bluuebunny/crossref_metadata_2025 huggingface dataset:
ELECTRICAL PROPERTIES OF SMOOTH MUSCLE CELL MEMBRANE AND NEUROMUSCULAR TRANSMISSION IN THE GUINEA‐PIG BASILAR ARTERY
Authors: KARASHIMA TSUYOSHI , KURIYAMA HIROSI
Published: July 2012

The membrane properties of smooth muscle cells and neuromuscular transmission in the guinea‐pig basilar artery were investigated by use of microelectrodes

The membrane potential was −47.0 mV and the muscle tissue possessed cable‐like properties as determined by the current‐voltage relationships. The mean value of the space constant was 0.78 mm

An outward current produced a graded response and, in some cases, spike generation. This membrane response was enhanced in the presence of tetraethylammonium (TEA, 5 mM), and an increased concentration of TEA (10 mM) generated spontaneous spikes in most of the cells. Action potentials induced by TEA were abolished in the presence of MnCl2 (5 mM) but not by isoprenaline (4×10−6M)

Acetylcholine (ACh), over 10−7 M, hyperpolarized the membrane and decreased the membrane resistance. This hyperpolarization increased in the presence of low [K]o (below 5.9 mM), but decreased in [K]o concentrations over 17.8 mM. Pretreatment with atropine (10−6 m) suppressed the ACh‐induced hyperpolarization. Therefore, this action of ACh is due to an increase in the K‐conductance of the membrane produced by activation of the muscarinic receptors

Noradrenaline in concentrations up to 10−4m did not modify the membrane potential and resistance, while 10−5M, histamine, 5‐hydroxytryptamine and adenosine triphosphate (ATP) depolarized the membrane. The depolarization induced by histamine or ATP was suppressed by reducing [Na]o. The histamine‐induced depolarization was accompanied by an increase and the ATP‐induced one by a decrease in the membrane resistance. The action of histamine was suppressed by treatment with H1‐ but not H2‐receptor blocking agents (dephenhydramine and cimetidine, respectively)

Perivascular nerve stimulation (0.2 ms pulse duration) evoked excitatory junction potentials (e.j.ps). An increase in the number and frequency of stimuli enhanced the e.j.p. amplitude. In the presence of 1 mM TEA, a spike was evoked on the e.j.ps. A very high concentration of phentolamine (3.6 × 10−4 m) or the usual concentration of tetrodotoxin (10−7 m) abolished the generation of e.j.ps. Spontaneously generated miniature e.j.ps were never recorded from the resting membrane

The results are discussed in relation to regional specificities of smooth muscle cells of cerebral arteries in the guinea‐pig.
INCREASE OF ACETYLCHOLINE‐RECEPTOR SENSITIVITY BY ADENOSINE TRIPHOSPHATE: A NOVEL ACTION OF ATP ON ACh‐SENSITIVITY
Authors: AKASU T. , HIRAI K. , KOKETSU K.
Published: July 2012

The sensitivity of the nicotinic acetylcholine (ACh)‐receptor, measured as the amplitude of ACh‐current induced by iontophoretic application of ACh to the frog skeletal muscle endplate, was increased by the action of adenosine triphosphate (ATP)

This potentiation was not due to the effect of ATP on ACh‐esterase, since the increase of the sensitivity could also be demonstrated by use of carbachol (CCh)

Kinetic analysis of the effect of ATP on the dose‐response curve of CCh‐current suggests that ATP increases the ACh‐sensitivity by acting on the allosteric site of receptor‐ionic channel complex without changing the affinity of ACh for its recognition site

The equilibrium potential and the life‐time of the endplate current (e.p.c.) are not altered by the presence of ATP

These results suggest that ATP increases the ACh‐sensitivity by increasing either the conductance of unit channels or the total number of available channels.
RAPID REVERSAL BY NALOXONE OF THE CHRONIC EFFECTS OF MORPHINE ON RAT LIVER AND BRAIN TRYPTOPHAN METABOLISM
Authors: BADAWY A.A.‐B. , EVANS M.
Published: July 2012

The chronic morphine‐induced inhibition of rat liver tryptophan pyrrolase activity and the resultant increases in tryptophan availability to the brain and brain 5‐hydroxytryptamine (5‐HT) synthesis are reversed within 10 min after naloxone administration. The possible involvement of hepatic tryptophan metabolism in morphine dependence is briefly discussed.
DEMONSTRATION OF BOTH β1‐ AND β2‐ADRENOCEPTORS MEDIATING RELAXATION OF ISOLATED RING PREPARATIONS OF RAT PULMONARY ARTERY
Authors: O'DONNELL STELLA R. , WANSTALL JANET C.
Published: July 2012

Cumulative concentration‐response (relaxation) curves to three β‐adrenoceptor agonists, fenoterol (β2‐selective), isoprenaline (non‐selective) and noradrenaline (β1‐selective) were obtained on isolated ring preparations of rat pulmonary artery contracted with 15 mM KCl. α‐Adrenoceptors and neuronal and extraneuronal uptakes were blocked with phenoxybenzamine. The agonist concentration‐response curves were reproducible.

Responses to each of the three agonists could be blocked by the β‐adrenoceptor antagonists atenolol (β1‐selective) or ICI 118,551 (β2‐selective) confirming the presence of β‐adrenoceptors.

The relative potencies of the agonists were isoprenaline: fenoterol: noradrenaline = 100: 38: 1.4. This indicated that the predominant β‐adrenoceptor type was β2.

Schild plots were obtained for atenolol and ICI 118,551 using the three different agonists. For each antagonist the location of the Schild plot varied depending on which agonist was used. This indicated that the β‐adrenoceptor population mediating relaxation responses to β‐adrenoceptor agonists was not homogeneous.

Atenolol was most potent when noradrenaline was the agonist and ICI 118,551 was most potent when fenoterol was the agonist.

