bluuebunny/crossref_metadata_2025 huggingface dataset:
Indirect evidence that purinergic modulation of perivascular adrenergic neurotransmission in the portal vein is a physiological process
Authors: Burnstock Geoffrey , Crowe Rahima , Kennedy Charles , Török Josef
Published: July 2012

The effects of adenine nucleotides and nucleosides on the contractile response to perivascular nerve stimulation were compared in the isolated portal vein of rabbit, rat and guinea‐pig.

2‐Chloroadenosine was more potent than adenosine and ATP, which were equipotent in producing inhibition of neurogenic contractions in the rabbit and rat via prejunctional P1‐purinoceptors.

In contrast, neurogenic contractions of the guinea‐pig portal vein were not inhibited by adenosine and were potentiated by 2‐chloroadenosine and, to a lesser extent, by ATP.

Fluorescence histochemical localization of quinacrine, which binds to high levels of ATP, revealed a dense perivascular nerve plexus in the portal vein of rabbit and rat but not of guinea‐pig.

After chemical sympathectomy, quinacrine‐positive nerves persisted in the rabbit (supporting other evidence for the presence of purinergic nerves) but not in the rat (supporting other evidence for ATP as a cotransmitter in adrenergic nerves).

It is concluded that a prejunctional purinergic modulatory mechanism operates in adrenergic neurotransmission in the portal vein of rabbit and rat but not guinea‐pig, and it is suggested that this indicates a physiological mechanism.
Substituted benzaldehydes designed to increase the oxygen affinity of human haemoglobin and inhibit the sickling of sickle erythrocytes
Authors: Beddell C.R. , Goodford P.J. , Kneen G. , White R.D. , Wilkinson S. , Wootton R.
Published: July 2012

Substituted benzaldehydes have been designed to bind preferentially to the oxy conformation of human haemoglobin at a site between the amino terminal residues of the α‐subunits. Such compounds should stabilize the oxygenated form of haemoglobin and thereby increase its oxygen affinity.

The compounds produce the expected effect, left‐shifting the oxygen saturation curve of dilute haemoglobin solutions and of whole blood, although the binding pattern to haemoglobin is more complex than envisaged by the design hypothesis.

The predicted best compound is also a potent inhibitor, at low oxygen pressure, of the sickling of erythrocytes from patients homozygous for sickle cell disease, and may prove to be a clinically useful anti‐sickling agent.
Selective antinociceptive effects of tizanidine (DS 103–282), a centrally acting muscle relaxant, on dorsal horn neurones in the feline spinal cord
Authors: Davies J. , Johnston S.E.
Published: July 2012

The effects of the centrally acting muscle relaxant tizanidine (DS103–282) have been examined on the responses of laminae IV and V dorsal horn neurones to peripheral noxious and non‐noxious stimuli in cats spinalized at L1.

Iontophoretic ejection of tizanidine near the cell bodies of the recorded neurones or more dorsally into laminae II‐III resulted in a marked and prolonged depression of excitation of laminae IV and V neurones evoked by noxious stimuli. Spontaneous firing was also depressed in many neurones but responses to innocuous stimuli were unaffected.

Intravenous administration of tizanidine also produced a long lasting and selective reduction in responses of laminae IV and V neurones to noxious stimuli and depressed the long latency excitation of these neurones evoked by electrical stimulation of small diameter unmyelinated primary afferents.

In contrast to the selective antinociceptive effect of tizanidine, ejection of γ‐aminobutyric acid (GABA) near laminae IV and V neurones or isoguvacine into laminae II‐III produced parallel reductions in responses to noxious and non‐noxious stimuli. Furthermore, ejections of the excitant amino acid kainate into laminae II‐III produced parallel enhancement of responses induced by both types of stimuli.

The site and mechanism of the antinociceptive action of tizanidine is not known but does not appear to involve an interaction with opiate receptors as it was not antagonized by naloxone. The possibility is discussed that tizanidine acts at synapses formed between excitatory interneurones in lamina II or III and laminae IV and V neurones, either interfering with transmitter release or its postsynaptic action.

The effects of iontophoretically administered tizanidine are quite distinct from those of baclofen, which produced non‐selective depression of responses to both noxious and innocuous stimuli, but were similar to those of noradrenaline. This raises the possibility that noradrenaline and tizanidine may act at a common site in the spinal cord.
Effect of muscarinic ligands on the electrical activity recorded from the hippocampus: a quantitative approach
Authors: Bevan Paul
Published: July 2012

The electrical activity of the hippocampus was recorded from the CA 1 region in rats anaesthetized with halothane and the effects of compounds assessed following their intravenous injection. Quantification of the effects was achieved following on‐line fast Fourier transformation of the signal.

The electrical activity recorded from the hippocampus of the halothane‐anaesthetized rat demonstrated identical characteristics to that recorded from the freely‐moving animal.

Three types of activity could be distinguished: rhythmical slow wave activity (RSA or theta); large amplitude slow wave activity (LIA); and small amplitude fast wave activity.

Muscarinic agonists induced RSA with a consequent reduction in power. The effects were dose‐dependent and were reversibly antagonized by scopolamine, but not methyl‐scopolamine, indicating that the effects are mediated centrally by muscarinic receptors.

The results show that, in halothane anaesthetized rats, a muscarinic RSA occurs which is unrelated to movement or behavioural arousal.
Effects of α2‐adrenoceptor agonists and of related compounds on aggregation of, and on adenylate cyclase activity in, human platelets
Authors: Clare Katherine A. , Scrutton Michael C. , Thompson Neil T.
Published: July 2012

A range of 2–(,5‐dihydroimidazolyl)‐benzene, ‐quinoline, and ‐quinoxaline derivatives and 2‐morpholino‐4‐catechol have been characterized as agonists or partial agonists for human platelet aggregation; and for inhibition of adenylate cyclase by measurement of their effect on platelet [cyclic‐3′,5′‐AMP]. Antagonist activity for these compounds versus adrenaline as agonist has also been assessed for these two responses.

