−6m) transiently stimulates SCC itself and abolishes ATP‐induced stimulation of the SCC.
ON THE CALCIUM RECEPTOR THAT MEDIATES DEPOLARIZATION‐SECRETION COUPLING AT CHOLINERGIC MOTOR NERVE TERMINALS
Authors: SILINSKY E.M.
Published: July 2012

The behaviour of the divalent cations Ca and Sr as agonists for receptors that mediate the synchronous evoked secretion of acetylcholine (ACh) was studied in the hope of determining whether the relationship between Ca binding and ACh secretion is determined only by the law of mass action or by the mathematical framework of receptor theory. Experiments were designed to evaluate the assumption that maximum effect requires occupation of all receptors by testing for the presence of spare Ca receptors on presynaptic terminals. Frog cutaneous nerve‐muscle preparations were employed in conjunction with conventional electrophysiological methods.

Curves of log [Ca] or log [Sr] against the mean number of ACh quanta released (m) were constructed to saturation. The log [Sr]‐m relationship was shifted to the right and had a smaller maximum than the log [Ca]‐m curve. This suggests that Ca has a higher efficacy than Sr and raises the possibility that spare binding sites are present for Ca.

As a qualitative test for spare Ca receptors, La3+(≤0.5 μm) or 2‐chloroadenosine (25 μm) was employed as an irreversible antagonist of the effects of extracellular Ca on evoked ACh release. Despite the irreversible blockade of a proportion of receptors, increases in the [Ca] overcame this antagonism and produced a parallel shift in the log [Ca]‐m relation to the right. This suggests an apparent receptor reserve for Ca. Antagonism of Sr‐mediated ACh release by either La3+ or 2‐chloroadenosine could not be overcome by increasing the [Sr].

As a quantitative test for spare Ca binding sites, the equilibrium affinity constant for Sr(KSr) as a competitive inhibitor of Ca was determined and compared with values for KSr calculated by two other methods which invoke the spare receptor assumption. All three methods produced comparable results. (KSr = 0.24‐0.27 mm−1).

The equilibrium affinity constant for Ca (KCa) was calculated by comparing reciprocal plots of the concentrations of Ca that produce equal levels of ACh release in the presence and absence of La3+(0.5 μm‐3 μm). KCa was estimated to be between 0.02 and 0.06 mM−1.

Efficacy (e), which is thought to reflect the ability of Ca or Sr once bound to receptors to support ACh release, was determined by the modified occupation theory of Stephenson (1956). The eCa was estimated to be 9–20 and eSr was 0.2‐0.5.

The experimentally determined values for ATCa, KSt, eCa, eSr along with the assumptions that spare Ca binding sites exist and that the non‐linearities in the log [Ca] or log [Sr]‐m curves are introduced beyond the sites of binding and efficacy were used to generate theoretical log [Me]‐m curves. The theoretical relationships were similar to the experimental results.

The results suggest that spare Ca receptors are present at motor nerve endings and that receptor theory provides an accurate quantitative description of the lumped events between Ca binding and ACh secretion. The possible physical correlates of affinity and efficacy are discussed.
THEOPHYLLINE INHIBITION OF RENAL AND CEREBRAL NUCLEOSIDE FORMATION
Authors: JENSEN MOGENS H.
Published: July 2012

Theophylline inhibits the enzymatic formation of purine nucleosides, among these adenosine (dephosphorylated adenosine 5′‐monophosphate), in kidney and brain of the rat.

Some pharmacological effects of theophylline on regional blood flow and electrophysiological activity of the nervous system may be caused by inhibition of the endogenous formation of adenosine.
THE EFFECTS OF ATROPINE AND OXOTREMORINE ON ACETYLCHOLINE RELEASE IN RAT PHRENIC NERVE‐DIAPHRAGM PREPARATIONS
Authors: ABBS E.T. , JOSEPH D.N.
Published: July 2012

Atropine (10−5m) enhanced the release of [3H]‐acetylcholine from rat isolated hemidiaphragms, previously incubated with [3H‐methyl]‐choline, stimulated via their phrenic nerves.

Oxotremorine (10−5m) did not affect the stimulated release of [3H]‐acetylcholine but antagonized the facilitatory effects of atropine (10−5m).