It is concluded that isolated pulmonary artery ring preparations of the rat contain a mixed population of β1‐ and β2‐adrenoceptors both mediating relaxation.
THE ACTION OF PROPRANOLOL ON FACTORS CONCERNED WITH THE DELIVERY OF OXYGEN TO THE TISSUES
Authors: LEDINGHAM JOHN M. , LEES DOUGLAS C.P.
Published: July 2012

In a previous study in conscious rats, orally administered propranolol acutely lowered cardiac output by 30.5% and oxygen uptake by 12.2%, while oxygen extraction rose by 31.5%. The present study is concerned with the way in which the rat meets its oxygen requirements against such a fall in perfusion.

The effect of known concentrations of propranolol on haemoglobin‐oxygen affinity was studied in vitro. The effect of orally administered propranolol (given acutely and chronically) was then determined and this was related to the concentration of the drug in plasma and red cells. Further studies were made on the action of propranolol on the Bohr effect and on arterial oxygen carriage.

In vitro, high concentrations of propranolol (1 × 10−4 m) influenced haemoglobin‐oxygen affinity in a biphasic manner and this was associated with changes in haematocrit and red cell and plasma pH. No change occurred in affinity after acute or chronic oral administration of the drug due to insufficient concentration in the blood. No direct action on the Bohr effect was detected.

Arterial oxygen content rose acutely due to an increase in haemoglobin concentration.

It is concluded that increased oxygen extraction in propranolol‐treated rats is not explained by the actions of the drug on haemoglobin‐oxygen affinity.
POLYMYXIN B SULPHATE PROTECTS CATS AGAINST THE HAEMODYNAMIC AND METABOLIC EFFECTS OF E. coli ENDOTOXIN
Authors: HUGHESI BERNADETTE , MADAN B.R. , PARRATT J.R.
Published: July 2012

The intravenous administration of E. coli endotoxin (2mg/kg) in cats anaesthetized with pentobarbitone resulted in an initial acute increase in right atrial pressure and a transient systemic hypotension. Later (from 1 h onwards) there was a progressive decrease in cardiac output, a reduced right atrial filling pressure, systemic hypotension and a profound metabolic acidosis (lactate of 30±1 mg/100ml at 5h compared with 5.1 ±0.5mg/100ml pre‐endotoxin). Only one of eight animals so treated survived 8 h.

Polymyxin B sulphate, given intravenously (1 min before endotoxin) as a bolus injection (5 mg/kg) followed by a continuous intravenous infusion (additional 5 mg/kg given over a 30 min period) prevented the endotoxin‐induced pulmonary (right atrial) hypertension but not the acute systemic hypotension.

Polymyxin B sulphate reduced the delayed haemodynamic effects of endotoxin (systemic hypotension, decrease in cardiac output); all the eight animals so treated survived 8 h compared with only 1/8 of the controls.

Polymyxin B did not prevent the initial (1–3 h) and marked metabolic acidosis following endotoxin; however, after 3h, arterial lactate levels returned towards control whereas in the endotoxin‐alone group they continued to increase until death.

The mechanism of this marked protective effect of the antibiotic and the possible clinical repercussions are discussed; the most likely explanation for the protection is in chemical combination with the lipid A moiety of the endotoxin.
THE EFFECTS OF INTRACEREBROVENTRICULAR CYCLOHEXIMIDE ON PROTEIN SYNTHESIS AND FEVER IN RABBITS
Authors: CRANSTON W.I. , GOURINE V.N. , TOWNSEND Y.
Published: July 2012

Cycloheximide(40μg)intracerebroventricularly(i.c.v.) had no effect on thermoregulation against cold, but reduced fever due to an i.e.v. injection of leucocyte pyrogen (LP) by 25%. and reduced incorporation of radioactive leucine into hypothalamic protein by 94%.
TOLERANCE OF GUINEA‐PIG AIRWAY MUSCLE PREPARATIONS TO RELAXANT AGONISTS INDUCED BY CHRONIC EXPOSURE TO ISO‐PRENALINE in vivo
Authors: BRINK CHARLES
Published: July 2012

The histamine sensitivities of complete tracheal spiral preparations from guinea‐pigs were similar to those of paired half tracheal tissues.

Airway muscle preparations from animals chronically treated with isoprenaline showed a significant increase in resting tone and a significant decreased responsiveness to histamine.

The paired half tracheal preparations exhibited no significant difference when either their isoprenaline or theophylline sensitivities were compared.

Paired half tracheal muscle preparations from chronically treated animals (0.4 μmol, 4.0 μmol, and 40.0 μmol isoprenaline, 3 times daily for 21 days, s.c.) showed a significantly reduced sensitivity to isoprenaline when compared to appropriate controls.

Theophylline concentration‐effect curves for the paired half tracheal preparations from chronically treated guinea‐pigs (4.0 μmol and 40.0 μmol isoprenaline) were significantly reduced compared with appropriate controls.

Indomethacin treatment reversed the isoprenaline desensitization induced by chronic treatment (0.4 μmol isoprenaline) but was ineffective in animals that received the higher doses of isoprenalinein vivo.
EFFECT OF VERAPAMIL ON THE PULMONARY VASOCONSTRICTOR ACTION OF PROSTAGLANDIN F2α AND A SYNTHETIC PGH2 ANALOGUE
Authors: ANGERIO ALLAN D. , FITZPATRICK THOMAS M. , KOT PETER A. , RAMWELL PETER W. , ROSE JOHN C.
Published: July 2012

The vasopressor response to prostaglandin F2α (PGF2α) and to ((15S)‐hydroxy‐11α, 9α‐(epoxymethano)‐prosta‐5Z, 13E‐dienoic acid) (U‐46619) in the canine isolated lung lobe was significantly attenuated following the administration of verapamil.

The pressor response to arachidonic acid (AA) was not affected by the presence of verapamil.

The pulmonary pressor effect of PGF2α and U‐46619 is dependent, at least in part, on Ca2+ influx into vascular smooth muscle cells.

The pulmonary pressor response to AA cannot be attributed to PGF2α or to endoperoxide intermediates but to some other product dependent on intracellular calcium stores.
RESTORATION OF VASOCONSTRICTOR RESPONSES TO NORADRENALINE BY PROSTAGLANDIN E2 AFTER α‐ADRENOCEPTOR BLOCKADE IN RAT ISOLATED MESENTERIC ARTERY
Authors: ADEAGBO A.S.O. , OKPAKO D.T.
Published: July 2012

The effects of prostaglandin E2 (PGE2) on responses to noradrenaline (NA) after α‐adrenoceptor blockade were studied in the isolated mesenteric artery of the rat.

