bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effect of 6‐cyano‐2,3‐dihydroxy‐7‐nitro‐quinoxaline (CNQX) on dorsal root‐, NMDA‐, kainate‐ and quisqualate‐mediated depolarization of rat motoneurones in vitro
Authors: Long S.K. , Smith D.A.S. , Siarey R.J. , Evans R.H. 
Published: July 2012

Mature in vitro rat spinal cord preparations have been used to compare the depressant effects of 6‐cyano‐2,3‐dihydroxy‐7‐nitroquinoxalinedione (CNQX) and kynurenate on transmission from low threshold myelinated primary afferents in dorsal roots. EC50 values ± s.e.mean (number of preparations in parentheses) for depression of the monosynaptic ventral root reflex were respectively 1.0 ± 0.3 μm (5) and 135 ± 15μm (3) for CNQX and kynurenate. Transmission through superior cervical ganglia was not significantly affected by concentrations of CNQX up to 100 μm or kynurenate up to 5 mm.
Immature in vitro rat spinal cord preparations were used to measure dose‐ratios for antagonism of depolarizations induced by N‐methyl‐d‐aspartate (NMDA), kainate or quisqualate by 4, 10 and 25 μm CNQX. In the presence of 0.75 mm Mg2+ pA2 values + s.e.mean were respectively 4.62 ± 0.05 (16), 5.79 ± 0.01 (4) and 5.59 ± 0.05 (16) for each agonist. These values were not significantly altered in the absence of added Mg2+. The mean pA2 values for kainate were significantly higher than those for quisqualate (P < 0.01).
Antagonism of NMDA‐induced depolarizations was evident at 10 and 25 but not 4 μm CNQX. The antagonism of NMDA was reversed by d‐serine (100 and 200 μm).
A similarity between the relative potencies of both CNQX and kynurenate for depression of synaptic transmission and antagonism of amino acid‐induced depolarizations indicates that monosynaptic transmission from myelinated primary afferents to motoneurones is mediated by kainate and/or quisqualate sub‐types of non‐NMDA receptors.
A 5‐hydroxytryptamine receptor in human atrium
Authors: Kaumann Alberto J. , Sanders Louise , Brown Anthony M. , Murray Kenneth J. , Brown Morris J. 
Published: July 2012

The effects of 5‐hydroxytryptamine (5‐HT) were investigated on right atrial appendages obtained from patients treated with β‐adrenoceptor blocking agents who were undergoing open heart surgery. Atrial strips were paced under isometric conditions.
5‐HT increased contractile force to approximately one half of the force produced by a saturating concentration of (−)−isoprenaline. Both 5‐HT and (−)−isoprenaline accelerated the onset of relaxation, as indicated by an abbreviation of time to peak force.
The effects of 5‐HT were resistant to blockade by 0.4 μm (±)‐propranolol, 1μm (−)−pindolol, 0.4 μm methiothepin, 4 μm yohimbine, 0.4 μm ketanserin, 10 μm phenoxybenzamine, 1μm methysergide, 2 μm MDL 72222 and 20 μm granisetron.
Cocaine 6 μm potentiated the effects of 5‐HT, increasing the pEC50 from 6.6 to 7.4. The inotropic potency of 5‐HT is five times greater than that of (−)−noradrenaline.
ICS 205930 antagonized competitively the effects of 5‐HT with a pKB of 6.7.
In the presence of 0.4 μm (±)‐propranolol, 10 μm 5‐HT increased both adenosine 3′:5′ cyclicmonophosphate (cyclic AMP) levels and cyclic AMP‐dependent protein kinase activity by approximately one half and two thirds respectively, of the corresponding effects of 200 μm (−)−isoprenaline.
Both the increase in cyclic AMP levels and the stimulation of protein kinase activity are consistent with the inotropic effects of 5‐HT being mediated by cyclic AMP‐dependent phosphorylation of Ca2+ channels and of proteins involved in contraction and relaxation.
The human atrial 5‐HT receptor resembles the neuronal ‘so called’ 5‐HT4 receptor of rodents both in increasing cyclic AMP levels and in its affinity for ICS 205930.
A salivary vasodilator in the blood‐sucking bug, Rhodnius prolixus
Authors: Ribeiro José M.C. , Marinotti Osvaldo , Gonzales Rafael 
Published: July 2012

