bluuebunny/crossref_metadata_2025_split huggingface dataset:
Comparison of the binding of radiolabelled neurokinin A and eledoisin in rat cortex synaptic membranes
Authors: Foster Alan C. , Tridgett Robert 
Published: July 2012

The binding of the 125I‐Bolton Hunter (BH) conjugates of neurokinin A and eledoisin to synaptic plasma membranes prepared from rat cerebral cortex was investigated.
Saturation analyses indicated that both radioligands labelled a similar number of binding sites, but [125I]BH‐eledoisin had a 7 fold higher affinity than [125I]BH‐neurokinin A.
An identical pharmacological profile was apparent for both radioligands and tachykinin peptides inhibited the binding in the order: neurokinin B > BH‐eledoisin > kassinin > L‐363,851, eledoisin > substance P, neurokinin A > physalaemin > DiMeC7 > substance P methylester, indicating a profile consistent with the NK3‐subtype of tachykinin receptors.
The binding of [125I]BH‐neurokinin A and [125I]BH‐eledoisin was equally sensitive to inhibition by the guanosine triphosphate (GTP) analogue, guanyly‐5′‐β‐γ‐imido) diphosphate.
These results indicate that [125I]BH‐neurokinin A and [125I]BH‐eledoisin appear to label a common site in rat cerebral cortex synaptic plasma membranes with the characteristics of an NK3‐receptor, and thus [125I]BH‐neurokinin A is not a selective radioligand for the NK2‐receptor.
Interactions between molecules of a steroid anaesthetic (alphaxalone) and ionic channels of nodal membrane in voltage‐clamped myelinated nerve fibre
Authors: Benoit E. , Carratù M.R. , Mitolo‐Chieppa D. 
Published: July 2012

The effects of the anaesthetic alphaxalone (0.05 to 1 mm) on the node of Ranvier of isolated myelinated nerve fibres of the frog were studied under voltage‐clamp conditions.
When added to the solution bathing voltage‐clamped nodes, alphaxalone modified neither linear leakage nor capacitative currents but rapidly and reversibly blocked K and Na currents. The blocking effects of the anaesthetic on both types of current were not dependent on the frequency of stimulation of the nerve fibres between 0.7 and 10 Hz.
The kinetics of the Na current were not modified by alphaxalone but, in the presence of the drug, the K current showed an apparent fast inactivation.
Alphaxalone rapidly and reversibly shifted towards negative voltages both the steady‐state K conductance‐voltage and the peak Na steady‐state inactivation‐voltage relationships, without noticeable modification of their shape. In contrast, the anaesthetic reversibly decreased the slope of the peak Na conductance‐voltage curve.
The reduction of the K current induced by alphaxalone was voltage‐dependent with an apparent dissociation constant first decreasing from about 0.25 to 0.08 mM between −20 mV and +20 mV and then remaining constant above +20 mV. In contrast, the apparent dissociation constant for the Na current was almost constant with increasing voltages and equalled about 0.30 mM. Hill coefficient values for both K and Na currents were noticeably less than one.
It is concluded that, at higher concentrations than those attainable in the brain or in the plasma during surgical anaesthesia in man, alphaxalone has a local anaesthetic‐like' action on the peripheral nervous system in that it specifically and differentially interacts with K and Na channel gating systems: it is suggested that the anaesthetic would preferentially modify open K and inactivated Na channels.
AH6809, a prostaglandin DP‐receptor blocking drug on human platelets
Authors: Keery R.J. , Lumley P. 
Published: July 2012

