bluuebunny/crossref_metadata_2025_split huggingface dataset:
Neuropeptide Y inhibits potassium‐stimulated glutamate release through Y2 receptors in rat hippocampal slices in vitro
Authors: Greber Susanne , Schwarzer Christoph , Sperk Günther 
Published: July 2012

We investigated the effects of neuropeptide Y (NPY), peptide YY (PYY), NPY13–36, NPY18–36, [Leu31][Pro34]NPY and of pancreatic polypeptide Y (PPY) on calcium‐dependent, potassium‐stimulated glutamate release in superfused rat hippocampal slices.
NPY, PYY and the Y2 receptor agonist NPY13–36 equipotently inhibited the release of glutamate. The half‐maximal response was observed at about 10 nm in a dose‐dependent manner (3 to 100 nm). Maximal inhibition of 50 to 60% was obtained at 100 nm. At higher concentrations of the peptides (300 nm and 1 μm) this inhibition was partially or entirely reversed. Porcine NPY13–36 and NPY18–36, inhibited glutamate release by about 44% at 100 nm.
The specific Y1 receptor agonist, [Leu31][Pro34]NPY, caused an insignificant increase in glutamate release at 100 to 300 nm concentrations. PPY had no effect on potassium‐evoked glutamate release in hippocampal slices at concentrations of 30 nm to 1 μm.
The experiments support previous electrophysiological data. They suggest a potent inhibitory action of NPY through NPY‐Y2 receptors on the release of the excitatory amino acid glutamate in rat hippocampus. Especially under conditions of increased NPY synthesis, such as in epilepsy, this mechanism may be of pathophysiological relevance.
Facilitation by procaterol, a β‐adrenoceptor agonist, of noradrenaline release in the pithed rat independently of angiotensin II formation
Authors: Kotsonis P. , Majewski H. 
Published: July 2012

The effects of the β2‐adrenoceptor agonist, procaterol, on sympathetic neuroeffector transmission were studied in the pithed adrenal demedullated rat to determine if generation of angiotensin II was involved in its effect. Pressor responses were elicited by either electrical stimulation (20 V, 2 Hz) of the entire spinal sympathetic outflow or methoxamine (0.1 mg kg−1, i.v.).
Sodium nitroprusside (3 and 5 μg−1 min−1, i.v.) produced hypotension and the pressor responses to both sympathetic nerve stimulation and methoxamine were reduced. This indicates that decreasing blood pressure in pithed rats reduces pressor responses. Procaterol (10 and 30ng kg−1 min−1, i.v.) also produced hypotension but did not alter pressor responses to sympathetic nerve stimulation. Nevertheless, procaterol (10 and 30 ng kg−1 min−1, i.v.) did reduce pressor responses to methoxamine. Together these results suggest that procaterol may have enhanced sympathetic neurotransmitter release. This was confirmed in another series of experiments where procaterol (30ngkg−1 min−1, i.v.) increased plasma noradrenaline levels during sympathetic nerve stimulation.
Captopril (5 mg kg−1, i.v.) produced hypotension and as expected reduced pressor responses to sympathetic nerve stimulation. When the hypotensive effect of captopril was abolished by concomitant vasopressin infusion (1.5‐4.5 i mu kg−1 min−1, i.v.), pressor responses to sympathetic nerve stimulation were restored to pre‐captopril levels. In this situation procaterol (10 and 30 ng kg−1 min−1, i.v.) reduced basal blood pressure and did not alter pressor responses to sympathetic nerve stimulation whereas the pressor responses were reduced by an equihypotensive infusion of sodium nitroprusside (3 and 5 μg kg−1 min−1, i.v.). The lack of reduction of pressor responses after procaterol in the presence of captopril is indirect evidence that procaterol may have enhanced noradrenaline release independently of angiotensin II.