The compounds can be divided into 4 groups. Group I contains compounds that are agonists for both responses; group II, compounds that are agonists for inhibition of adenylate cyclase but antagonists for the aggregatory response; group III, compounds that are agonists for the aggregatory response but are antagonists for inhibition of adenylate cyclase by adrenaline; and group IV, compounds that are antagonists for both responses.

In group I the EC50 values for induction of aggregation are not significantly different from the EC50 values for inhibition of adenylate cyclase except for 2‐morpholino‐4‐catechol which is significantly more potent as an inhibitor of adenylate cyclase.

In group IV a linear correlation is observed between the K1 values for the two responses for 8 compounds but 2 other compounds do not conform to this correlation.

The data are not consistent with a model in which a single x2‐adrenoceptor mediates both the aggregatory response and inhibition of adenylate cyclase and hence support a model in which unique x2‐adrenoceptors mediate these two responses.
The inhibitory effect of aspirin on lymphatic contractility
Authors: Allen J.M. , Burke E.P. , Johnston M.G. , McHale N.G.
Published: July 2012

Spontaneous contractions and those elicited by two different methods of electrical stimulation were studied in isolated segments of bovine mesenteric lymphatic vessels.

The effect of aspirin (a cyclo‐oxygenase inhibitor) on spontaneous and evoked contractions of isolated lymphatic vessels was investigated.

Aspirin at doses of 10−6m or greater depressed both spontaneous and action potential‐dependent evoked contractions, but failed to inhibit contractions evoked by high current field stimulation. These latter contractions were rapidly depressed by the application of D600.

When aspirin was applied for five minute periods, inhibition never occurred within the period of drug administration but was delayed, with maximum inhibition occurring approximately 10 min after washout of the drug.

It is concluded that the inhibitory action of aspirin is unlikely to be a non‐specific depression of the contractile mechanism, but rather a reduction in excitability probably as a result of cyclo‐oxygenase inhibition.
Glutamate inhibitory action of matrine at the crayfish neuromuscular junction
Authors: Ishida M. , Shinozaki H.
Published: July 2012

The effect of some alkaloids from Sophora flavescens (matrine, oxymatrine and N‐methylcytisine) on glutamate‐induced responses was investigated using electrophysiological techniques at the crayfish neuromuscular junction.

At concentrations greater than 0.1 mm, matrine depressed both glutamate‐induced responses and neurally evoked excitatory junctional potentials. Oxymatrine was less powerful than matrine, and N‐methylcytisine was not effective. Matrine also depressed quisqualate‐induced responses at this site, but did not have an effect on γ‐aminobutyric acid (GABA)‐induced responses. Matrine had no influence upon either the resting membrane potential or the input resistance of the crayfish opener muscle.

The inhibition of the glutamate‐induced response by matrine was not affected by the membrane potential of the muscle fibre.

Matrine reduced the size of extracellularly recorded excitatory junctional potentials without affecting their quantal content.

Matrine did not affect the decay of extracellular excitatory junctional currents at the resting membrane potential.

The results presented clearly demonstrate that matrine has an inhibitory action on glutamate‐induced responses.
Effects of dopamine and bromocriptine on colonic motility in dog
Authors: Bueno L. , Fargeas M.J. , Fioramonti J. , Honde C.
Published: July 2012

The effects of intravenous infusions of dopamine (0.1 to 1 mg kg−1 h−1) and bromocriptine (10 to 40 μg kg−1 h−1) on colonic motility were investigated in fasted dogs fitted with permanent strain gauges on the ascending, transverse and descending colon.

Infused at rates of 0.5 and 1 mg kg−1 h−1 during 1 h, dopamine immediately stimulated the motility of the descending colon; after a delay of 40 to 60 min this effect was balanced by an inhibition of the motility of the ascending and transverse colon. Bromocriptine infused intravenously at doses of 10 to 40 μg kg−1 h−1 stimulated the motility of the whole colon but these effects were limited to the duration of the infusion (60 min).

Both propranolol (0.5 mg kg−1) and tolazoline (2 mg kg−1) failed to block the effects of dopamine and bromocriptine whereas phentolamine (0.1 mg kg−1) and prazosin (0.2 mg kg−1) partially reduced the inhibitory effects of dopamine on the proximal colon. Haloperidol at doses higher than 0.2 mg kg−1 and domperidone blocked the bromocriptine‐induced stimulation of colonic motility which was unaffected by previous treatment with α‐ and β‐adrenoceptor blocking agents.

These results suggest that in the dog, dopamine and bromocriptine stimulate colonic motility through specific dopamine receptors. However, they suggest that the inhibitory effects of dopamine on the proximal colon which are blocked by dopamine antagonists are also partially due to an effect on α1‐adrenoceptors.
Inhibition of calcium spikes and transmitter release by γ‐aminobutyric acid in the guinea‐pig myenteric plexus
Authors: Cherubini E. , North R. A.
Published: July 2012

The effect of γ‐aminobutyric acid (GABA) (1 μM‐1 mM) on synaptic transmission in isolated myenteric ganglia of guinea‐pig ileum was investigated with intracellular recording techniques.

GABA (up to 1 mM) had no effect on the resting membrane potential and membrane conductance of S neurones.

GABA reduced the amplitude of the fast excitatory postsynaptic potential (e.p.s.p.) without changing the amplitude of the nicotinic response to ionophoretic application of acetylcholine (ACh). This effect was mimicked by baclofen (10–100 μM) and was not blocked by bicuculline (10 μM). The preparation did not become desensitized during prolonged GABA applications.