Salivary gland homogenates of the blood‐sucking bug, Rhodnius prolixus induced transient, dose‐dependent relaxation of rabbit aortic preparations pre‐constricted with 200 ng ml−1 noradrenaline, 1 μg ml−1 histamine or 20 ng ml−1 angiotensin II. Such relaxations were less marked when the aorta was constricted by 60 mm KCl. These effects were observed with as little as 0.2 μg ml−1 of crude salivary gland protein.
The vasodilator effect was endothelium‐independent, abolished by 50 μm hydroquinone or 50 μm methylene blue, and potentiated by 30 u ml−1 superoxide dismutase.
Salivary homogenates generated a coloured compound when reacted with sulfanilic acid in the presence of N‐(1‐naphtyl)‐ethylediamine, indicating the presence of reactive nitrogen groups, equivalent to 35 ± 3 ng of sodium nitrite per pair of glands.
Molecular sieving high performance liquid chromatography of salivary gland homogenates generated a single peak of vasorelaxant activity which coincided with the presence of platelet antiaggregating and spasmolytic (guinea‐pig ileum contracted with histamine) activities, as well as with reactive nitrogen groups.
It is concluded that a protein of molecular weight 16,500 daltons in the salivary glands of R. prolixus contains reactive nitrogen groups which assist the bug during a blood meal. It is suggested that saliva of blood sucking arthropods is a natural resource of novel pharmacological activities.
A series of novel, highly potent and selective agonists for the κ‐opioid receptor
Authors: Hayes A.G. , Birch P.J. , Hayward N.J. , Sheehan M.J. , Rogers H. , Tyers M.B. , Judd D.B. , Scopes D.I.C. , Naylor A. 
Published: July 2012

This paper describes the opioid receptor pharmacology and in vivo activity of several novel benzeneacetamidopiperidine and benzeneacetamidopiperazine analogues.
These compounds all showed potent, naloxone‐reversible, full agonist activiy in the field‐stimulated rabbit vas deferens, indicating that they are κ‐opioid agonists; but showed very little activity in the rat or hamster vas deferens, indicating good selectivity with regard to μ‐ and δ‐opioid receptors.
They were all potent antinociceptive agents, the most potent compound, GR103545, having an ED50 value in the mouse abdominal constriction test of 0.25 μg kg−1 s.c. The compounds also produced sedation and diuresis, but had little effect on respiration rate or gastrointestinal motility.
It is concluded that the seven novel compounds described are all potent and selective agonists for the κ‐opioid receptor.
Phannacokinetic‐pharmacodynamic modelling of the anticonvulsant effect of oxazepam in individual rats
Authors: Dingemanse Jasper , Voskuyl Rob A. , Langemeijer Mariska W.E. , Postel‐Westra Ineke , Breimer Douwe D. , Meinardi Harry , Danhof Meindert 
Published: July 2012

The purpose of this investigation was to examine in vivo drug‐concentration anticonvulsant effect relationships of oxazepam in individual rats following administration of a single dose.
Whole blood concentration vs time profiles of oxazepam were determined following administration of doses of 4, 8 and 12 mg kg−1. The pharmacokinetics could be described by an open 2‐compartment pharmacokinetic model. Following 12 mg kg−1 the values (mean ± s.e., n = 11) of clearance and volume of distribution were 28 ± 2 ml min−1 kg−1 and 2.6 ± 0.31 kg−1, respectively, and were not significantly different from the values obtained at the other doses.
The anticonvulsant effect was quantitated by a new technique which allows repetitive determination of the convulsive threshold by direct cortical stimulation within one rat. Significant dose‐dependent elevations of the seizure threshold were observed.
By pharmacokinetic‐pharmacodynamic modelling, a log‐linear relationship was found between concentration and anticonvulsant effect. Following 12 mg kg−1 the values (mean ± s.e., n = 11) of the pharmacodynamic parameters slope and minimal effective concentration (Cmin) were 243 ± 27 μA and 0.11 ± 0.02 mg l−1, respectively and not significantly different from the values obtained at the other doses.
In a repeatability study the pharmacodynamic parameters were determined twice on two different occasions with an interval of two weeks in the same group of 11 rats. The inter‐animal variability in the pharmacodynamic parameter slope was 46%, whereas the intra‐animal variability was 24 ± 18%. The value of the minimal effective concentration was in each animal and on each occasion close to zero within the relatively narrow range of 0.01–0.30 mgl−1.
The results of this study showed that it is possible to determine in vivo concentration‐anticonvulsant effect relationships of oxazepam under non‐steady‐state conditions in individual rats. The anti‐convulsant effect of oxazepam appeared to be a rapidly reversible direct effect and acute tolerance did not develop within the time frame of the experiments.
Reversal of the anorectic effect of (+)‐fenfluramine in the rat by the selective cholecystokinin receptor antagonist MK‐329
Authors: Cooper S.J. , Dourish C.T. , Barber D.J. 
Published: July 2012