In another series of experiments, plasma noradrenaline levels elicited by sympathetic nerve stimulation were not altered by captopril (5 mg kg−1, i.v.). In the presence of captopril (5 mg kg−1, i.v.), procaterol (30 ng kg−1 min−1, i.v.) no longer enhanced plasma noradrenaline levels during sympathetic nerve stimulation. However, since the dose of captopril is well above that required to block angiotensin converting enzyme (ACE) the effect may be non‐specific. Therefore, the selective AT1 receptor antagonist, losartan (10 mg kg−1, i.v.), was also used. Losartan (10 mg kg−1, i.v.) did not alter plasma noradrenaline levels during sympathetic nerve stimulation, and in the presence of losartan procaterol (30 ng kg−1 min−1, i.v.) enhanced plasma noradrenaline levels during sympathetic nerve stimulation. This result further suggests that β‐adrenoceptor facilitation of noradrenaline release from sympathetic nerves in the pithed rat occurs by a mechanism independent of angiotensin II generation.
Y2‐receptor‐mediated selective inhibition of slow, inhibitory postsynaptic potential in submucous neurones of guinea‐pig caecum
Authors: Cunningham Shauna M.C. , Mihara Satoshi , Lees Gordon M. 
Published: July 2012

The subtype of neuropeptide Y receptor mediating the selective inhibition of the slow inhibitory postsynaptic potential (i.p.s.p.) of submucous neurones in guinea‐pig caecum was investigated by use of conventional intracellular electrophysiological recording techniques.
Neuropeptide Y (NPY) (1‐300nM) was found to depress or abolish reversibly the slow i.p.s.p. evoked by focal stimulation of internodal fibre tracts. At low concentrations (1‐30nM), a reduction in the duration of the slow i.p.s.p. was often apparent before any inhibition of the amplitude of this synaptic potential.
These inhibitory effects of NPY were mimicked by peptide YY (PYY; 0.3–100 nm), NPY13‐36 (1–300 nm) and NPY22‐36 (10‐100nM); [Leu31, Pro34]NPY ([Pro34]NPY) and bovine pancreatic polypeptide (bPP) were without pre‐ or postsynaptic effects at concentrations of up to 300 nm. The IC50 s.e. mean values for PYY, NPY, and NPY13‐36 were 2.7 ± 0.3, 7.8 ± 2.1 and 30 ± 4.8nM, respectively, and were significantly different from each other. Thus, the apparent rank order of potency was PYY>NPY>NPY13‐36>[Pro34]NPY and bPP.
In concentrations of up to 300 nm, NPY and its analogues had no depressant effects on the active and passive properties of the impaled neurone and did not affect the amplitude or duration of either cholinergic fast synaptic potentials or non‐cholinergic, slow excitatory postsynaptic potentials (e.p.s.ps). Furthermore, none of these peptides altered the amplitude or time‐course of changes in membrane potential induced by focal application of acetylcholine or noradrenaline.
It is, therefore, concluded that the selective inhibition of the slow i.p.s.p. is mediated by Y2‐receptors, located presynaptically on noradrenergic nerve terminals.
Effects of RP 67580, a tachykinin NK1 receptor antagonist, on a primary afferent‐evoked response of ventral roots in the neonatal rat spinal cord
Authors: Hosoki Rumiko , Yanagisawa Mitsuhiko , Guo Jian‐Zhong , Yoshioka Koichi , Maehara Taketoshi , Otsuka Masanori 
Published: July 2012

The pharmacological characteristics of RP 67580, a non‐peptide tachykinin NK1 receptor antagonist, and its effects on a reflex response evoked by stimulation of primary afferent fibres, were examined in isolated neonatal spinal cord preparations of the rat. Potentials were recorded extracellularly from a lumbar ventral root and drugs were bath‐applied in normal artificial cerebrospinal fluid (CSF) or in the presence of tetrodotoxin (TTX).
In normal artificial CSF, RP 67580 (0.1‐0.3 μm) caused rightward shifts of the concentration‐response curves for substance P (SP), neurokinin A (NKA) and substance P methyl ester (SPOMe), an NK1selective agonist, with pA2 values of 7.25, 7.47 and 7.49, respectively.