Cholinergic and non‐cholinergic slow e.p.s.ps evoked by single or repetitive presynaptic nerve stimulation were reduced in amplitude by GABA. GABA did not depress muscarinic responses to ionophoretic application of ACh.

GABA reduced the duration of the action potential in AH neurones in concentrations that did not affect the membrane potential or conductance. The effect was very marked when electrodes were filled with CsCl, and tetrodotoxin was in the supervising solution. This effect was also mimicked by baclofen, was insensitive to bicuculline and was not reduced with repeated application or GABA.

It is concluded that GABA inhibits release of ACh and the transmitter mediating the slow e.p.s.p. This effect may result from inhibition of an inward calcium current.
The anti‐ulcerogenic activity of the unripe plantain banana (Musa species)
Authors: Best Ralph , Lewis David A. , Nasser Nasser
Published: July 2012

Various preparations of dried unripe plantain banana were found to be anti‐ulcerogenic against aspirin‐induced ulceration in the rat and were effective both as a prophylactic treatment and in healing ulcers already induced by aspirin. Ripe fruit bananas were inactive.

The active factor(s) were water soluble and were concentrated by extraction to approximately three hundred times that in the dried banana powder.

The anti‐ulcerogenic action of banana preparations appears to be due to their ability to stimulate the growth of gastric mucosa.

Aluminium hydroxide, cimetidine, prostaglandin E2, N6, O2‐dibutyryl adenosine 3′,5′ cyclic monophosphate but not 5‐hydroxytryptamine were also anti‐ulcerogenic when used prophylactically in rats but were ineffective in healing ulcers already formed by aspirin. These substances did not stimulate the growth of gastric mucosa.
Desensitization of the guinea‐pig urinary bladder by the enantiomers of adenylyl 5′‐(β,γ‐methylene)‐diphosphonate and by substance P
Authors: Hourani S.M.O.
Published: July 2012

Adenosine 5′‐triphosphate (ATP), substance P (SP) and non‐cholinergic nerve stimulation contracted the guinea‐pig urinary bladder. SP and two poorly‐degradable analogues of ATP, the enantiomers of adenylyl 5′‐(β,γ‐methylene)‐diphosphonate (AMP‐PCP and L‐AMP‐PCP), were used to desensitize the guinea‐pig bladder.

Desensitization of the bladder by AMP‐PCP (50 μM) or by L‐AMP‐PCP (50 μM) abolished the responses to ATP, and inhibited the responses to non‐cholinergic nerve stimulation and to SP. The responses to histamine were unaffected.

Desensitization by SP (1 μM) inhibited the responses to SP itself, but not the responses to ATP, L‐AMP‐PCP or non‐cholinergic nerve stimulation.

These results suggest that SP may act partly by releasing ATP, and support the suggestion that ATP rather than SP is the non‐cholinergic stimulatory transmitter.
Changes in bronchial anaphylactic reactivity induced in guinea‐pigs by long‐term treatment with histamine H2‐agents
Authors: Andersson Per , Bergstrand Håkan
Published: July 2012

Guinea‐pigs were sensitized to ovalbumin (OA) by immunization regimens chosen to cause antigen‐induced bronchial anaphylactic responses mediated mainly either by IgE‐like antibodies or by IgG1‐like antibodies.

Treatment of the IgE‐producing animals for three weeks with the histamine H2‐receptor antagonist cimetidine (1 mg kg−1 i.p. once a day) or with the H2‐agonist dimaprit (0.1, 1.0, or 10 mg kg−1 i.p. once a day) led to a significantly reduced bronchial response capacity compared with that of the saline‐treated controls challenged intravenously with antigen one week after the end of treatment. The changes were biphasic and not strictly dose‐dependent. In contrast, acute treatment of immunized animals with a single dose of cimetidine (10 or 30 mg kg−1 i.v.) or dimaprit (1 or 10 mg kg−1 i.v.) 2 min before challenge with OA did not significantly affect the bronchial anaphylactic response.

However, long‐term treatment with cimetidine (10 mg kg−1) or the dimaprit analogue, S‐[4‐(N, N‐dimethylamino)‐butyl] isothiourea (SKF Compound 91488) (1 mg kg−1), which is reported not to activate H2‐receptors, had no effect on the response capacity.

Treatment with cimetidine (1 mg kg−1) or dimaprit (1 mg kg−1) did not influence the response capacity to antigen challenge in IgG1‐ type animals. Dimaprit (1 mg kg−1) did not affect the responsiveness to intravenous provocation with histamine in ‘IgE‐type’ animals. Antigen‐induced release of histamine from chopped lung tissue in vitro was not significantly affected in ‘IgE‐type’ animals treated with cimetidine (1 mg kg−1) or dimaprit (1 mg kg−1).

Treatment of immunized animals with cimetidine or dimaprit one week before and one week after a booster injection of antigen also led to reduced response capacity compared with that of saline‐treated controls. However, the serum levels of IgE‐like homocytotropic antibodies of these animals were not reduced; on the contrary, those of IgG1‐antibody were increased in dimaprit‐treated animals.

These data show that intermittent treatment with histamine H2‐agents reduces reagin‐mediated anaphylactic response capacity in vivo in actively sensitized guinea‐pigs by an as yet undefined mode of action.
Muscarinic receptor occupation and receptor activation in the guinea‐pig ileum by some acetamides related to oxotremorine
Authors: Ringdahl Björn
Published: July 2012

The dissociation constants (KD values) and relative efficacies of seven acetamide analogues of oxotremorine, including two enantiomeric pairs, at muscarinic receptors in the guinea‐pig isolated ileum were determined. The method used involved analysis of dose‐response data before and after fractional inactivation of receptors with propylbenzilylcholine mustard.

All of the compounds studied had lower affinities than oxotremorine, but some had substantially higher relative efficacies.