Phentolamine (32 nm) tolazoline (41 μm) and yohimbine (1.28 μm) blocked NA‐induced vasoconstriction competitively with dose‐ratios of 13.9 ± 1, 22.0 ± 1 and 26.6 ± 0.9 respectively.

PGE2 (28 nm) restored responses to NA during α‐adrenoceptor blockade and reduced NA dose‐ratios to 2.8 ±0.1 (phentolamine), 5.9 ±0.4 (tolazoline) and 1.7 ±0.1 (yohimbine).

At low concentrations (0.29 nm), phenoxybenzamine blockade of NA‐induced vasoconstriction was also antagonized by PGE2.

PGE2 did not reduce the pA2 of the competitive antagonists; therefore the antagonism of α‐adrenoceptor block by PGE2 was not due to a reduction in the affinity of the antagonist for the receptor.

The calcium ionophore, A23187, also antagonized competitive α‐adrenoceptor blockade but was less potent than PGE2.

Evidence is provided to suggest that although both PGE2 and A23187 can potentiate the action of NA in this preparation, the two compounds probably reverse α‐adrenoceptor blockade by different mechanisms.

Inhibition of NA‐induced vasoconstriction caused by the calcium antagonists cinnarizine, verapamil and high concentrations of phenoxybenzamine (>2 nm) were not affected by PGE2.

It is proposed that PGE2 restores responses to NA after α‐adrenoceptor blockade by increasing intracellular Ca2+ ion concentration or by activating α‐adrenoceptor‐associated Ca2+ channels.
FURTHER ANALYSIS OF INHIBITORY EFFECTS OF PROPRANOLOL AND LOCAL ANAESTHETICS ON THE CALCIUM CURRENT IN Helix NEURONES
Authors: AKAIKE N. , ITO H. , NISHI K. , OYAMA Y.
Published: July 2012

The effects of propranolol and local anaesthetics on Ca2+ current (ICa), individually separated from other ionic currents, in Helix neurones were studied under voltage clamp, using a suction pipette technique.

Increases in external Ca2+ concentrations overcame the inhibitory action of propranolol on lea‐Double reciprocal plots for peak ICa versus external Ca2+ concentrations in the presence or absence of propranolol did not intersect at the ordinate.

Internal application of propranolol (10−4m) inhibited ICa to about 40–60% of the control in a time‐dependent manner.

Lignocaine and procaine at concentrations of 10−3–10−2m inhibited ICa without shifting the threshold in the I‐V relationships. Internal application of lignocaine (10−3–10−2 m) also inhibited ICa: the ratio of depression of the ICa was almost equivalent to that of the agent applied externally.

The results provide evidence that propranolol inhibits ICa in a noncompetitive manner with Ca2+ at the cell membrane, and suggest that the agents may occupy the receptor site in the Ca2+ ‐channel somewhere between the outer surface and inner phase of the membrane.
INCREASED HISTAMINE‐OUTPUT FROM THE ISOLATED GASTRIC MUCOSA OF THE RAT IN RESPONSE TO PENTAGASTRIN AND METHACHOLINE
Authors: MAIN I.H.M. , PEARCE J.B.
Published: July 2012

A rat isolated gastric mucosal preparation was used to monitor histamine output and acid secretion during stimulation by different secretagogues.

In non‐stimulated preparations, spontaneous histamine output decreased over 450 min.

Stimulation of secretion with 4(5)‐methylhistamine or dibutyryl cyclic adenosine 3′,5′‐monophosphate (db cyclic AMP) and theophylline did not influence histamine output.

Pentagastrin, gastrin and methacholine increased both acid secretion and histamine output. Pentagastrin and gastrin mobilized six times more histamine in relation to acid secretion than did methacholine.

Spontaneous histamine output and secretagogue‐induced increases were unaffected by changes in external Ca2+ (0.0 to 7.2 mm) or Mg2+ (1.2 to 4.8 mm).

These results support the hypothesis that mucosal histamine plays a more important role in the action of gastrin than of cholinomimetics on the parietal cell.
THE BINDING CHARACTERISTICS OF [3H]‐DIHYDROERGOCRYPTINE ON INTACT HUMAN PLATELETS
Authors: ELLIOTT J.M. , GRAHAME‐SMITH D.G.
Published: July 2012

We have characterized the binding of [3H]‐dihydroergocryptine to intact human platelets.

The values of the association and dissociation rate constants, affinity and capacity of specific [3H]‐dihydroergocryptine binding on intact cells closely resemble those previously reported on the human platelet lysate preparation.

The affinity of α‐adrenoceptor antagonists, determined from inhibition of [3H]‐dihydroergocryptine binding, is similar in intact and lysed platelet preparations, but the affinity of agonists is considerably lower in intact cells.

The potency of α‐adrenoceptor antagonists as inhibitors of noradrenaline‐induced platelet aggregation and as inhibitors of [3H]‐dihydroergocryptine binding on intact platelets demonstrate a significant correlation (r = 0.92, P <0.01).

The affinity and capacity of [3H]‐dihydroergocryptine binding to platelets from a group of healthy, young, male subjects show a high degree of consistency both between subjects (Kd = 2.81 ± 0.27 nm; Bmax = 63 ± 3 fmol/108 platelet: mean ± s.e. mean, n = 10) and between sampling occasions in a single subject (Kd = 3.28nm ± 13%; Bmax = 70 fmol/108 platelet ± 16%: mean ± coefficient of variation, n = 5).

There is no significant difference in the binding capacity of platelets from a group of elderly male subjects (mean age 73) compared to those from young males (mean age 27) or elderly females (mean age 77). The affinity of binding is slightly but significantly (P < 0.05) higher in the elderly male group compared to the two other groups.