It is suggested that there are presynaptic inhibitory muscarinic receptors that modulate the release of acetylcholine in the phrenic nerves of the rat.
INHIBITION OF ARACHIDONIC ACID RELEASE AS THE MECHANISM BY WHICH GLUCOCORTICOIDS INHIBIT ENDOTOXIN‐INDUCED DIARRHOEA
Authors: DOHERTY NIALL S.
Published: July 2012

Dexamethasone blocked endotoxin‐induced diarrhoea in mice, but not that induced by arachidonic acid or prostaglandin E2.

Indomethacin blocked endotoxin and arachidonic acid‐induced diarrhoea, but not that induced by prostaglandin E2.

Codeine blocked all three forms of diarrhoea.

The above data, when considered in relation to literature reports that endotoxin induces prostaglandin synthesis, suggest that dexamethasone blocks diarrhoea by preventing the release of arachidonic acid, the substrate for prostaglandin biosynthesis.

The activities of indomethacin and dexamethasone in castor oil diarrhoea support the above conclusion and their inactivity in 5‐hydroxytryptophan‐induced diarrhoea confirms the absence of ‘codeine‐like’ direct effects on the gut.

Other glucocorticoids (hydrocortisone, prednisolone) were also able to block endotoxin diarrhoea, but oestradiol, testosterone and progesterone did not.

The inhibitory action of dexamethasone on endotoxin diarrhoea could not be blocked by the protein synthesis inhibitor, cycloheximide, nor by the glucocorticoid receptor antagonist, progesterone. Thus, involvement of glucocorticoid receptor‐mediated gene activation could not be demonstrated.
EVIDENCE FOR AN INHIBITORY PRESYNAPTIC COMPONENT OF NEUROLEPTIC DRUG ACTION
Authors: de BELLEROCHE J.S. , BRADFORD H.F.
Published: July 2012

The action of five neuroleptic drugs (haloperidol, cis‐flupenthixol, chlorpromazine, fluphenazine and thioridazine) was studied on the synthesis and release of dopamine from rat striatal synaptosomes.

In vitro application of the drugs induced an inhibition of synthesis of [14C]‐dopamine from l‐[U‐14C]‐tyrosine and a decrease in the tissue content of [14C]‐dopamine, with IC50 values for the latter effect ranging from 3.6 × 10−7 to 5.9 × 10− 5 m. The rank order of their potency was similar to the order of their clinical effectiveness: haloperidol>fluphenazine>cis‐flupenthixol>chlorpromazine>thioridazine. Trans flupenthixol was without effect up to a concentration of 10−4 m.

The tissue level and release of GABA were not affected by concentrations of the neuroleptics up to 10−4 m.

When the neuroleptics were administered in vivo, changes were also detected in the synthesis and release of [14C]‐dopamine from subsequently prepared synaptosomes. A marked inhibition of the K+‐induced increase in [14C]‐dopamine synthesis was seen following a dose of 2 mg/kg cis‐flupenthixol and haloperidol. At this concentration, haloperidol also increased the control release of [14C]‐dopamine and reduced the K+‐induced increase in release of [14C]‐dopamine.

Cis‐flupenthixol at a dose of 20 mg/kg reduced the K+‐induced release of [14C]‐dopamine by 48% and to a lesser extent, that of γ‐aminobutyric acid (GABA, 25%).

An inhibitory mode of action is proposed for neuroleptics mediated through a presynaptic mechanism.
ENKEPHALIN RECEPTORS IN THE EMETIC CHEMORECEPTOR TRIGGER ZONE OF THE DOG
Authors: BHARGAVA K.P. , DIXIT K.S. , GUPTA Y.K.
Published: July 2012

The emetic action of Met‐enkephalin, morphine and naloxone was studied following their administration into the cerebral ventricles of dogs through chronically implanted cannulae and the effect on the responses of ablating the chemoreceptor trigger zone (CTZ) was investigated. The opiate antagonist, naloxone, was used to determine the role of enkephalin receptors in emetic responses.