Replacement of the pyrrolidine ring of N‐methyl‐N‐(4‐pyrrolidino‐2‐butynyl)acetamide(I), the parent compound in the series, by a dimethylamino or a trimethylammonium group decreased the affinity 32 and 4.5 fold, respectively, whereas the relative efficacy increased 5.7–8.3 times.

There was no correlation between relative efficacies and affinities of the compounds. The structural requirements for high affinity and high efficacy appeared to be quite different.
Inhibition of allergic and non‐allergic histamine secretion from rat peritoneal mast cells by calcium antagonists
Authors: Chand N. , Diamantis W. , Pillar J. , Sofia R.D.
Published: July 2012

Bepridil, TMB‐8 (8‐(diethylamino)octyl 3,4,5‐trimethoxybenzoate hydrochloride),diltiazem, verapamil and nifedipine exerted concentration‐dependent inhibition of antigen and calcium ionophore A23187‐induced histamine release from rat peritoneal mast cells.

The inhibitory effects of verapamil and bepridil against calcium ionophore A23187‐induced histamine secretion were antagonized by increased Ca2+ concentrations in the extracellular medium. These observations suggest that both agents act by interfering with the influx of Ca2+ into the mast cells.

The inhibitory activities of five different Ca2+ channel blockers on allergic and non‐allergic histamine secretion from rat peritoneal mast cells varied considerably depending upon the nature of the secretagogue as well as concentration and type of Ca2+‐antagonist examined.
Synergistic interaction between histamine and ouabain on ventricular fibrillation threshold
Authors: Trzeciakowski Jerome P.
Published: July 2012

The interaction between histamine and ouabain on the ventricular fibrillation threshold (VFT) was studied in the isolated, Langendorff‐perfused heart of the guinea‐pig.

When administered separately, histamine and ouabain each reduced the VFT in a concentration‐related manner with ED50 values of 84.3 and 250 nM, respectively.

When perfused in combination the effects of these two drugs on VFT were significantly greater than the sum of their individual contributions.

Mepyramine and cimetidine both antagonized the fibrillatory effects of the histamine‐ouabain combination. Neither antagonist affected the fibrillation concentration‐response curve for ouabain.

These results suggest that both classes of histamine receptor may participate in the histamine‐ouabain interaction.
Comparison of negative inotropic potency, reversibility, and effects on calcium influx of six calcium channel antagonists in cultured myocardial cells
Authors: Barry W.H. , Horowitz J.D. , Smith Thomas W.
Published: July 2012

The negative inotropic effects of calcium channel antagonists on the myocardium were used as a standard for the definition and determination of potency of this group of drugs.

The effects of six calcium channel antagonists (verapamil, methoxyverapamil (D600), nifedipine, lidoflazine, perhexiline and diltiazem) were compared on cultured chick embryo ventricular cells.

Drug concentrations producing 50% inhibition of contractile amplitude, derived from linearized concentration‐response curves, varied from 2.8 × 10−8 M for nifedipine to 8.3 × 10−7 M for perhexiline. Equipotent negative inotropic concentrations of verapamil, D600, perhexiline, diltiazem and lidoflazine produced a similar inhibitory effect on 45Ca uptake into cultured cells. Nifedipine produced no significant inhibition of 45Ca uptake.

The time required for recovery of contractility after cessation of drug superfusion varied in the order lidoflazine > perhexiline >D600> verapamil > nifedipine > diltiazem. This relative order accords closely with the reported in vivo half‐lives of these drugs.

It is concluded that while some inhibition of 45Ca2+ uptake into cardiac cells can be demonstrated with five of the six calcium channel blockers studied, the relationship between the degree of inhibition of calcium influx and negative inotropic effects may not be uniform for all calcium channel antagonists.
Pressor sensitivity to exogenous vasopressin in conscious, adult rats treated neonatally with capsaicin
Authors: Bennett T. , Gardiner S.M.
Published: July 2012

Pressor responses to exogenous arginine vasopressin were assessed in adult rats that had been treated neonatally with capsaicin or its vehicle. Measurements were made under control conditions, after inhibition of baroreflexes (with pentolinium), and after inhibition of baroreflexes (with pentolinium) and the production of angiotensin II (with captopril).

Resting arterial blood pressures and pressor sensitivities to exogenous arginine vasopressin were similar in capsaicin‐treated and vehicle‐injected rats.

Sixty minutes after the administration of pentolinium, systolic and diastolic blood pressures were reduced in both groups of rats and the pressor responses to arginine vasopressin were similarly and significantly enhanced.

In both groups of rats 60 min after administration of pentolinium and captopril, systolic and diastolic blood pressures were lower than in the presence of pentolinium alone, but pressor responses were not different from those seen in control conditions.

The possibility that the present results are explicable in terms of baroreflexes, the renin‐angiotensin system and endogenous vasopressin interacting to influence the pressor sensitivity to exogenous vasopressin is discussed. From the present findings, it seems that our previous observation of impaired, vasopressin‐mediated blood pressure recovery following acute hypotension in capsaicin‐treated rats cannot be attributed to a reduced pressor sensitivity to the hormone.
Comparison of the antagonistic effects of phentolamine on vasoconstrictor responses to exogenous and neurally released noradrenaline in vivo
Authors: Bell C.
Published: July 2012

The antagonistic effects of the α‐adrenoceptor blocking agent phentolamine on vasoconstrictor responses to intraluminal noradrenaline and lumbar sympathetic nerve stimulation were compared in the hindlimb of the anaesthetized dog.

Sympathetic stimulation with 1 pulse or trains of 4–10 pulses at 0.4–40 Hz produced graded vasoconstrictor responses that were matched in amplitude by intra‐arterial injections of 10−8–10−6 g noradrenaline. Phentolamine (0.5 mg kg−1 i.v.) attenuated amplitude‐matched responses to both types of stimuli to quite similar extents.