We conclude that [3H]‐dihydroergocryptine binds to the α2‐adrenoceptor of intact human platelets which is responsible for noradrenaline‐induced platelet aggregation. The high consistency of the binding characteristics of [3H]‐dihydroergocryptine indicate that this assay may be useful as a monitor of platelet α‐adrenoceptor sensitivity in clinical investigation.
GLUCOCORTICOIDS INDUCE THE FORMATION AND RELEASE OF ANTI‐INFLAMMATORY AND ANTI‐PHOSPHOLIPASE PROTEINS INTO THE PERITONEAL CAVITY OF THE RAT
Authors: BLACKWELL G.J. , CARNUCCIO ROSA , DI ROSA M. , FLOWER R.J. , LANGHAM C.S.J. , PARENTE L. , PERSICO PAOLA , RUSSELL‐SMITH N.C. , STONE D.
Published: July 2012

Dexamethasone and hydrocortisone induce the release of anti‐phospholipase proteins into the peritoneal cavities of rats.

Adrenocorticotropic hormone (ACTH) also releases these proteins in normal but not in adrenalectomized rats.

Peritoneal lavage proteins were separated by ion‐exchange and size exclusion chromatography. The anti‐phospholipase activity occurred in four separate fractions with the major component having an apparent mol. wt. of 40 k.

Column fractions containing these anti‐phospholipase proteins had anti‐inflammatory effects in the rat carrageenin pleurisy model whereas other fractions were inactive.

The proteins appear to be identical to macrocortin and lipomodulin, the ‘second messengers’ of glucocorticoid hormone action on the arachidonate system.
EFFECT OF ETYA AND BW 755c ON ARACHIDONATE‐INDUCED CONTRACTIONS IN THE GUINEA‐PIG ISOLATED TRACHEA
Authors: MITCHELL H.W.
Published: July 2012

Arachidonic acid caused larger contractions in indomethacin‐treated guinea‐pig trachea than in control tracheae.

No change in contractions was obtained in tracheae treated with 5, 8, 11, 14, eicosatetraynoic acid (ETYA 10 μm).

ETYA (100 μm) blocked the effect of indomethacin on arachidonic acid‐induced responses. Likewise BW 755c (113 μm) reversed the effect of indomethacin.

The results show that arachidonate lipoxygenase products may be responsible for the contractile responses seen in the presence of indomethacin.
DISTRIBUTION AND TYPES OF ADRENOCEPTORS IN THE GUINEA‐PIG ILEUM: THE ACTION OF α‐ AND β‐ADRENOCEPTOR BLOCKING AGENTS
Authors: BAUER V.
Published: July 2012

Transmurally stimulated segments of the guinea‐pig ileum have been used to analyse the different adrenoceptors in the terminal (0 to 3 cm) and the proximal (> 50 cm from the ileocaecal valve) ileum.

The prejunctional adrenoceptors (located on the final, cholinergic, motor nerve terminals) and postjunctional adrenoceptors (located on the smooth muscle membrane) have been characterized according to their sensitivity to α‐ and β‐agonists and antagonists.

Phentolamine, phenoxybenzamine and yohimbine, in concentrations of 0.1 μm, transiently enhanced (up to 10%) the twitch response. At higher concentrations all the α‐ and β‐antagonists studied depressed the neurogenic twitches and relaxed the smooth muscle.

The twitch‐inhibitory effects of adrenoceptor agonists (noradrenaline, adrenaline and ephedrine) were not antagonized by phenoxybenzamine (0.1, 0.5 and 1 μm), carbidine (0.5, 1 and 5 μm) and propranolol (0.5, 1 and 5 μm); however, they were depressed by phentolamine (0.1, 0.5, 1.25 and 5 μm) and yohimbine (0.25, 0.5 and 5 μm).

The smooth muscle contractions induced by noradrenaline and adrenaline in the terminal ileum and by phenylephrine in both the terminal and proximal ileum were antagonized by phenoxybenzamine, carbidine and phentolamine but were not influenced by yohimbine and propranolol.

The smooth muscle relaxations of the proximal ileum induced by noradrenaline, adrenaline and ephedrine were inhibited by yohimbine, phentolamine, carbidine and phenoxybenzamine, and the isoprenaline‐induced relaxation was antagonized by propranolol.

All the agonists studied, except phenylephrine, elicited relaxations of the acetylcholine‐induced sustained contraction of both proximal and terminal ileum. The relaxation induced by isoprenaline was antagonized by propranolol, and the effects of noradrenaline and ephedrine by yohimbine.

It is concluded that in the guinea‐pig ileum there are postsynaptic β‐adrenoceptors and at least two types of α‐adrenoceptors: α1‐excitatory postjunctional adrenoceptors activated by phenylephrine, noradrenaline and adrenaline and antagonized by phenoxybenzamine, carbidine and phentolamine; α2‐inhibitory prejunctional adrenoceptors activated by ephedrine, noradrenaline and adrenaline and inhibited by yohimbine and phentolamine. The inhibitory postjunctional α‐adrenoceptors are more close to the α2‐adrenoceptors, since they were stimulated predominantly by ephedrine and noradrenaline and inhibited by yohimbine.

It has been shown that all α‐adrenoceptor subtypes are to be found at every distance (0 to 70 cm) from the ileocaecal valve and that they can be activated in the resting or in the acetylcholine‐contracted states.
EFFECTS OF INHIBITORS OF ANAPHYLACTIC MEDIATORS IN TWO MODELS OF BRONCHIAL ANAPHYLAXIS IN ANAESTHETIZED GUINEA‐PIGS
Authors: ANDERSSON PER
Published: July 2012

The effects of pretreatment with various inhibitors of anaphylactic mediators on antigen‐induced bronchoconstriction were studied in anaesthetized guinea‐pigs, actively sensitized according to two different regimens (one producing IgE‐ and IgG‐like antibodies and the other producing exclusively IgG antibodies).

The phospholipase A2‐inhibitors mepacrine and p‐bromphenacylbromide caused a dose‐dependent inhibition of the antigen‐induced bronchoconstriction in guinea‐pigs sensitized to produce both IgE and IgG antibodies. No effect was seen in those sensitized to produce only IgG antibodies.

In both models indomethacin pretreatment led to an increased anaphylactic bronchoreactivity, whereas mepyramine and FPL 55712 reduced it.