In the presence of TTX (0.3 μm), RP 67580 also caused rightward shifts of the concentration‐response curves for SPOMe and NKA. The pA2 value of RP 67580 against SPOMe (6.75) was significantly lower than that against NKA (7.22). RP 67580 (0.3‐1 μm) did not cause a clear parallel shift of the concentration‐reponse curves for SP, and it depressed the depolarizations induced by low concentrations of SP, but slightly potentiated those induced by high concentrations of SP.
RP 67580 (1 μm) did not depress the depolarizing responses to bombesin, 1–glutamate, γ‐aminobutyric acid (GABA), thyrotropin‐releasing hormone and muscarine. RP 67580 (1 μm), however, depressed the response to acetylcholine in the presence of atropine and the response to nicotine. RP 68651 (1 μm), the enantiomer of RP 67580 devoid of activity at tachykinin NK1 receptors, also depressed the response to acetylcholine in the presence of atropine.
RP 67580 (1 μm) did not induce GABA release from the rat spinal cord.
In the neonatal gerbil spinal cord, the antagonist effects of RP 67580 (0.3‐1 μm) against SPOMe were much less potent than in the neonatal rat spinal cord.
In the rat spinal cord‐saphenous nerve preparation, electrical stimulation of the saphenous nerve at C‐fibre strength evoked a prolonged depolarization of the ipsilateral L3 ventral root (slow VRP). RP 67580 (0.1‐1 μm) depressed the saphenous nerve‐evoked slow VRP. In contrast, RP 68651 (0.3 μm) had no effect on the slow VRP.
The results of the present study indicate that RP 67580 acts as a high affinity NK1 receptor antagonist in the neonatal rat spinal cord, although it also possesses an antinicotinic action. This study further suggests the existence of a subpopulation of tachykinin NK1 receptors that are activated by NKA and SPOMe, as well as by low concentrations of SP, and are sensitive to the antagonist action of RP 67580 in the neonatal rat spinal cord. This study also provides further evidence for the involvement of SP and NKA in the slow VRP evoked by C‐fibre stimulation in the neonatal rat spinal cord.
The effects of administration of monoamine oxidase‐B inhibitors on rat striatal neurone responses to dopamine
Authors: Berry M.D. , Scarr E. , Zhu M.‐Y. , Paterson I.A. , Juorio A.V. 
Published: July 2012

(−)−Deprenyl has been shown to potentiate rat striatal neurone responses to dopamine agonists at doses not altering dopamine metabolism. Since there are a number of effects of (−)−deprenyl which could result in this phenomenon, we have investigated the effects of MDL 72,145 and Ro 19–6327, whose only common effect with (−)−deprenyl is an inhibition of monoamine oxidase‐B (MAO‐B), on rat striatal neurone responses to dopamine and on striatal dopamine metabolism.
Using in vivo electrophysiology, i.p. injection of either MDL 72,145 or Ro 19–6327 was found to produce a dose‐dependent potentiation of striatal neurone responses to dopamine but not γ aminobutyric acid.
Neurochemical investigations revealed that this occurred at doses (0.25‐1 mg kg−1) which, while not affecting levels of dopamine or its metabolites, 3,4‐dihydroxyphenylacetic acid or homo vanillic acid, did cause a significant, dose‐dependent, elevation in striatal levels of the putative neuromodulator, 2‐phenylethylamine (PE).
Inhibition of PE synthesis by i.p. injection of the aromatic 1‐amino acid decarboxylase inhibitor, NSD 1015, produced a reversal of the effects of MDL 72,145 and Ro 19–6327.
Neurochemical analysis revealed this to occur at a dose of NSD 1015 (10 mg kg−1) selective for reduction of elevated PE levels.
These results suggest that PE can act as a neuromodulator of dopaminergic responses and that MAO‐B inhibitors may potentiate neuronal responses to dopamine via the indirect mechanism of elevation of PE following MAO‐B inhibition.
Antithrombotic actions of argatroban in rat models of venous, ‘mixed’ and arterial thrombosis, and its effects on the tail transection bleeding time
Authors: Berry Christopher N. , Girard Denise , Lochot Sylvette , Lecoffre Catherine 
Published: July 2012

The antithrombotic action of argatroban, a synthetic thrombin inhibitor, was studied in three models of thrombosis in the rat, and in the tail transection bleeding time test. Heparin was studied as a reference anticoagulant.