The extent of the effect of phentolamine on neurogenic responses was greater with 1 pulse stimulation than with trains, and greater with 4 pulse than with 10 pulse trains. The effect was maximal within 2 min of phentolamine administration and wore off in parallel with that on responses to injected noradrenaline.

The results are consistent with the view that transmitter released from noradrenergic vasoconstrictor nerves acts primarily on subjunctional α‐adrenoceptors.
Quantification of the characteristics of antagonists exhibiting both competitive antagonism and functional interaction
Authors: Hughes I.E. , Mackay D.
Published: July 2012

Null equations have been derived which, when applied to log10 concentration‐tissue state curves for an agonist determined in the presence and absence of a competitive antagonist which also exhibits functional interaction, allow quantitation of the characteristics of the competitive and functional interactant effects.

Both the affinity constant of the antagonist for its receptors and numerical values characterizing the functional interaction can be obtained.

The null equations have been tested in a model system by using a mixture of papaverine hydrochloride (either 5 or 20 μM) and methyl atropine bromide (10 nM) to mimic a competitive antagonist which also shows functional interaction.

Agreement between values derived directly and indirectly from the model is good and validates the use of the null equations.
Similarity between μ‐opioid receptors in mouse vas deferens and guinea‐pig ileum
Authors: Goodall Jacqueline , Hughes I.E. , Mackay D.
Published: July 2012

The effects of the opioid receptor agonist RX783006 and of the opioid receptor partial agonist (+)‐meptazinol have been examined on electrically‐induced twitch responses of the guinea‐pig isolated ileum and of the mouse isolated vas deferens.

Log10 concentration‐tissue state curves were determined for (+)‐meptazinol and for RX783006, alone, in combination and, when appropriate, in the presence of naloxone (30 nM).

Analysis of these log10 concentration‐tissue state curves using the null equations derived and verified in the previous paper allows quantitation of the characteristics of the interaction of (+)‐meptazinol with the opioid receptors in these tissues.

The results indicate that the apparent differences in the actions of (+)‐meptazinol on isolated electrically‐stimulated guinea‐pig ileum and mouse vas deferens can be accounted for without the need to postulate differences between μ‐opioid receptors in these two tissues.
Cellular uptake disguises action of L‐glutamate on N‐methyl‐D‐aspartate receptors: With an appendix: Diffusion of transported amino acids into brain slices
Authors: Garthwaite J.
Published: July 2012

Pharmacological properties of the guanosine 3′5′‐cyclic monophosphate (cyclic GMP) responses to excitatory amino acids and their analogues were compared in slices and dissociated cells from the developing rat cerebellum maintained in vitro. The intention was to determine the extent to which cellular uptake might influence the apparent properties of receptor‐mediated actions of these compounds.

In slices, the potencies of the weakly (or non‐) transported analogues, N‐methyl‐D‐aspartate (NMDA) and kainate (KA) (EC50 = 40 μM each) were higher than those of the transported amino acids, D‐ and L‐aspartate (EC50 = 250 μM and 300 μM) and D‐ and L‐glutamate (EC50 = 540 μM and 480 μM). Quisqualate (up to 300 μM) failed to increase cyclic GMP levels significantly. The sensitivity of agonist responses to the NMDA receptor antagonist, DL‐2‐amino‐5‐phosphonovalerate (APV), was in the order NMDA > L‐aspartate > L‐glutamate, KA.

In dissociated cells, L‐glutamate was 280 fold more potent (calculated EC50 = 1.7 μM). L‐ and D‐aspartate (calculated EC50 = 13 μM) and D‐glutamate (EC50 = 130 μM) were also more effective than in slices. The potencies of NMDA and KA were essentially unchanged. Responses to NMDA, L‐glutamate and L‐aspartate under these conditions were equally sensitive to inhibition by APV but the response to KA remained relatively resistant to this antagonist.

The implications of these results are that, in slices, cellular uptake is responsible for (i) the dose‐ response curves to L‐glutamate, L‐ and D‐aspartate bearing little or no relationship to the true (or relative) potencies of these amino acids; (ii) the potency of APV towards the actions of transported agonists acting at NMDA receptors being reduced and (iii) a differential sensitivity to APV of responses to L‐glutamate and L‐aspartate being created, the consequence being that a potent action of L‐glutamate on NMDA receptors is disguised.

These conclusions are supported by theoretical considerations relating to the diffusion of transported amino acids into brain slices, as elaborated in the Appendix.
Different responsiveness of prostaglandin D2‐sensitive systems to prostaglandin D2 and its analogues
Authors: Narumiya Shuh , Toda Noboru
Published: July 2012

Prostaglandin D2 (PGD2) and six PGD2 analogues were used to classify responsiveness of several PGD2‐sensitive systems. The analogues used were 9β‐PGD2, 5‐(6‐carboxyhexyl)‐1‐(3‐cyclohexyl‐3‐hydroxypropyl)hydantoin (BW245C), 17‐phenyl‐18,19,20‐trinor‐PGD2 (17‐phenyl‐PGD2), PGD2 amide, PGD2 N‐monomethylamide and 11‐keto‐15α‐hydroxy‐δ5,9,12‐prostenoic acid (9‐deoxy‐δ9,12‐PGD2). The PGD2‐sensitive systems examined were human platelets, rat peritoneal mast cells, rabbit transverse stomach strip, guinea‐pig tracheal ring chain and helical strip of the dog cerebral artery.

PGD2, 9β‐PGD2 and BW245C inhibited the aggregation of human platelets, increased adenosine 3′:5′‐cyclic monophosphate (cyclic AMP) in rat mast cells and relaxed the rabbit stomach strip. The rank order of potency was BW245C>PGD2>9β‐PGD2. PGD2 amide and PGD2 N‐monomethylamide were inactive in the former two systems but elicited relaxant activity on the rabbit stomach strip. 17‐Phenyl‐PGD2 was virtually inactive in the above three systems.