BW 755C significantly reduced antigen‐induced bronchoconstriction in guinea‐pigs sensitized to produce both IgE and IgG antibodies. In this model, the residual bronchoconstriction evident after combined pretreatment with indomethacin and mepyramine was prevented by additional pretreatment with mepacrine, FPL 55712 or budesonide.

Arachidonic acid given intravenously caused a marked bronchoconstriction that was prevented by indomethacin but not by budesonide, FPL 55712 or p‐bromphenacylbromide.

Although the same pattern of anaphylactic mediators is released in the two models of anaphylactic bronchoconstriction, a different activation mechanism is indicated by the results obtained with phospholipase A2 inhibitors.
EVIDENCE AGAINST THE UNITARY HYPOTHESIS OF AGONIST AND ANTAGONIST ACTION AT PRESYNAPTIC ADRENOCEPTORS
Authors: KALSNER STANLEY
Published: July 2012

The concept that presynaptic receptors regulate noradrenergic transmitter release via a system of inhibitory receptors mediating negative feedback relies on a supposed association between increases in stimulation‐induced efflux of [3H]‐noradrenaline by antagonists and blockade by them of the inhibitory effects of exogenous noradrenaline.

It was shown in guinea‐pig ureter, that yohimbine (3 × 10−7 m), a presumed selective presynaptic antagonist, increased transmitter efflux substantially at 1 Hz and 5 Hz with 100 pulses, purportedly representing antagonism of the inhibitory effect of locally released noradrenaline but did not reduce the inhibitory effect of exogenous noradrenaline (1.8 × 10−6 m or 1.8 × 10−7 m) except in one case.

Additionally, the inhibitory effect of oxymetazoline (1.0 × 10−7m or 1.0 × 10−8m) on stimulation‐induced efflux was in no way antagonized by yohimbine (3 × 10−7 m).

It is concluded that the increased efflux of [3H]‐noradrenaline produced by antagonists and the decreased efflux produced by exogenous agonists may represent actions at different loci and that the hypothesis of presynaptic feedback regulatory sites is still not substantiated.
IRREVERSIBLE INHIBITION OF EPITHELIAL SODIUM CHANNELS BY ULTRAVIOLET IRRADIATION
Authors: CUTHBERT A.W. , FANESTIL D.D. , HERRERA F.C. , PRYN S.J.
Published: July 2012

The effects of u.v. irradiation at 254 nm and 350 nm on sodium transport across frog skin epithelium have been investigated.

Irradiation at 254 nm but not at 350 nm produces a dose‐dependent, functionally selective blockade of sodium transport. The effect is apparently due to the irreversible closure of apical sodium channels.

The amiloride‐sensitive conductance was directly related to sodium transport as measured by short circuit current (SCC) both in normal and irradiated tissues, although both conductance and current were reduced in irradiated tissues.

The sensitivity of epithelia to irradiation at 254 nm was defined from the rate constants for the decline in SCC during three 2 min periods of irradiation at 1850 μW cm−2. The rate constant for the initial 2 min irradiation was 0.093 ± 0.008 min−1.

Lowering the sodium concentration to 5.5 mm from 110 mm increased the rate constant to 0.141 ± 0.014 min−1, consistent with the view that more functional sodium channels exist at lowered sodium concentration.

Lowering the temperature to 7°C from 23°C reduced the rate constant to 0.032 ± 0.007 min−1 suggesting that blockade of channels is not due to a direct interaction with photons.

Using a variety of experimental protocols we were unable to demonstrate that bromamiloride or iodoamiloride can act as photoligands for sodium channels in the epithelium of Rana temporaria. This is in contrast to earlier reports with other epithelia.
INFLUENCE OF NEONATALLY ADMINISTERED CAPSAICIN ON BARORECEPTOR AND CHEMORECEPTOR REFLEXES IN THE ADULT RAT
Authors: BOND SUSAN M. , CERVERO F. , McQUEEN D.S.
Published: July 2012

Baroreceptor and chemoreceptor reflex activity was studied in anaesthetized adult rats which had been treated neonatally with a single injection of capsaicin (50 mg/kg s.c).

Pressor responses to bilateral carotid artery occlusion were significantly lower in capsaicin‐treated rats compared with vehicle‐treated controls. Pressor responses to intravenously injected noradrenaline were similar in the two groups of rats.

Resting respiratory minute volume and tidal volume were lower in anaesthetized capsaicin‐treated animals than in vehicle‐treated controls, but there was no significant difference in respiratory frequency.

The increases in respiration evoked by intravenous administration of the peripheral arterial chemoreceptor stimulant, sodium cyanide, or by breathing a hypoxic gas mixture, were significantly lower in capsaicin‐treated rats compared with the controls.

It is concluded that baroreceptor and chemoreceptor reflex activity are significantly reduced in anaesthetized adult rats which had been treated neonatally with capsaicin, and that this is likely to result from the destruction of unmyelinated baro‐ and chemoreceptor afferent fibres.
ANTICONVULSANT ACTIONS OF THE PUTATIVE γ‐AMINOBUTYRIC ACID (GABA)‐MIMETIC, ETHYLENEDIAMINE
Authors: MORGAN P.F. , STONE T.W.
Published: July 2012

Ethylenediamine, 31.6–1000 mg/kg intraperitoneally, inhibited the convulsive effects of pentylenetetrazol, 100 mg/kg (i.p.) in mice.

Ethylenediamine, 100–1000 mg/kg (i.p.) increased the convulsion threshold to the intravenous infusion of three convulsants in the order pentylenetetrazol > bicuculline > strychnine.

The benzodiazepine antagonist Ro15–1788, 10 mg/kg (i.p.), significantly inhibited the anticonvulsant action of diazepam, 50 μg/kg, but not ethylenediamine, 1000 mg/kg.

These results clearly indicate that ethylenediamine has anticonvulsant properties and are consistent with the hypothesis that ethylenediamine is a γ‐aminobutyric acid (GABA)‐mimetic.
THE EFFECTS OF pH ON THE AFFINITY OF PIRENZEPINE FOR MUSCARINIC RECEPTORS IN THE GUINEA‐PIG ILEUM AND RAT FUNDUS STRIP
Authors: BARLOW R.B. , CHAN MARGARET
Published: July 2012

Dose‐ratios obtained with pirenzepine on the guinea‐pig ileum at 30°C are indistinguishable from those obtained at 37°C.