In the model of venous thrombosis induced by thromboplastin followed by stasis of the abdominal vena cava, argatroban had an ED50 of 125 μg kg−1, when administered as an i.v. bolus 5 min prior to the thromboplastin injection: the ED50 of heparin was 42 μg kg−1, where ED50 is the dose which reduces the weight of the thrombus by 50% compared with that of the control animals. When the two compounds were administered by continuous i.v. infusion, argatroban (ED50= 1.5 μg kg1 min−1) had the same potency as heparin (ED50= 1.2 μg kg1 min1).
Argatroban was active in the arterio‐venous shunt model with an ED50 of 0.6mg kg−1 when the compound was given as a bolus. The ED50 of herapin was 0.04 mg kg−1 under the same conditions. The two compounds had ED50 values of 6 μg kg1 min−1(argatroban) and 3 μg kg1 min−1(heparin), when administered by continuous i.v. infusion.
When tested against occlusive arterial thrombus formation by electrical stimulation of the left carotid artery, both compounds given as either an i.v. bolus or a continuous infusion led to dose‐dependent increases in the duration of post‐lesion vessel patency. Heparin bolus was more active than argatroban on a weight basis, in that 2mg kg−1 gave a similar increase in the time to occlusion as 8mg kg−1argatroban. As in the other models, when given as continuous infusions, argatroban (111% increase in time to occlusion at 20 μg kg−1, min−1) had similar activity to that of heparin (180% increase at 25 μg kg−1 min−1) on a weight basis. Hoever, the antithrombotic effects of argatroban were accompanied by only moderate changes in the coagulation parameters (thrombin time and activated partial thromboplastin time, APTT), whereas, even at a subthreshold dose of heparin (12.5 μg kg−1 min−1), both the thrombin time and the APTT were greater than 150 s.
Infusions of both compounds caused dose‐dependent increases in the tail transection bleeding time, with the dose of argatroban that doubles the bleeding time (11 μg kg−1 min−1) being five times greater than that of heparin (ED100= 2.2 μg kg−1 min−1).
These data show that, when administered as an intravenous infusion, argatroban is a potent antithrombotic agent in rat models of venous ‘mixed’ and arterial thrombosis, this effect can be obtained with a lower degree of systemic anticoagulation than with heparin in the arterial model, and argatroban has a lower haemorrhagic potential than that of heparin.
The binding of 1,3‐[3H]‐dipropyl‐8‐cyclopentylxanthine to adenosine Ai receptors in rat smooth muscle preparations
Authors: Peachey J.A. , Hourani S.M.O. , Kitchen I. 
Published: July 2012

The binding of 1,3‐[3H]‐dipropyl‐8‐cyclopentylxanthine ([3H]‐DPCPX), an antagonist radioligand selective for adenosine A1 receptors, was studied in rat duodenum, colon muscularis mucosae and longitudinal muscle, urinary bladder and vasa deferentia.
[3H]‐DPCPX bound with high affinity to a single site in all membrane preparations studied with the exception of the rat urinary bladder in which no specific binding was detected. The affinity (Kd) of the binding site for [3H]‐DPCPX was similar in all membrane preparations, the colon longitudinal muscle (1.18 ± 0.47 nm), colon muscularis mucosae (0.84 ± 0.15 nm), duodenum (1.59 ± 0.18 nm) and vasa deferentia (0.93 ± 0.17 nm). The density of [3H]‐DPCPX binding sites was similar in the duodenum (38.8 ± 4fmol mg−1 protein), muscularis mucosae (43 ± 3.5 fmol mg−1 protein) and vasa deferentia (43.3 ± 12.2 fmol mg−1 protein), but in the longitudinal muscle 6–7 fold more binding sites (295 ± 70 fmol mg−1 protein) were identified.