PGD2 and 17‐phenyl‐PGD2 contracted the guinea‐pig tracheal ring chain and the helical strip of dog cerebral arteries with almost equal potency. 9β‐PGD2 and BW245C antagonized competitively the contractile action of PGD2. PGD2 amide and PGD2 N‐monomethylamide showed weak agonistic actions in the tracheal preparation.

9‐Deoxy‐δ9,12‐PGD2, showing stronger growth inhibition than PGD2 on cultured tumour cells, was inactive in human platelets, rat mast cells and guinea‐pig trachea, and elicited contractile response in the rabbit stomach strip.

These results indicate the presence of three groups of PGD2‐sensitive systems that respond differently to PGD2 and its analogues.
The properties of the clonidine withdrawal response of guinea‐pig isolated ileum
Authors: Chahl Loris A.
Published: July 2012

The dependence‐inducing effects of clonidine were investigated on the guinea‐pig isolated ileum. Clonidine produced relaxation of the ileum with a threshold concentration between 0.01 and 0.1 μmol 1−1. Washout of clonidine did not induce a withdrawal contraction.

Following 2 min contact of the ileum with clonidine, 1 μmol 1−1, addition of phentolamine, 5 μmol 1−1, induced a contracture. The phentolamine‐precipitated withdrawal contracture did not increase in height with a longer period of contact (32 min) of the ileum with clonidine.

The phentolamine‐precipitated withdrawal contracture following 2 min contact of ileum with clonidine was abolished by atropine, 5 μmol 1−1, and substance P (SP) antagonists, (D‐Pro2, D‐Phe7, D‐Trp9)‐SP and spantide, 10 μmol 1−1.

[Met5]enkephalin, 1 μmol 1−1, abolished the withdrawal response to clonidine and clonidine, 1 μmol 1−1, abolished the withdrawal response to [Met5]enkephalin.

Following 2 min contact of the ileum with noradrenaline, 5 μmol 1−1, washout or addition of phentolamine or yohimbine, 5 μmol 1−1, also induced a withdrawal response. The noradrenaline washout withdrawal response was abolished by atropine, 5 μmol 1−1, and spantide, 10 μmol 1−1.

Since clonidine dependence may be induced as rapidly as opiate dependence in the ileum and the pharmacology of the withdrawal responses is similar, it is suggested that they both induce the same post‐receptor neuronal feedback disturbance in which substance P neurones play a major role.
Stimulation rate modulates effects of the dihydropyridine CGP 28 392 on cardiac calcium‐dependent action potentials
Authors: Kamp Timothy J. , Miller Richard J. , Sanguinetti Michael C.
Published: July 2012

Calcium (Ca2+)‐dependent action potentials were recorded from 22 mM potassium (K+)‐depolarized guinea‐pig papillary muscle at several different pacing frequencies in the absence and presence of CGP 28 392 (10 μM), a Ca2+ channel agonist. The maximum upstroke velocity (max) of the slow response action potential was measured to determine relative changes in Ca2+ current as a function of pacing frequency.

CGP 28 392 increased max more than two fold at low rates of stimulation (1 or 12 pulses min−1), but had no significant effect on max during rapid pulsing (200 pulses min−1).

The enhancement of max was dependent upon extracellular [K+]. Increasing extracellular [K+] from 22 mM to 27 mM suppressed the frequency‐dependent agonist effects and increased the antagonist effects on max.

These results indicate that CGP 28 392 is a partial Ca2+‐channel agonist and suggest that its effects on Ca2+ current are voltage‐dependent.
A pharmacological study on respiratory rhythm in the isolated brainstem‐spinal cord preparation of the newborn rat
Authors: Murakoshi Takayuki , Suzue Toshihiko , Tamai Sunao
Published: July 2012

An in vitro brainstem‐spinal cord preparation of the newborn rat was used to examine the effects of neurotransmitters and transmitter candidates on respiratory frequency.

Spontaneous periodic depolarization of the spinal ventral roots of the 4th or 5th cervical segment was observed at a frequency of 5–15 min−1 constantly for more than 5 h. The frequency of this depolarization was monitored as an index of the respiratory frequency.

An elevation of the concentration of Ca2+ or Mg2+ caused a decrease in the respiratory frequency, whereas an elevation of K+ concentration caused an increase. The frequency was also increased by a reduction of pH. The highest frequency was observed at 27–28°C.

Dopamine, 5‐hydroxytryptamine, histamine, acetylcholine, glutamic acid, substance P, and thyrotropin releasing hormone accelerated the respiratory frequency when applied by perfusion to the brainstem, whereas noradrenaline, γ‐aminobutyric acid, glycine, and [Met5] enkephalin and [Leu5] enkephalin slowed the frequency. Experiments with antagonists suggested that the stimulant effect of acetylcholine on respiratory frequency was mediated mainly by muscarinic receptors and the depressant effect of noradrenaline was mediated by α‐adrenoceptors.
TI‐233 as a glutamate channel blocker at the crayfish neuromuscular junction
Authors: Ishida M. , Shinozaki H.
Published: July 2012

Effects of TI‐233 (4‐isopropyl‐1‐[N2‐(5,6‐dimethyl‐aminonaphthalene‐1‐sulphonyl)‐L‐arginyl]‐piperidine) on glutamate‐induced responses and nerve‐evoked synaptic responses were compared at the crayfish neuromuscular junction.

Intracellularly recorded excitatory junctional potentials (e.j.ps) were markedly augmented by TI‐ 233 when they were evoked at long intervals, whereas the unit size of extracellular e.j.ps was hardly affected by TI‐233 and, at that stage, the glutamate‐induced current was markedly reduced by TI‐233.