In 0.1 m NaCl at 37°C the pKa of pirenzepine for the loss of its last ionizable proton is 8.2. The ionization of pirenzepine is therefore markedly affected by changes in pH in the physiological range.

In experiments with pirenzepine on guinea‐pig ileum and rat fundus made over a range of pH, the dose‐ratio increases with the proportion of the protonated form present. As expected, the slope of the graph of dose‐ratio against proportion protonated depends on the concentration of antagonist. The changes in pH produce only small effects on dose‐ratios obtained with pirenzepine monomethiodide. These effects of pH can account for some of the differences between estimates of the affinity of pirenzepine.

The logarithm of the affinity constant of the protonated form of pirenzepine for the receptors in guinea‐pig ileum is estimated to be 6.93, compared with 6.94 for the receptors in rat fundus. However, for the non‐protonated form the values appear to be below 5 for the ileum compared with about 6.4 for the rat fundus.
DOES PIRENZEPINE DISTINGUISH BETWEEN ‘SUBTYPES’ OF MUSCARINIC RECEPTORS?
Authors: SZELENYI I.
Published: July 2012

Pharmacological studies with pirenzepine were carried out on the isolated ileum and atrium of the guinea‐pig and on the acid secretion from the isolated stomach of the mouse. Pirenzepine inhibited the bethanechol‐evoked changes in all three organs in a dose‐dependent manner. The slopes of the Schild‐plots confirmed the competitive nature of the antagonism by pirenzepine. The estimated pA2‐values were very similar. Based on these data, it might be concluded that pirenzepine is an anticholinoceptor compound without specific affinity for gastric muscarinic receptors.
INVOLVEMENT OF THE MEDIAN RAPHE NUCLEUS IN ANTINOCICEPTION INDUCED BY MORPHINE, BUPRENORPHINE AND TILIDINE IN THE RAT
Authors: BRYANT ROSAMUNDE M. , OLLEY JEAN E. , TYERS M.B.
Published: July 2012

Antinociception induced by three analgesics with differing profiles of activity, morphine, buprenorphine and tilidine, have been evaluated in the hot plate and paw pressure tests after administration by the subcutaneous route and directly into the median raphe nucleus in the conscious rat.

Behavioural and neurological effects of the three analgesics were also assessed.

The typical profiles of antinociceptive activity induced by the three analgesics were qualitatively similar after either route of administration. Morphine induced naloxone‐sensitive dose‐dependent effects in both tests. Buprenorphine showed naloxone‐sensitive effects with a bell‐shaped dose‐response curve in the thermal test but dose‐dependent activity in the pressure test. Tilidine induced naloxone‐sensitive dose‐dependent effects in the thermal test but demonstrated naloxone‐insensitive activity in the paw pressure test.

The behavioural and neurological effects of the analgesics in the dose range used would not have affected the animals' ability to respond to the nociceptive stimuli.

The results suggest that the median raphe could participate in drug‐induced antinociception. The mechanisms by which this might occur are discussed.
Therapy of organophosphate poisoning: the marmoset as a model for man
Authors: van Helden H.P.M. , van der Wiel H.J. , Wolthuis O.L.
Published: July 2012

The ability of various bis‐pyridinium oximes to restore organophosphate‐inhibited neuromuscular transmission in vitro was compared in human intercostal and marmoset diaphragm muscles.

HI‐6 (2‐hydroxyiminomethyl‐pyridinium‐1‐methyl‐4′‐carbamoyl‐pyridinium‐1′‐methyl ether dichloride monohydrate) appeared very effective against VX (O‐ethyl S‐2‐diisopropylaminoethyl methylphosphonothioate) and sarin in both muscles, whereas obidoxim was quite effective against tabun.

Against soman, HI‐6, HS‐6 (2‐hydroxyiminomethyl‐pyridinium‐1‐methyl‐3′‐ carbamoylpyridinium‐1′‐methyl ether dichloride dihydrate) and obidoxim had little effect in the human muscle and only slight activity in the marmoset muscle; HGG‐12 (2‐hydroxyiminomethyl‐pyridinium‐1‐methyl‐3′‐phenylcarbonyl‐pyridinium‐1′‐methyl ether dichloride) and benzyl‐P2A (1‐benzyl‐2‐hydroxyiminomethyl‐pyridinium methanesulphonate) were ineffective.

Anaesthetized, atropinized marmosets were poisoned with soman (4 × LD50, i.v.) and subsequently treated with HI‐6, HS‐6 or HGG‐12. Only HI‐6 and HS‐6 were marginally effective in restoring respiration and neuromuscular transmission.

Marmoset muscle is a reasonable model for human muscle for the study of organophosphate poisoning and therapy.
Purine receptors in the guinea‐pig internal anal sphincter
Authors: Crema A. , Frigo G.M. , Lecchini S. , Manzo L. , Onori L. , Tonini M.
Published: July 2012

In the isolated internal anal sphincter of the guinea‐pig, adenosine 5′‐triphosphate (ATP) and adenosine induced a concentration‐dependent and tetrodotoxin‐insensitive relaxation.

Pretreatment with theophylline (25–50 μm) had no significant effect on the concentration‐response curves obtained with either purine compound.

Reactive blue 2 (25–100 μm) shifted the curve to ATP to the right in a dose‐dependent fashion leaving that to adenosine unaltered. The antagonism appeared to be non‐competitive.

Neither reactive blue 2 nor purine receptor occupation by ATP or adenosine altered the electrically‐induced non‐adrenergic, non‐cholinergic inhibitory response.

The actions of ATP and adenosine in the guinea‐pig internal anal sphincter appear to be mediated by separate receptors. These receptors are not involved in the nerve‐mediated relaxation.
The inhibitory effects of 5‐hydroxytryptamine on gastric acid secretion by the rat isolated stomach
Authors: Canfield S.P. , Spencer J.E.
Published: July 2012

The effect of 5‐hydroxytryptamine (5‐HT) on acid secretion by a rat isolated stomach preparation has been studied.