Administration of Met‐enkephalin (1.0 μg/kg) into the IVth ventricle regularly evoked emesis with an average latency of 35 s. A dose of morphine (2.5 μg/kg) which was five times larger was required for a consistent emetic response when introduced into the lateral cerebral ventricle (i.c.v.) as compared to the dose required by the IVth ventricular route. The latency of emetic responses by the latter route of injection of morphine was shorter. This is in accord with an action of morphine on the emetic CTZ.

After bilateral ablation of the CTZ, intraventricular injections of Met‐enkephalin and morphine failed to produce emesis even when given in doses that were 5 to 10 times the dose which regularly elicited emesis in animals with intact CTZ. The emesis produced in dogs by intraventricular Met‐enkephalin and morphine is thus fully accounted for by an action on the CTZ.

Naloxone (i.c.v.) in doses up to 10.0 μg/kg did not cause emesis. However, higher doses of naloxone elicited dose‐dependent emesis in dogs. The 100% emetic dose of naloxone was found to be 160 μg/kg and the latency of emesis was 180 s. Unlike Met‐enkephalin and morphine, naloxone continued to elicit emesis in CTZ‐ablated animals.

Pretreatment with intraventricular naloxone (1 to 8 μg/kg) blocked the emetic responses induced by intraventricular Met‐enkephalin and morphine but not that to apomorphine. The selective protective action of the opiate antagonist against Met‐enkephalin and morphine supports the presence of enkephalin receptors in the emetic CTZ.
THE EFFECTS OF CHRONIC SECTION OF DORSAL ROOTS ON THE RESPONSIVENESS OF MOTONEURONES TO 5‐HYDROXYTRYPTAMINE AND A SUBSTANCE P ANALOGUE
Authors: ROBERTS M.H.T. , WRIGHT D. M.
Published: July 2012

Experiments were performed on rats 14–21 days after unilateral dorsal root section in order to determine if the effects on motoneurone excitability of a substance P analogue, 5‐hydroxy‐tryptamine (5‐HT) and noradrenaline were altered by section of primary afferents.

The effects of iontophoretic applications of these agents on motoneurone excitability were quantified by measuring the change in amplitude of the short latency field potentials evoked antidromically, by ventral root stimulation.

Iontophoretic application of the substance P analogue (eledoisin‐related peptide, ERP) always produced an increase in the amplitude of the field potential. These increases in amplitude were 25.9% larger on the sides of the cords with sectioned dorsal roots. This was not a statistically significant difference (P<0.05).

Section of dorsal roots did not alter responses to noradrenaline.

Responses to 5‐HT were significantly larger following section of dorsal roots. There is very little evidence for the release of 5‐HT by primary afferents and denervation supersensitivity is an improbable explanation. It is possible that descending 5‐HT systems directly excite motoneurones and indirectly inhibit primary afferent transmission. Dorsal root section would alter the balance between these actions of 5‐HT in favour of an excitatory effect.
MECHANISM OF ANTI‐INFLAMMATORY ACTION OF GLUCOCORTICOIDS: RE‐EVALUATION OF VASCULAR CONSTRICTION HYPOTHESIS
Authors: SUGIO KAZUO , TSURUFUJI SUSUMU
Published: July 2012

The question whether constriction of local vessels is essential for the anti‐inflammatory action of glucocorticoids in carrageenin‐induced granulomatous inflammation was studied.

The vasodilator prostaglandin E1 injected into the granuloma pouch fluid increased the exudation of plasma protein into the granuloma tissue.

Noradrenaline significantly reduced plasma exudation, possibly through α‐adrenoceptor stimulation.

Cortisol and dexamethasone in doses sufficient to inhibit vascular permeability were without effect on the blood content in the granuloma tissue.

The results suggest that constriction of local vessels does not play an essential role in the anti‐exudative effect of glucocorticoids in chronic proliferative inflammation.
PHARMACOLOGICAL DATA ON DERMORPHINS, A NEW CLASS OF POTENT OPIOID PEPTIDES FROM AMPHIBIAN SKIN
Authors: BROCCARDO M. , ERSPAMER V. , FALCONIERI G. , IMPROTA G. , LINARI G. , MELCHIORRI P. , MONTECUCCHI PC.
Published: July 2012

Dermorphin and Hyp6‐dermorphin are the first representatives of a new class of potent opioid peptides occurring in amphibian skin. They present the unique feature of having a D‐Ala residue incorporated in the peptide molecule.