The effect of AH6809 (6‐isopropoxy‐9‐oxoxanthene‐2‐carboxylic acid) has been studied upon the antiaggregatory and aggregatory actions of various agents on human platelets in whole blood.
Prostaglandin D2 (PGD2), BW245C, 9α,11β‐PGF2, PGI2 and 5′‐N‐ethylcarboxamide adenosine (NECA) all inhibited ADP‐induced platelet aggregation in whole blood. The anti‐aggregatory activity of PGD2, BW245C and 9α,11β‐PGF2 but not PGI2 or NECA was antagonized by AH6809. NECA was antagonized by AH6809.
The antagonism of the anti‐aggregatory activity of PGD2 by AH6809 was concentration‐related and could be overcome by increasing the concentration of PGD2. Analysis of the data yielded an apparent pA2 for AH6809 of 5.35.
At approximately 10 fold higher concentrations than those required to antagonize the action of PGD2, AH6809 also antagonized the aggregatory effect of U‐46619 in whole blood (pA2 = 4.45). However, concentrations of AH6809 up to 300 μm were without effect upon either ADP‐ or platelet activating factor (Paf)‐induced aggregation (pA2 < 3.5).
The potency of AH6809 against PGD2 and U‐46619 was increased in a resuspended platelet preparation suggesting that the drug is extensively bound to plasma proteins. However, in resuspended platelets the specificity of AH6809 relative to that seen in whole blood was reduced since aggregation by ADP and Paf was also slightly antagonized.
In conclusion, AH6809 appears to be a weak but specific DP‐receptor blocking drug on human platelets and should prove to be a useful drug tool for defining the involvement of endogenous PGD2 in platelet aggregation and classifying the mode of action of anti‐aggregatory prostanoids.
Muscarinic inhibition of [3H]‐noradrenaline release on rabbit iris in vitro: effects of stimulation conditions on intrinsic activity of methacholine and pilocarpine
Authors: Bognar Irene T. , Pallas Sylvia , Fuder Hermann , Muscholl Erich 
Published: July 2012

Rabbit isolated irides were loaded with [3H]‐noradrenaline and superfused with Tyrode solution. The inhibition by the muscarinic agonists (±)‐methacholine and pilocarpine of the [3H]‐noradrenaline overflow into the superfusate evoked by field stimulation (pulses of 1 ms duration, 75 mA) was measured as an index of activation of presynaptic muscarinic receptors.
The fractional rate of release per pulse during the first stimulation period (S1) was low with 360 pulses at 3 Hz, intermediate with 360 pulses at 10 Hz and high with 1200 pulses at 10 Hz. Upon repetitive stimulation (7 periods at 20 min intervals), the fractional rates of release per pulse during S7 no longer differed, suggesting a ‘long‐term’ regulation of [3H]‐noradrenaline release depending on the stimulation conditions.
The evoked [3H]‐noradrenaline overflow was depressed by (±)‐methacholine in a concentration‐dependent manner. The EC50 ranged from 0.29 to 0.42 μm. Methacholine nearly abolished the transmitter release evoked at 3 Hz but reduced that induced at 10 Hz by only 50%. Under the latter condition the methacholine concentration‐inhibition curve was bell‐shaped and no muscarinic inhibition was observed in the presence of methacholine 30 μm. After washout of methacholine the evoked [3H]‐noradrenaline release was temporarily enhanced.
Atropine 0.1 μm enhanced the [3H]‐noradrenaline overflow (evoked by stimulation with 360 or 1200 pulses at 10 Hz), probably antagonizing a presynaptic inhibition by endogenous acetylcholine. The inhibition by methacholine was competitively antagonized by atropine 0.1 μm (apparent ‐log KB = 8.5–9.0).
Depending on the concentration, pilocarpine reduced the [3H]‐noradrenaline overflow evoked by 360 pulses at 3 Hz up to 63%. However, at 10 Hz stimulation frequency the compound was inactive as an agonist but competitively antagonized the presynaptic inhibition induced by methacholine. The KB under the latter condition (0.95 μm) was very close to the EC50 value determined at 3 Hz (0.85 μm).
The results demonstrate a muscarinic inhibition of noradrenaline release from the rabbit isolated iris. The activation by pilocarpine of the presynaptic receptors provides an alternative explanation for the miosis induced in the rabbit in vivo, which might be the result of a decreased sympathetic tone in the iris dilator muscle.
Characterization of histamine receptors in isolated human cerebral arteries
Authors: Ottosson Anders , Jansen Inger , Edvinsson Lars 
Published: July 2012