5‐HT at 10−5 M in the serosal bathing fluid produced significant inhibition of the acid secretory responses to histamine, pentagastrin and isoprenaline but was without effect on basal secretion or that due to bethanechol, dibutryl cyclic adenosine 3′,5′‐monophosphate (db cyclic AMP) or phosphodiesterase inhibition with ICI 63197. Increasing the concentration of 5‐HT to 5 × 10−5 m did not change this pattern of response whilst 5‐HT at 10−6 M did not cause consistent inhibition.

The inhibitory action of 5‐HT could be prevented by the antagonist methysergide (2.5 × 10−5 m). This concentration of methysergide alone did not affect responses to secretagogues or basal acid output.

Neither propranolol (2.5 × 10−5 m) nor tetrodotoxin (10−6 m) antagonized the inhibitory action of 5‐HT.

Both indomethacin (2.8 × 10−5 m) and ibuprofen (2.4 × 10−4 m) antagonized the action of 5‐HT. Indomethacin alone had no effect upon secretagogue responses.

5‐HT at 10−5 m had no inhibitory action when applied to the mucosal side of the preparation.

The results indicate that 5‐HT can act directly on the stomach of the rat to produce inhibition of acid output. This inhibition is selective and may involve the products of cyclo‐oxygenase activity.
A role for 5‐hydroxytryptamine in the GABA‐mimetic potentiation of α‐flupenthixol‐induced catalepsy in the rat
Authors: Davies John A. , Williams John
Published: July 2012

α‐Flupenthixol (α‐FPT)‐induced catalepsy in the rat was potentiated by diaminobutyric acid (DABA), an inhibitor of the neuronal high affinity uptake of γ‐aminobutyric acid (GABA).

The depletion of 5‐hydroxytryptamine (5‐HT) with p‐chlorophenylalanine (PCPA) abolished the DAB A potentiation of α‐FPT‐induced catalepsy; this response was restored with 5‐hydroxytryptophan.

Potentiation of α‐FPT‐induced catalepsy by clonazepam was significantly reduced by methysergide. Conversely, the potentiation of catalepsy by clomipramine was significantly reduced by Picrotoxin.

These results are interpreted as evidence supporting a role for 5‐HT in modifying the GABA‐ergic inhibition of dopaminergic pathways, possibly by regulating the release of GABA.
Analysis of current noise evoked by nicotinic agonists in rat submandibular ganglion neurones
Authors: Gray P.T.A. , Rang H.P.
Published: July 2012

The kinetics of the responses of rat submandibular ganglion neurones to nicotinic agonists were investigated by the analysis of agonist‐induced membrane current noise.

Two kinetic components are found in the responses of these cells to acetylcholine, carbachol, suberyldicholine, dimethyl‐4‐phenylpiperazinium and nicotine, in agreement with previous findings of two components in evoked synaptic currents in these cells.

Small, though significant, differences in the relative amplitudes of the two kinetic components were observed in the spectra of noise evoked by the different agonists. In particular, the fast component in the response to carbachol was relatively larger with respect to the slow component than with any other agonist tested.

No measurable dependence of the relative sizes of the two components on agonist concentration or membrane potential was observed.

The evidence supports the hypothesis that the two kinetic components are the product of two independent channel populations for which the agonists tested show some slight differences in selectivity.
The role of prostacyclin in modulating cholinergic neurotransmission in guinea‐pig ileum
Authors: Gaion R.M. , Trento M.
Published: July 2012

The mechanism of action of prostacyclin (PGI2) on isolated segments of guinea‐pig terminal ileum was studied by recording the changes in isometric tension.

In these preparations PGI2 (1 nm‐1 μm) caused a concentration‐dependent increase in muscle tension. This effect was rapid and short‐lasting.

PGI2‐induced contractions were inhibited by atropine and potentiated by physostigmine.

Hemicholinium‐3 reduced the response to PGI2 and the inhibition was quantitatively comparable at any PGI2 concentration tested.

Tetrodotoxin as well as low temperature (20°C) abolished and β‐bungarotoxin reduced the effect of PGI2.

Hexamethonium decreased the response to submaximal, but not to maximal PGI2 concentrations.

PGI2 potentiated the twitch response of the ileum to electrical stimulation.

In the presence of tetrodotoxin, PGI2 did not alter the effect of a sub‐maximal concentration of acetylcholine (ACh).

The present results give indirect evidence for the ability of PGI2 to facilitate ACh release from intramural nerves possibly by increasing the excitability of cholinergic cell bodies.
On the specificity and type of receptor involved in carotid body chemoreceptor activation by adenosine in the cat
Authors: McQueen D.S. , Ribeiro J.A.
Published: July 2012

Experiments were performed on cats anaesthetized with pentobarbitone in which carotid chemoreceptor activity was recorded from the peripheral end of a sectioned carotid sinus nerve.

Intracarotid injections of adenosine 5′‐triphosphate (ATP) (1–100 μg i.e.) caused a dose‐related increase in chemosensory discharge which was delayed in onset.

The adenosine uptake inhibitor dipyridamole potentiated the chemoexcitatory effects of injected adenosine and ATP.

The stable ATP analogue α‐β‐methylene ATP (10–100 μg i.c.) depressed chemoreceptor discharge, which suggests the presence of a P2‐purinoceptor in the carotid body, and provides evidence that the chemoexcitatory effect of ATP results from its hydrolysis to adenosine 5′‐phosphate (AMP)/adenosine.

Adenine, inosine, guanosine, cytidine and uridine had no appreciable effect on chemoreceptor discharge.

The adenosine R‐site agonists 2′‐chloroadenosine and N6‐methyladenosine had chemoexcitatory effects which were similar to those of adenosine, whereas the P‐site agonist 2′‐deoxyadenosine had no appreciable effect on discharge.

We conclude that the adenosine receptor in the cat carotid body has some of the characteristics of an R‐site receptor according to the classification of Londos & Wolff (1977).
Characterization of the binding of dl‐[3H]‐2‐amino‐4‐phosphonobutyrate to l‐glutamate‐sensitive sites on rat brain synaptic membranes
Authors: Butcher S.P. , Collins J.F. , Roberts P.J.
Published: July 2012

The binding of dl‐[3,4‐3H] 2‐amino‐4‐phosphonobutyric acid dl[3H]‐APB to rat whole brain synaptic membranes was investigated.