Dermorphin displayed a potent depressive action on electrically stimulated contractions of the guinea‐pig ileum and mouse vas deferens preparations. Dermorphin was respectively 57,294, 18 and 39 times more potent than Met‐enkephalin, Leu‐enkephalin, β‐endorphin, and morphine on the guinea‐pig ileum opiate receptors. On the vas deferens receptors, dermorphin was about as potent as the enkephalins and 40 times more potent than morphine. Naloxone was a powerful antagonist to dermorphin in both preparations.

Dermorphin produced potent and long‐lasting analgesia in mice by intravenous injection, and in rats by intracerebroventricular injection, the ED50 being here of the order of 13–23 pmol/rat. Morphine was 752 and 2170 times less potent, depending on the analgesia test used. At high intracerebroventricular doses analgesia was accompanied by catalepsy.

Intracerebroventricular infusion of dermorphin induced development of tolerance and precipitation of withdrawal symptoms upon administration of naloxone. Both tolerance and physical dependence were consistently less marked with dermorphin than with morphine.

The minimum sequence requirement for full dermorphin activity was represented by the N‐terminal tetrapeptide. The presence of the D‐Ala2 residue was of crucial importance.
EFFECTS OF DIVALENT AND LANTHANIDE IONS ON MOTILITY INITIATION IN RAT CAUDAL EPIDIDYMAL SPERMATOZOA
Authors: LEE W.M. , TSANG A.Y.F. , WONG P.Y.D.
Published: July 2012

Sperm motility initiation of rat caudal epididymal spermatozoa in vitro has been studied.

Spermatozoa flushed out from the cauda epididymis with a sodium‐free medium exhibited a transient motility which decreased progessively. At 40 min, the forward motility was completely suppressed. However, if they were resuspended in a sodium containing medium their motility was completely restored to normal within 15 min.

This initiation of sperm motility required the presence of extracellular calcium. Maximal stimulation was obtained at a calcium concentration of 10 −3M. Above this concentration, further increase in calcium produced a fall in motility and at 10 −2M, motility initiation was completely suppressed.

The initiation of sperm motility has been shown to depend closely on sodium. Sperm motility initiation alters in a curvilinear fashion with extracellular sodium concentration showing saturation kinetics. High calcium (above 10−3m) was found to depress motility initiation induced by sodium, without affecting the apparent affinity constant for sodium.

The effect of Ca2+ on sperm motility initiation could be mimicked by Sr2+ but not by Mg2+, La3+ or Eu3+.

In the presence of extracellular calcium (1.27 or 2.54 mM), La3+ and Eu3+ exerted a dose‐dependent inhibition of sperm motility initiation. The IC50 values for both ions were about 5 × l0−5M.

The possible mechanism of inhibition by lanthanide ions is discussed.
ON THE MECHANISM BY WHICH VERATRIDINE CAUSES A CALCIUM‐INDEPENDENT RELEASE OF γ‐AMINOBUTYRIC ACID FROM BRAIN SLICES
Authors: CUNNINGHAM JO , NEAL M.J.
Published: July 2012

The mechanisms by which veratridine increases the release of γ‐aminobutyric acid (GABA) from brain slices have been studied.

Exposure of superfused cerebro‐cortical, nigral or cerebellar slices to veratridine (5 μm) or KC1 (50 mM) caused large increases in the efflux of [3H]‐GABA.

Reduction of the external Ca concentration [Ca]0 to zero had strikingly different effects on the veratridine and K‐evoked release of [3H]‐GABA. The K‐evoked release from all three areas was greatly reduced in Ca‐free medium, but the veratridine‐evoked release from cerebeller slices was not affected, and the release of [3H]‐GABA from cortical and nigral slices was increased three fold. The potentiation of the veratridine evoked release of GABA which occurred in Ca‐free medium was not due to the reduction in divalent ions, because it still occurred in medium in which the Ca was replaced by an equivalent amount of Mg.