The subtypes of histamine‐receptors which mediate dilatation of small human cerebral arteries have been characterized in vitro using ‘selective’ agonists and antagonists.
Dilator responses were studied after preconstriction with prostaglandin F2α, since contraction was not seen with histamine concentrations up to 10−4 m. Histamine caused a concentration‐related relaxation of cerebral vessels with an IC50 value of 5.2 ± 1.6 × 10−8 m.
Mepyramine caused a parallel shift to the right of the histamine concentration‐response curve whereas cimetidine was without observable effect. This suggests the presence of histamine H1‐receptors only. However, combined treatment with mepyramine and cimetidine caused a more marked displacement of the concentration‐response curve to the right. Schild analysis indicated that in situations of near complete blockade of either of the histamine receptor subtypes, simple competitive antagonism both at H1‐ and H2‐receptors can be revealed with a pA2 value of 8.64 for mepyramine and a pA2 value of 6.52 for cimetidine.
The ‘selective’ H1‐receptor agonists pyridylethylamine, 2‐methylhistamine (2‐Me‐histamine) and thiazolylethylamine, and the H2‐receptor agonists dimaprit, impromidine and 4‐methylhistamine (4‐Me‐histamine) all mimicked the histamine response, but were less potent than histamine. The order of potency was thiazolylethylamine > dimaprit > impromidine > 2‐Me‐histamine > pyridylethylamine > 4‐Me‐histamine.
These results indicate that the histamine‐induced dilatation in small human cerebral arteries is mediated by both H1‐ and H2‐receptors and that the former subtype of histamine receptor predominates.
The effect of ozone on reactivity of upper and lower airways in guinea‐pigs
Authors: Holroyde Martin C. , Norris Alan A. 
Published: July 2012

The effect of ozone inhalation on the responsiveness of upper and lower airways to histamine was examined in guinea‐pigs.
The exposure of conscious guinea‐pigs to 3.5 p.p.m. ozone for 30 min rendered their lower airways 2–3 fold more sensitive to the bronchoconstrictor action of i.v. histamine, as assessed subsequently under anaesthesia.
The development of lower airway hyperreactivity was not modified by bilateral cervical vagotomy or pretreatment with BW 755C, FPL 55712 or SC‐39070.
Under the conditions used, ozone exposure produced a mild inflammatory response as monitored by bronchoalveolar lavage, characterized by epithelial damage and prostaglandin E2 generation, but no cellular infiltration or oedema.
In contrast to the lower airways, upper airway resistance was reduced by i.v. histamine. This response was not affected by ozone exposure.
Isolated tracheal preparations taken from ozone‐exposed guinea‐pigs were not significantly more sensitive to histamine than control tissues.
The mechanism of hyperreactivity in this model is unknown but does not depend on leukotriene generation or a vagal reflex.
Neuropeptide Y and reserpine‐resistant vasoconstriction evoked by sympathetic nerve stimulation in the dog skeletal muscle
Authors: Pernow John , Kahan Thomas , Lundberg Jan M. 
Published: July 2012

The effects of sympathetic nerve stimulation (evoked by recordings of authentic irregular vasoconstrictor nerve fibre discharge with average frequencies of 0.59, 2.0 and 6.9 Hz) on the perfusion pressure and the overflow of noradrenaline (NA) and neuropeptide Y‐like immunoreactivity (NPY‐LI) were investigated in the blood‐perfused gracilis muscle of the dog in situ.
Nerve stimulation in the untreated control group evoked a frequency‐dependent increase in perfusion pressure and overflow of NA. A significant overflow of NPY‐LI was found at the highest frequency only.
In a separate group of animals, the sympathetic supply was unilaterally interrupted by preganglionic decentralization before the administration of reserpine (1 mg kg−1 i.v.) 24 h before the experiment. Reserpine reduced the NA content of the intact and decentralized gracilis and gastrocnemius muscle by 98–99%. Reserpine also induced a marked (80%) reduction of the muscular content of NPY‐LI. The depletion of NPY‐LI was, in contrast to that of NA, prevented by the decentralization, suggesting that nerve impulse activity was of primary importance for the reserpine‐induced depletion of NPY‐LI.
A slowly developing and long‐lasting perfusion pressure increase was evoked by nerve stimulation, at 2.0 and 6.9 Hz after reserpine treatment. These responses were larger in the decentralized, as compared to the intact gracilis muscle and correlated with the nerve stimulation evoked overflow of NPY‐LI (r = 0.79, P < 0.001). Stimulation at 0.59 Hz caused vasoconstriction in the decentralized but not in the intact gracilis.
Administration of α,β‐methylene adenosine triphosphate did not evoke an increase in perfusion pressure in the gracilis muscle of reserpine‐treated animals.
In conclusion, a large perfusion pressure increase to sympathetic nerve stimulation occurs in the reserpine‐pretreated skeletal muscle vasculature of the dog in vivo, providing that preganglionic decentralization has been performed. It is suggested that the released NPY‐LI may mediate this vasoconstrictor response.
Behavioural responses to the selective D1‐dopamine receptor agonist R‐SK&F 38393 and the selective D2‐agonist RU 24213 in young compared with aged rats
Authors: Molloy Anthony G. , Waddington John L. 
Published: July 2012