Binding was linear with membrane protein concentration, and optimal at physiological pH and temperature. The association rate was rapid, achieving equilibrium within 10 min. Prolonged incubations (> 20 min) revealed additional sites, which apparently possessed identical binding characteristics to those detected with 10 min incubations.

Binding of dl‐[3H]‐APB was enriched in synaptic membrane fractions, and assessment of the regional distribution, indicated greatest binding in those areas with a rich glutamatergic innervation.

The binding of dl‐[3H]‐APB in HEPES‐KOH buffer exhibited an absolute requirement for Cl−. The addition of Ca2+ resulted in a further enhancement of binding.

Saturation analysis revealed the presence of specific glutamate‐sensitive dl‐[3H]‐APB binding sites, with a KD = 1.26 μm and Bmax = 12.08 pmol mg−1 protein. A Hill plot revealed a slope slightly greater than unity, which could possibly be a reflection of a contribution to binding of a further site which is relatively insensitive to glutamate. Analysis of 60 min incubation data indicated an approximately 3 fold increase in the capacity of the system, but a relatively unchanged KD.

Examination of the pharmacological specificity of binding, showed that for both agonist and antagonist molecules, the l‐enantiomers were invariably more active than the d‐forms. For example, the l‐(+)‐2‐amino‐4‐phosphonobutyrate isomer was 15 times more active than the d‐(−)‐form in inhibiting the binding of dl‐[3H]‐APB. This is in close agreement with the ability of these compounds to produce depression of synaptic transmission. The most potent inhibitor of binding was quisqualate. It is suggested that APB may interact with a quisqualate‐preferring class of excitatory amino acid receptors, possibly localised predominantly on presynaptic terminals.
Lanthanides are transported by ionophore A23187 and mimic calcium in the histamine secretion process
Authors: Amellal M. , Landry Y.
Published: July 2012

Ionophore A23187 induced histamine release from peritoneal rat mast cells in the presence of lanthanum or terbium as it did in the presence of calcium.

Low concentrations of lanthanides (10−5 to 2 × 10−4m) were more efficient than similar concentrations of calcium.

The effect of low concentrations of calcium and lanthanides were additive.

Increasing the concentration of lanthanides above 10−3 m decreased histamine release. This decrease was partly reversed by calcium.

Calmodulin inhibitors, phenothiazines, R24571 and mepacrine, inhibited the histamine release induced by either calcium or lanthanides.

Zn2+, a calmodulin inhibitor transported by A23187, inhibited more potently the calcium‐dependent histamine release.

Lanthanides decrease histamine release induced by 48/80 in the absence of added calcium.

These data show that ionophore A23187 can transport lanthanides across the plasma membrane of mast cells, allowing the trivalent cations to substitute for calcium in the activation of calmodulin or calmoduline‐like proteins.
Differential effect of acetylsalicylic acid and dipyrone on prostaglandin production in human fibroblast cultures
Authors: Lüthy Christa , Multhaupt Marcel , Oetliker Oskar , Perisic Miodrag
Published: July 2012

Human skin fibroblasts incubated with arachidonic acid in culture show basal release of prostaglandins. They produce the same prostaglandins after stimulation with bradykinin.

Basal release of prostaglandins I2 (6‐oxo‐PGF1α), F2α and E2 is inhibited dose‐dependently by both acetylsalicylic acid (ASA) and dipyrone (P < 0.05). The examined dose‐range was 10−7 to 10−4 M for both drugs. During the first 5 min after removal of the drugs from the incubation medium, bradykinin‐stimulated release remains dose‐dependently inhibited (P < 0.001) in ASA‐, but not in dipyrone‐treated cultures. The difference between the effects of ASA and of dipyrone is highly significant (P < 0.0001), whereas the dipyrone‐treated cultures are not different from controls.

The findings are consistent with cyclo‐oxygenase inhibition by ASA as well as by dipyrone. However, the data demonstrate rapid reversibility of the effect of dipyrone. This suggests that in contrast to ASA, dipyrone does not inhibit cyclo‐oxygenase by binding covalently to the enzyme.
The source of thromboxane and prostaglandins in experimental inflammation
Authors: Higgs G.A. , Moncada S. , Salmon J. A. , Seager Kaye
Published: July 2012

Although cyclo‐oxygenase products have been detected at inflammatory sites the tissue of origin remains uncertain.

Inflammatory exudates were collected from rats 4, 6, 8, 12 or 24 h after subcutaneous implantation of carrageenin‐impregnated sponges.

Concentrations of the cyclo‐oxygenase products prostaglandin E2 (PGE2), 6‐oxo‐PGF1α and thromboxane B2 (TXB2) in inflammatory exudates and serum (obtained from blood clotted at 37° C) were measured by specific radioimmunoassays.

TXB2 concentrations in exudates increased to about 100 ng ml−1 at 8 h but decreased to less than 20 ng ml−1 after 24 h. PGE2 concentrations increased from 4–12 h and remained between 80 and 120 ng ml−1 from 12–24 h. 6‐oxo‐PGF1α had the same time course as that of PGE2 but concentrations were approximately one third of PGE2 values.

TXB2 concentrations in serum from thrombocytopaenic rats were less than 5% of control values. Thrombocytopaenia did not affect TXB2, PGE2 or 6‐oxo‐PGF1α concentrations or total leukocyte numbers in inflammatory exudates.

Methotrexate‐induced neutropaenia did not affect serum TXB2 concentrations but cyclo‐oxygenase products (including TXB2) in 6 h inflammatory exudates were reduced by 60–95%.

Colchicine (1.0 mg kg−1 s.c.) prevented leukocyte accumulation in sponge exudates and this was accompanied by a reduction in TXB2, PGE2 and 6‐oxo‐PGF1α concentrations at 6 h.

These results indicate that platelets are the source of TXB2 in clotting blood but do not contribute to cyclo‐oxygenase activity in experimental inflammation. The results also suggest that migrating leukocytes are the major source of thromboxane and to a lesser degree prostaglandins in acute 6 h inflammatory exudates.