The veratridine‐evoked release of [14C]‐glycine from slices of spinal cord was also significantly increased in Ca‐free medium. In contrast, the release of cortical [3H]‐noradrenaline and [14C]‐acetylcholine caused by the alkaloid was greatly diminished in Ca‐free medium.

The veratridine but not the K‐evoked release of [3H]‐GABA was abolished when the external Na concentration [Na]0 was reduced to zero and by tetrodotoxin (TTX) (0.2 μm). Cl‐free medium did not affect the veratridine‐evoked release of [3H]‐GABA or its potentiation by Ca‐free medium.

Exposure of the tissue to depolarizing concentrations of external K ([K]0 = 120 mM) did not abolish the veratridine evoked release of [3H]‐GABA or its potentiation by Ca‐free medium.

Pre‐incubation of cortical slices with L‐2,4, diaminobutyric acid (DABA), or substitution of Na in the superfusion medium with Li, did not affect the veratridine‐evoked release of [3H]‐GABA, indicating that the alkaloid does not stimulate GABA efflux by a carrier‐mediated transport process.

Exposure of the tissue to ruthenium red (10 μm) increased the veratridine evoked release of [3H]‐GABA in both normal and in Ca‐free medium but almost abolished the K‐evoked release.

It is suggested that veratridine causes GABA release by increasing the permeability of the nerve terminals to Na. In normal medium, the resulting influx of Ca2+ ions through voltage‐dependent Ca2+ channels may be involved in triggering the release of GABA. However, a major part of the GABA efflux appears to be triggered by the release of Ca2+ ions from intraterminal mitochondria, which results from the increase in[Na]i. Since Ca2+ ions antagonize the action of veratridine, the potentiation of the drug‐evoked release of GABA that occurs in Ca‐free medium, might be due to the absence of the antagonistic Ca2+ ions. The resulting greater increase in Na entry and [Ca]i caused by Ca release from intracellular stores, must presumably more than balance the contribution normally made by any influx of extracellular Ca2+.
DIVALENT CATIONS INCREASE [3H]‐PROSTACYCLIN BINDING TO MEMBRANES OF NEURONAL SOMATIC HYBRID CELLS
Authors: BLAIR IAN A. , CRESP TERRY M. , MacDERMOT JOHN
Published: July 2012

[3H]‐prostacyclin binding to membranes of a highly differentiated neuronal somatic hybrid is increased equally in the presence of Ca2+, Ba2+, Mg2+ or Sr2+ ions.

Analysis of the binding of [3H]‐prostacyclin in the presence of low (1 mm) or high (50mm) Mg2+ ion concentrations has revealed a cation‐dependent increase in ligand receptor affinity (Kd− values = 57.4 nM and 21.9 nM).

The increase in [3H]‐prostacyclin binding due to divalent cations is not accompanied by an alteration in the maximum binding capacity of the membranes.
SEPARATE 5‐HYDROXYTRYPTAMINE RECEPTORS ON THE SALIVARY GLAND OF THE BLOWFLY ARE LINKED TO THE GENERATION OF EITHER CYCLIC ADENOSINE 3‘,5’‐MONOPHOSPHATE OR CALCIUM SIGNALS
Authors: BERRIDGE MICHAEL J. , HESLOP JOHN P.
Published: July 2012

5 ‐Hydroxytryptamine (5 ‐HT) stimulates the formation of two separate second messengers in the salivary gland of the blowfly. Activation of adenylate cyclase raises cyclic adenosine 3′, 5′‐monophosphate (cyclic AMP) whereas the hydrolysis of phosphatidylinositol (PI) is associated with an increase in calcium permeability. The possibility that these two signal pathways might be controlled by separate 5‐HT receptors was studied by testing the specificity of 5‐HT analogues and antagonists.

The parent compound 5‐HT was found to stimulate both cyclic AMP formation and the related parameters of PI hydrolysis and calcium transport with similar dose‐response relationships.

Certain analogues such as 4‐ and 5‐fluoro‐α‐methyltryptamine were capable of raising cyclic AMP levels and stimulating fluid secretion but did not stimulate the hydrolysis of PI or the entry of calcium.

Other analogues, which had chloro or methyl substituents at the 5‐position, were found to stimulate the hydrolysis of PI and the transport of calcium at much lower doses than those required to stimulate the formation of cyclic AMP.