The decay rate of extracellular e.j.ps was slightly increased 3 min after the addition of TI‐233 at concentrations higher than 0.05 mM.

Repetitive stimulation of the excitatory axon at a high frequency caused a gradual decrease in the amplitudes of extracellular e.j.ps in the presence of TI‐233. After prolonged application of TI‐233 with repetitive nerve stimulation, the glutamate‐induced response became significantly smaller than the control.

TI‐233 increased the input resistance of the crayfish muscle fibre and facilitated transmitter release at the excitatory neuromuscular junction. These two effects would entirely explain the augmentation of intracellular e.j.ps by TI‐233.

TI‐233 (> 3 μM) reduced the amplitude of current responses to trains of glutamate pulses in a dose‐dependent manner, but this reduction by TI‐233 was time‐ and activity‐dependent. The effect of TI‐233 on glutamate‐induced responses was voltage‐dependent and hyperpolarization increased this effect.

Pretreatment of the muscle fibre with concanavalin A did not affect the gradual decline, caused by TI‐233, of the successive currents evoked by a train of glutamate pulses.

The apparent differences between the glutamate‐induced current and nerve‐evoked synaptic response revealed by TI‐233 can be explained by open‐channel block of the glutamate‐activated ion‐ channel, and do not confute the hypothesis that glutamate is the natural transmitter substance at this junction.
Differential blocking actions of idazoxan against the inhibitory effects of 6‐fluoronoradrenaline and clonidine in the rat vas deferens
Authors: Hicks P.E. , Langer S.Z. , Macrae A.D.
Published: July 2012

The prejunctional inhibitory effects of clonidine and 6‐fluoronoradrenaline (6‐FNA) have been evaluated in the isolated prostatic segment of the rat vas deferens, against the twitch response evoked by low frequency (0.1 Hz) field stimulation.

The inhibitory potency of 6FNA was significantly increased in the presence of cocaine (1 μM) or pargyline (10 μM), but was not modified in the vas deferens from rats pretreated with reserpine when the endogenous levels of noradrenaline (NA) were decreased by 97%. Clonidine was significantly more potent than 6‐FNA as an inhibitory agonist, and the potency of clonidine was not modified after cocaine, pargyline or reserpine.

The α2‐adrenoceptor blocking agent idazoxan, was a competitive antagonist against the inhibitory effects of clonidine under all experimental conditions. In contrast, the only antagonism shown by idazoxan against the inhibitory effects of 6‐FNA was in the presence of cocaine (1 μM), and this antagonist effect of idazoxan was not concentration‐related.

Low concentrations of 6‐FNA caused concentration‐dependent facilitatory effects on the twitch response, which were significantly greater after treatment with idazoxan (1 μM) in reserpine‐treated vas deferens. These facilitatory effects of 6‐FNA were always observed in the presence of prazosin (300 nM) and also after treatment of the preparations with phenoxybenzamine (10 μM), a concentration which abolished the inhibitory actions of both clonidine and 6‐FNA. The facilitatory effects on the twitch response induced by low concentrations of 6‐FNA are therefore unlikely to be due to either α1‐ or α2‐adrenoceptor stimulation.

In conclusion, the failure of idazoxan to block the inhibitory effects of 6‐FNA, while exerting a potent competitive antagonism of clonidine‐induced inhibitory effects, supports the proposal that α2‐adrenoceptors may in fact be subdivided into two subclasses, involving imidazoline and phenylethylamine recognition sites.
The 5‐HT1 receptor agonist RU‐24969 decreases 5‐hydroxytryptamine (5‐HT) release and metabolism in the rat frontal cortex in vitro and in vivo
Authors: Brazell M.P. , Marsden C.A. , Nisbet A.P. , Routledge C.
Published: July 2012

K+‐stimulated release of [3H]‐5‐hydroxytryptamine ([3H]‐5‐HT) from rat frontal cortex slices was decreased by the 5‐HT receptor agonists 5‐methoxy‐n1N‐dimethyltryptamine and 5‐methoxy‐3(1,2,3,6,‐tetrahydro‐4‐pyrindinyl)‐1H‐indole (RU‐24969) (1 × 10−5 M).

RU‐24969 (10 mg kg−1, i.p.) decreased extracellular 5‐HT and its metabolite 5‐hydroxyindoleacetic acid measured in vivo by use of intracerebral dialysis combined with high performance liquid chromatography and electrochemical detection.

The decrease in extracellular 5‐hydroxyindoleacetic acid in vivo after RU‐24969 (10 mg kg−1, i.p.) was also observed by in vivo voltammetry.

The non‐selective 5‐HT antagonist metergoline prevented the RU‐24969‐induced decrease in 5‐HT release and metabolism in vivo while the 5‐HT2 receptor antagonist R‐55669 (ritanserin) did not.

The results support the view that RU‐24969 stimulates a 5‐HT1 receptor that is involved in the autoregulation of 5‐HT release and metabolism.
Electrophysiological analysis of the nature of adrenoceptors in the rat basilar artery during development
Authors: Byrne N.G. , Hirst G.D.S. , Large W.A.
Published: July 2012

The nature of adrenoceptors in basilar arteries of neonatal rats was investigated by means of electrophysiological techniques.

In immature (2–6 day postnatal) rats, micro‐injection of noradrenaline elicited a depolarization which consisted of two components. The initial ‘fast’ component (time to peak of 0.3–4 s) was slightly reduced by phentolamine and was not antagonized by propranolol. The second ‘slow’ component (time to peak of about 50 s) was not blocked by phentolamine but was antagonized by low concentrations (10−7 M) of propranolol.

In immature rats, micro‐injection of isoprenaline was more potent than noradrenaline in evoking the ‘slow’ depolarization but less effective in eliciting the ‘fast’ response. The pharmacology with respect to adrenoceptor antagonists of both components of the isoprenaline‐ and noradrenaline‐induced depolarizations was similar. There was some evidence of inhibitory β‐adrenoceptors in immature rat basilar vessels.