In aged male Sprague‐Dawley rats (22 months) with a selective loss of D2‐ but not of D1‐dopamine receptors, stereotyped behaviour induced by 0.5 mg kg−1 apomorphine was increased and prolonged in comparison with young (4 month) counterparts. This suggested a pharmacokinetic effect rather than a pharmacodynamic change.
The syndrome of non‐stereotyped behavioural responses to the selective D1‐agonist R‐SK&F 38393, 1.25–20.0 mg kg−1, was unchanged in aged vs young animals, but the topography of individual behaviours constituting this overall syndrome was altered with aging.
Neither the overall syndrome of low intensity stereotyped behaviour nor the topography of individual behaviours induced by the selective D2‐agonist RU 24213, 1.25–20.0 mg kg−1, were altered in aged vs young animals.
Loss of D2‐ but not D1‐receptors with aging was therefore found to be associated with no change in responsivity to a D2‐receptor agonist. The decreased intense grooming and increased vacuous chewing responses to the D1‐agonist with aging parallel the previously demonstrated effects of selective D2‐antagonists on these D1‐stimulated behaviours.
It is suggested that age‐related decline in D2‐receptor activity may have greater functional consequences in relation to D1‐:D2‐interactions than in simply influencing responsivity to a D2‐agonist. Such interactive effects should be taken into account when considering the pathophysiology and treatment of age‐related extrapyramidal movement disorders.
Adenosine receptor‐mediated contraction and relaxation of guinea‐pig isolated tracheal smooth muscle: effects of adenosine antagonists
Authors: Farmer Stephen G. , Canning Brendan J. , Wilkins Deidre E. 
Published: July 2012

The effects of several adenosine analogues and antagonists on guinea‐pig isolated trachea have been examined.
5′‐N‐ethylcarboxamidoadenosine (NECA), 5′‐N‐methylcarboxamidoadenosine (MECA) and adenosine (in the presence and absence of dipyridamole) elicited concentration‐dependent tracheal relaxation.
The R(−)− and S(+)‐enantiomers of N6‐(2‐phenylisopropyl)adenosine (R‐PIA and S‐PIA respectively), N6‐cyclohexyladenosine (CHA) and 2‐chloroadenosine (CADO) caused contractions at low concentrations (0.05–2.0 μm), whereas at higher concentrations, relaxation resulted.
For tracheal relaxation, the adenosine analogues exhibited the following rank order of potency: NECA > CADO > R‐PIA = MECA > S‐PIA > adenosine. The rank order of potency for inducing contractions was R‐PIA > CHA > CADO > S‐PIA. These data suggest that relaxation is mediated by adenosine A2‐receptors, whereas contraction is the result of activation of A1‐receptors.
8‐Phenyltheophylline (8‐PT), aminophylline, the triazoloquinazoline CGS 15943A and NPC205 (1,3‐di‐n‐propyl‐8‐(4‐hydroxyphenyl)xanthine) each inhibited the R‐PIA‐induced contractile response, whereas enprofylline was without effect. NPC205, aminophylline and 8‐PT were competitive antagonists, but CGS15943A was non‐competitive.
That the most potent antagonist was the A1‐selective agent, NPC205 (pA2 = 7.80), further suggests that the contraction is mediated by A1‐receptors. Moreover, NPC205 was 13 times more potent as an antagonist of R‐PIA‐induced contractions (A1) than of NECA‐induced relaxations (A2).
The antagonists were also found to relax the trachea by an unknown mechanism. That enprofylline did not antagonize the R‐PIA‐induced contractions, but was 3–4 times more potent a tracheal relaxant than aminophylline, further suggests that a direct effect on airway smooth muscle, rather than antagonism of endogenous adenosine, is more relevant to the bronchodilator effect of alkylxanthines in the treatment of asthma.
Potentiation by neuropeptide Y of vasoconstriction in rat resistance arteries
Authors: Andriantsitohaina Ramaroson , Stoclet Jean Claude 
Published: July 2012