Inhibition studies using DPCPX (0.1–100 nm), N6‐cyclopentyladenosine (CPA) (0.1–100 nm), 5′‐N‐ethylcarboxamidoadenosine (NECA) (2nM‐10 μm) and (R)‐N6‐phenylisopropyladenosine (R‐PIA) (1 nm‐1 μm) to displace the binding of [3H]‐DPCPX at a concentration around the Kd value (1 nm), demonstrated an order of potency of displacement in all tissues of DPCPX ≥ CPA > R‐ PIA > NECA. This potency order is characteristic of an A1 receptor, indicating that [3H]‐DPCPX binds to adenosine A1 receptors in the rat duodenum, colon and vasa deferentia. Two site analysis revealed that the agonists bind to both a high and low affinity state of the receptor.
The existence of A1 binding sites in the rat vasa deferentia, colon muscularis mucosae and duodenum, and their absence in the urinary bladder, is consistent with previous functional studies. However, in contrast to the findings of the [3H]‐DPCPX binding assay, no functional response mediated by adenosine A1 receptors could be detected by measuring contractile or relaxant responses to CPA in the colon longitudinal muscle. The functional significance of the binding sites in this tissue has therefore yet to be determined.
Effect of type A and B monoamine oxidase selective inhibition by Ro 41–1049 and Ro 19–6327 on dopamine outflow in rat kidney slices
Authors: Pestana M. , Soares‐da‐Silva P. 
Published: July 2012

The influence of pargyline and of selective inhibitors of type A and B monoamine oxidase (MAO), Ro 41–1049 and Ro 19–6327 respectively, on the outflow of dopamine and 3,4‐dihydroxyphenylacetic acid (DOPAC) in slices of rat renal cortex loaded with exogenous L‐3,4‐dihydroxyphenylalanine (L‐DOPA) was examined. Dopamine and DOPAC in the tissues and in the effluent were assayed by means of h.p.l.c. with electrochemical detection.
The levels of newly‐formed dopamine and DOPAC in the perifusate decreased progressively with time. In control conditions, DOPAC/dopamine ratios in the perifusate were 3 to 5 fold those in the tissue and were found to increase progressively with time. The addition of pargyline (100 μm), produced a marked decrease in the outflow levels of DOPAC (45 to 54% reduction) and significantly increased the levels of dopamine in the effluent (102 to 158% increase); DOPAC/dopamine ratios in the perifusate remained stable throughout the perifusion and were similar to those found in the tissues. The addition of the MAO‐A inhibitor Ro 41–1049 to the perifusion fluid also significantly decreased DOPAC outflow (41% to 54% reduction) and increased dopamine outflow (19% to 80% increase). In the presence of Ro 41–1049 DOPAC/dopamine ratios in the perifusate were lower (P < 0.01) than in controls; in contrast with the effect of pargyline, this ratio was found to increase (P < 0.01) throughout the perifusion period. Ro 19–6327 did not reduce the outflow of DOPAC, but significantly increased (by 40–60%) that of dopamine. In the presence of Ro 19–6237, the proportion of DOPAC to dopamine in the perifusate was similar to that of controls and significantly increased throughout the perifusion; however, this increase was less than that observed in the control group.
When benserazide (50 μm) was added to the perifusion fluid, the levels of both dopamine and DOPAC in the effluent were similar to those observed in the absence of benserazide. However, in the presence of benserazide, DOPAC/dopamine ratios in the perifusate did not increase with time. In conditions of decarboxylase inhibition, the effects of pargyline, Ro 41–1049 and Ro 19–6327 on dopamine and DOPAC outflow were less pronounced than in experiments conducted in the absence of benserazide.
In conclusion, the results presented here show that the fraction of newly‐formed dopamine which leaves the compartment where the synthesis has occurred is a constant source for deamination into DOPAC. The results provide evidence favouring the view that MAO‐A is the main form of the enzyme involved in this process; however, the data described here suggest that dopamine would also have access to MAO‐B.
Peripheral and central sites of action of GABA‐B agonists to inhibit the cough reflex in the cat and guinea pig
Authors: Bolser Donald C. , DeGennaro Frances C. , O'Reilly Sandra , Chapman Richard W. , Kreutner William , Egan Robert W. , Hey John A. 