In adult rats (6 week old) noradrenaline produced a large ‘fast’ depolarization which was followed by a ‘slow’ tail response. Both components were not antagonized by phentolamine or propranolol.

It appears that in the basilar artery of neonatal rats there are excitatory α‐ and inhibitory β‐adrenoceptors but the major responses to noradrenaline and isoprenaline are mediated by γ‐ and excitatory β‐receptors. In adult animals the γ‐adrenoceptor predominates.

Experiments were carried out in which agonists were applied by ionophoresis. These results confirm the presence of excitatory β‐receptors in neonatal basilar vessels and show the response has slow kinetics and it is likely that the β‐receptors are distributed uniformly over the smooth muscle surface. In adult animals it was not possible to elicit an excitatory β‐receptor‐mediated response.

The ionophoretic application of noradrenaline never evoked a perceptible depolarization which could be attributed to γ‐adrenoceptor stimulation. This result is discussed in terms of receptor distribution with respect to synaptic function in a syncytium.
Effects of a combination of metoprolol and dazmegrel on myocardial infarct size in rats
Authors: Bullock Gillian R. , Leprán Istvan , Parratt James R. , Szekeres Laszlo , Wainwright Cherry L.
Published: July 2012

The effects of acute pretreatment with metoprolol, dazmegrel and a combination of these two drugs has been examined on myocardial infarct size in rats. Ischaemic damage was assessed 4 h after coronary artery occlusion in anaesthetized rats and after 48 h of ischaemia in conscious rats. Infarct size was measured histochemically (by using periodic‐acid‐Schiff diastase reaction for glycogen) and by standard histological examination (haematoxylin and eosin stain).

There was some evidence of protection of the myocardium by metoprolol following 4 h of ischaemia (determined histologically) but this was not apparent 48 h after occlusion.

When given alone, dazmegrel had no significant effects on infarct size assessed by either method. A clear reduction in the extent of glycogen depletion and histological damage was observed with the combination of metoprolol and dazmegrel 48 h after the onset of ischaemia. This protection was seen to occur in the horizontal plane of the heart, preventing the extension of the infarct towards the posterior wall of the left ventricle and showing some salvage of the epicardial surfaces.
The effects of Anemonia sulcata toxin II on vertebrate skeletal muscle
Authors: Harris John B. , Pollard Sandra , Tesseraux Irene
Published: July 2012

Some effects of the sea anemone toxin, ATX‐II, on vertebrate skeletal muscle have been described.

At a concentration of 1 × 10−7 ‐ 1 × 10−6 M, ATX‐II caused a sodium‐dependent depolarizaton of the muscle fibres of the rat soleus and extensor digitorum longus, of the mouse soleus and extensor digitorum longus and of the chicken posterior latissimus dorsi. The muscle fibres of the frog sartorius were insensitive to the toxin.

Action potentials generated by direct stimulation were prolonged by ATX‐II, but the degree of prolongation was variable. Chicken posterior latissimus dorsi muscle fibres were most sensitive in this regard, and mouse extensor digitorum longus were least sensitive.

Both denervated and immature muscle fibres were more sensitive to ATX‐II than mature innervated muscle fibres. The sensitivity to ATX‐II declined rapidly as muscle fibres matured.

In some muscles, the prolongation of the action potential was enhanced by repetitive stimulation, but not by the passive depolarization or hyperpolarization of the muscle fibres.

The actions of ATX‐II could be reversed by washing in all but the innervated soleus of the mature rat.
The effect of reserpine treatment on the extraneuronal uptake of [3H]‐isoprenaline into rat atria
Authors: Morton A.J.
Published: July 2012

Treatment of rats with reserpine (1 mg kg−1 day−1) for up to 7 days resulted in a marked decrease in a corticosterone‐sensitive component of the extraneuronal accumulation of [3H]‐isoprenaline into their atria.

The change in extraneuronal uptake did not appear to be due to a direct action of reserpine on the uptake mechanism, since it was several days before the treatment had a significant effect on the accumulation of [3H]‐isoprenaline. Further, reserpine in vitro did not inhibit extraneuronal uptake.

The reserpine‐induced change in the accumulation of [3H]‐isoprenaline was not an artifact due to changes in water balance, ion distribution, extracellular space or tissue atrophy. Nor was the change due to an increase in the efflux of [3H]‐isoprenaline from the tissue.

These experiments support the suggestion that the extraneuronal uptake is dependent upon a functional adrenergic innervation.
Inflammatory oedema induced by synergism between calcitonin gene‐related peptide (CGRP) and mediators of increased vascular permeability
Authors: Brain S.D. , Williams T.J.
Published: July 2012

The potent vasodilator calcitonin gene‐related peptide (CGRP, human synthetic), when mixed with histamine and injected intradermally in the rabbit, induced a marked potentiation of local oedema.

CGRP also potentiated oedema induced by other mediators of increased microvascular permeability in the rabbit; bradykinin, platelet‐activating factor (Paf), C5a des Arg, N‐formylmethionyl‐leucyl‐phenylalanine (FMLP) and leukotriene B4 (LTB4).

Substance P alone, or mixtures of substance P and CGRP, failed to induce oedema in rabbit skin. In rat skin, however, substance P induced oedema and this was potentiated by CGRP.

CGRP had a protracted potentiating action following intradermal injection in the rabbit. The time for half loss of activity for CGRP was 40.1 ± 7.5 min compared to 18 ± 1 min for prostaglandin E2 (PGE2).

No loss of potentiating activity was detected after incubation of CGRP in rabbit plasma or blood for 60 min.

We postulate that endogenous CGRP, if released locally from nerve endings, could have a marked enhancing effect on oedema induced by other mediators in an inflammatory reaction.