The effects of neuropeptide Y (NPY) on resistance arteries were investigated on 3rd generation mesenteric arterioles of the rat.
Contractions were elicited by noradrenaline (NA), 5‐hydroxytryptamine (5‐HT), prostaglandin F2α (PGF2α), depolarization (KCl substituted for NaCl) and by the calcium agonist Bay K 8644, in the absence and in the presence of NPY (100 nm), a concentration which by itself did not induce vasoconstriction.
NPY produced a leftward shift of the concentration‐response curves to the agonists and to KCl, without any alteration of maximal contractions.
NPY also potentiated contractions elicited by addition of CaCl2 to KCl‐depolarized vessels, but its effect on calcium‐induced contractions decreased with increasing KCl concentrations (from 20 to 100 mm).
Calcium‐induced contractions were inhibited by the calcium channel blocker nitrendipine, both in the presence and absence of NPY (100 nm). NPY increased slightly (but significantly) the sensitivity to nitrendipine (the apparent KB increased from 2.9 × 10−10 m to 1.6 × 10−10 m).
The KCl concentration necessary for the maximal effect of Bay K 8644 was decreased in the presence of NPY, and the sensitivity to the calcium channel agonist was increased.
Elevating the KCl concentration in the bath from 5 to 20 mm (which gives the same displacement to the left of the KCl concentration‐effect curve seen in the presence of NPY) induced a parallel leftward shift of NA and 5‐HT concentration‐response curves. This shift was identical to the one induced by NPY on 5‐HT‐evoked contractions, but it was significantly smaller (P < 0.001) than the shift of the NA concentration‐response curve observed in the presence of NPY. In the latter case, NPY enhanced more markedly the contractions induced by low NA concentrations (between 10−9 and 3 × 10−8 m) than those induced by high concentrations (up to 3 × 10−7 m), thus giving a shallow concentration‐response curve.
The results strongly suggest that NPY partially depolarizes the arterioles and induces an increase in calcium entry through voltage‐dependent channels, thus enhancing contractions elicited by agonists or by KCl‐depolarization. In addition, they support the view that another mechanism also plays a part in the potentiation by NPY of the effects of low concentrations of NA.
Mechanism of action of nicotine in isolated urinary bladder of guinea‐pig
Authors: Hisayama Tetsuhiro , Shinkai Michiko , Takayanagi Issei , Toyoda Toshie 
Published: July 2012

Nicotine produced a transient contraction of isolated strips of guinea‐pig urinary bladder. The response to nicotine was antagonized by the nicotinic receptor antagonist, hexamethonium but was insensitive to tetrodotoxin.
The nicotine‐induced contraction was potentiated by the cholinesterase inhibitor, physostigmine, and was reduced to 50% and 70% by the muscarinic cholinoceptor antagonist, atropine and the sympathetic neurone blocking drug, guanethidine, respectively. Chemical denervation with 6‐hydroxydopamine abolished the inhibitory effect of guanethidine. Simultaneous treatment with atropine and guanethidine did not abolish the response to nicotine, but the degree of inhibition was comparable to that obtained with atropine alone.
The nicotine‐induced contraction was insensitive to bunazosin and yohimbine (α1‐ and α2‐adrenoceptor antagonists, respectively), and exogenously applied noradrenaline did not cause a contraction even in the presence of blockade of noradrenaline uptake mechanisms with desipramine and normetanephrine and of β‐adrenoceptors with propranolol, suggesting a non‐adrenergic nature of the sympathomimetic effect of nicotine in this tissue.
The nicotine‐induced contraction in the presence of atropine was abolished after desensitization of P2‐purinoceptors with α, β‐methylene adenosine 5′‐triphosphate, a slowly degradable ATP analogue selective for P2‐purinoceptors. By this desensitization, the response to ATP, but not to histamine, was also abolished.
A cyclo‐oxygenase inhibitor flurbiprofen partially inhibited the nicotine‐induced contraction. The degree of the inhibition was more pronounced in the presence of atropine than in its absence. Flurbiprofen antagonized the response to exogenously applied ATP in an unsurmountable manner, but not that to carbachol.
The present results suggest that nicotine might induce a contraction through an interaction with nicotinic receptors located on the terminals of, possibly, (i) parasympathetic cholinergic, (ii) sympathetic non‐adrenergic and (iii) non‐sympathetic purinergic nerves in guinea‐pig detrusor preparations, and that a portion of the contraction due to the purine nucleotide released is possibly potentiated by intramural prostaglandin(s). Parasympathetic cholinergic output might be modulated by an unknown excitatory substance released by nicotine from sympathetic nerve.
Nicotine reveals a latent excitatory effect of the sympathetic hypogastric nerve which innervates guinea‐pig detrusor.