Antagonists were also found to exert selective effects. Methysergide was a potent inhibitor of PI hydrolysis whereas cinanserin was far more selective in blocking the stimulatory effect of 5‐HT on cyclic AMP formation.

It is concluded that 5‐HT acts on two separate receptors, a 5‐HT1 receptor acting through calcium and a 5‐HT2 receptor which mediates its effects through cyclic AMP.
DISTINCTION BETWEEN THE EFFECTS OF BARBITURATES, BENZODIAZEPINES AND PHENYTOIN ON RESPONSES TO γ‐AMINOBUTYRIC ACID RECEPTOR ACTIVATION AND ANTAGONISM BY BICUCULLINE AND PICROTOXIN
Authors: SIMMONDS M.A.
Published: July 2012

Interactions of depressant and anticonvulsant drugs with the neuronal γ‐aminobutyric acid (GABA) receptor + effector system have been examined on afferent fibres to the rat cuneate nucleus in vitro. Three types of interaction have been measured: (a) potentiation of depolarizing responses to the GABA analogue, muscimol: (b) reduction in the potency of bicuculline as an antagonist of muscimol at the GABA receptor: (c) reduction in the potency of picrotoxin as an antagonist of muscimol acting on the effector mechanism.

Phenobarbitone reduced the potency of picrotoxin in doses which did not affect the potency of bicuculline and which caused only a small potentiation of muscimol. Pentobarbitone did not show such selectivity, a reduction in potency of picrotoxin always being accompanied by a reduction in potency of bicuculline and a substantial potentiation of muscimol.

Flurazepam and lorazepam both reduced the potency of picrotoxin without affecting that of bicuculline and with very little potentiation of muscimol. Phenytoin had no effect on the potency of picrotoxin whilst potentiating muscimol to the same extent as phenobarbitone.

The spectrum of drug activity in reducing the potency of picrotoxin correlates well with the reported anticonvulsant effects of these drugs against kindled amygdaloid seizures. Potentiation of muscimol and reduction of bicuculline potency appear more closely related to hypnotic properties.
VASCULAR AND SENSORY RESPONSES OF HUMAN SKIN TO MILD INJURY AFTER TOPICAL TREATMENT WITH CAPSAICIN
Authors: CARPENTER SANDRA E. , LYNN BRUCE
Published: July 2012

Immediately after several topical applications of capsaicin at 2‐hourly intervals, human forearm skin would no longer develop flare (vasodilatation) around a small injury. At the same time heat pain thresholds were reduced on average by 3.5°C. These results are consistent with block by capsaicin of the effector side of the axon reflex, perhaps by depleting nerve terminals of substance P.

Over a period from several days to several weeks after treatment, flare was diminished and heat pain thresholds were slightly elevated. These changes may be due to long‐lasting damage of cutaneous nerve terminals by capsaicin.
THE EFFECTS OF 4‐AMINOPYRIDINE ON THE ISOLATED VAS DEFERENS AND ITS EFFECTS ON THE INHIBITORY PROPERTIES OF ADENOSINE, MORPHINE, NORADRENALINE AND γ‐AMINOBUTYRIC ACID
Authors: STONE T.W.
Published: July 2012

Adenosine, adenosine 5′‐triphosphate (ATP), morphine, noradrenaline, γ‐aminobutyric acid (GABA) phentolamine and amyl nitrite were used to inhibit electrically‐evoked contractions of the isolated superfused vas deferens of the mouse.

The inhibitory effects of adenosine ATP, morphine, noradrenaline and GABA, which are thought to be due to presynaptic action, were reduced by perfusion with media containing 4‐aminopyridine (4AP) or tetraethylaminonium (TEA) ions. The inhibitory effects of phentolamine and amyl nitrite were unaffected by 4AP or TEA.

Quinidine, which like 4AP and TEA produced some increase of twitch height, did not reduce responses to the various agonists, indicating that an increased muscle contraction was not itself responsible for the reduced responses.

It is concluded that antagonism between 4AP and adenosine is not a specific interaction, as had been suggested, but probably reflects an interaction with Ca2+ requiring processes in the presynaptic terminal.