Published: July 2012

The GABA‐B receptor agonists baclofen and 3‐aminopropylphosphinic acid (3‐APPi) have antitussive activity in the cat and guinea pig. The purpose of this study was to investigate the sites of action of these GABA‐B receptor agonists to inhibit the cough reflex.
Single intracerebroventricular (i.e.v.) cannulas were placed in the lateral ventricles of anaesthetized guinea pigs. Approximately 1 week later, the animals were exposed to aerosols of capsaicin (0.3 μm) to elicit coughing. Coughs were detected with a microphone and counted.
Cough was produced in anaesthetized cats by mechanical stimulation of the intrathoracic trachea and was recorded from electromyograms of respiratory muscle activity. Cannulas were placed for intravenous (i.v.) or, in separate groups of animals, intravertebral arterial (i.a.) administration of baclofen, 3‐APPi, the centrally active antitussive drug codeine or the peripherally active antitussive drug BW443c. Dose‐response relationships for i.v. and i.a. administration of each drug were generated to determine a ratio of i.v. ED50 to i.a. ED50, known as the effective dose ratio (EDR). The EDR will be 20 or greater for a centrally acting drug.
In the guinea pig, baclofen (3 mg kg−1, s.c.) and 3‐APPi (10 mg kg−1, s.c.) inhibited capsaicin‐induced cough by 50% and 35% respectively. The antitussive activity of baclofen was completely blocked by i.e.v. administration of the GABA‐B receptor antagonist CGP 35348 (10 μg). Conversely, the antitussive effect of 3‐APPi was unaffected by i.e.v. CGP 35348. However, systemic administration of CGP 35348 (30 mg kg−1, s.c.) completely blocked the antitussive activity of 3‐APPi (10 mg kg−1, s.c). In separate experiments baclofen alone (1 μg, i.c.v.) inhibited capsaicin‐induced cough by 78%. 3‐APPi (10 and 100 μg, i.c.v.) had no effect on capsaicin‐induced cough in the guinea pig.
In the cat, potencies (ED50) of the standards and GABA‐B agonists by the i.v. route were: codeine (0.34 mg kg−1), BW443C (0.17 mg kg−1), baclofen (0.63 mg kg−1) and 3‐APPi (2.3 mg kg−1). Potencies of these drugs by the i.a. route were: codeine, 0.013 mg kg−1; BW443C, 0.06 mg kg−1; baclofen, 0.016 mg kg−1; and 3‐APPi, 0.87 mg kg−1. The EDRs for each drug were: codeine, 26; BW443C, 3; baclofen, 39; and 3‐APPi, 3.
We conclude that in both the cat and guinea pig baclofen inhibits cough by a central site of action, while 3‐APPi inhibits cough by a peripheral site of action.
Modulation of morphine antinociception in the mouse by endogenous nitric oxide
Authors: Brignola Giovanni , Calignano Antonio , Di Rosa Massimo 
Published: July 2012

L‐Arginine (100–1000 mg kg−1) administered orally (p.o.) or intraperitoneally (i.p.), but not intracerebroventricularly (i.c.v., 0.08 mg per mouse), reduced the antinociceptive effect of morphine (0.5–10 mg kg−1 s.c.) assessed in mice using three different tests: hot plate, tail‐flick and acetic acid‐induced writhing. D‐Arginine (up to 1000 mg kg−1 p.o. or i.p.) was ineffective.
NG‐Monomethyl‐L‐arginine (L‐NMMA, 5–50 mg kg−1 i.p.) and NG‐nitro‐L‐arginine methyl ester (L‐NAME, 5‐ 30 mg kg−1 i.p.), but not NG‐nitro‐D‐arginine methyl ester (D‐NAME, 30 mg kg−1 i.p.), reversed in all assays the effect of L‐arginine on morphine‐induced antinociception.
Morphine (10 mg kg−1 s.c), L‐arginine (1000 mg kg−1 p.o.) or L‐NAME (30 mg kg−1 i.p.), either alone or in combination, did not produce changes in locomotor activity or sensorimotor performance of animals.
These results suggest that the L‐arginine‐nitric oxide pathway plays a modulating role in the morphine‐sensitive nociceptive processes.