Experiments were conducted to determine whether or not the effect of (+)‐fenfluramine (3.0 mg kg−1, i.p.) on food intake can be antagonized by the selective cholecystokinin receptor antagonist MK‐239 (formerly L364/718; (3S(−)‐N‐(2,3‐dihydro‐1‐methyl‐2‐oxo‐5‐phenyl‐1‐H‐1,4‐benzodiazepin‐3‐yl)‐1H‐indole‐2‐carboxamide). Two feeding paradigms were employed. In the first, non‐deprived rats were familiarized with eating a highly palatable, sweetened mash in a 30 min test. In the second, freely‐feeding rats were trained to consume powdered chow in their home‐cages, and their intake was monitored over the first 6 h of the night‐period.
In doses of 30.0 and 100.0 μg kg−1, s.c., MK‐329 almost completely blocked the anorectic effect of (+)‐fenfluramine in the palatable food intake test. These doses of MK‐329 have previously been reported to antagonize the anorectic effect produced by exogenous cholecystokinin‐octapeptide (CCK8) in rats. Both doses of MK‐329 were also effective in significantly attenuating the anorectic effect of (+)‐fenfluramine in nocturnal free‐feeding animals over a 6 h‐period.
MK‐329 (10.0–100.0 μg kg−1, s.c.) failed to antagonize the anorectic effect of either the specific dopamine D2‐receptor agonist quinpirole (0.3 mg kg−1, s.c.) or the β‐carboline FG 7142 (10.0 mg kg−1, i.p.) in the palatable food intake test.
MK‐329 (10.0–300.0 μg kg−1, s.c.) had no effect, when administered alone, on the level of palatable food intake in non‐deprived rats, even when substantial satiation was produced by a pre‐feeding procedure. Furthermore, MK‐329 had no effect, when administered alone, on nocturnal food intake in freely‐feeding rats.
In conclusion, not only was MK‐329 a potent antagonist of the effect of CCK8 on food intake, it also blocked the effect of (+)‐fenfluramine to a significant degree. The effect of MK‐329 was selective in that the anorectic effects of either quinpirole or FG 7142 remained unaffected. Administered alone, MK‐329 did not affect food intake, indicating that its reversal of (+)‐fenfluramine‐induced anorexia was not secondary to an intrinsic hyperphagic effect. The results provide some evidence that the depressant effect of (+)‐fenfluramine on food intake depends on the activity of endogenous CCK.
κ‐Opioid‐receptor agonists modulate the renal excretion of water and electrolytes in anaesthetized rats
Authors: Ashton N. , Balment R.J. , Blackburn T.P. 
Published: July 2012

Subcutaneous injection of the κ‐opioid agonists U50,488 (10 mg kg−1) and tifluadom (3.5 mg kg−1) into Inactin‐anaesthetized, saline‐infused rats was associated with a diuresis, antinatriuresis and anti‐kaliuresis which lasted for up to 2h. A high (5 mg kg−1), but not low (0.1 mg kg−1), dose of naloxone blocked the renal effects of U50,488.
U50,488 administration in anaesthetized, vasopressin‐deficient Brattleboro DI rats was associated with an attenuated diuresis, though the antinatriuretic response remained intact.
The diuretic action of U50,488 was associated with an increase in glomerular filtration rate while fractional fluid reabsorption remained steady. In contrast, fractional sodium and potassium reabsorption were increased.
These data suggest that κ‐opioid agonists alter renal handling of both water and electrolytes. This appears to be mediated by two separate mechanisms: increased fluid loss largely reflects altered glomerular events while the fall in electrolyte excretion results from altered tubular handling.
Pharmacological subclassification of α1‐adrenoceptors in vascular smooth muscle
Authors: Muramatsu Ikunobu , Ohmura Tsuyoshi , Kigoshi Shigeru , Hashimoto Shigeki , Oshita Masafumi 
Published: July 2012

We examined whether α1‐adrenoceptors in various blood vessels can be divided into subtypes by antagonist affinity or by susceptibility to chloroethylclonidine or nifedipine.
Noradrenaline or phenylephrine produced concentration‐dependent contractions in all the tissues tested, which were competitively inhibited by phentolamine, yohimbine, prazosin, WB4101 and HV723. However, there were large differences between the tissues in the pA2 values for all the antagonists except phentolamine.
The blood vessels could be classified into three groups (I, II and III) on the basis of their affinity variation. In group I (dog mesenteric artery and vein, saphenous vein), the pA2 values for HV723 were greater than 9, and those for HV723 and WB4101 were approximately 1 log unit higher than for prazosin. This rank order of affinity reversed in group II (dog carotid artery and rat thoracic aorta), where prazosin was more potent (pA2 values greater than 9.5) than HV723 or WB4101. In group III (rabbit mesenteric artery, thoracic aorta and carotid artery and guinea‐pig thoracic aorta), on the other hand, prazosin, HV723 and WB4101 inhibited the noradrenaline response with a similar affinity (pA2 values ranging from 8 to 9).
Yohimbine inhibited the responses to noradrenaline and phenylephrine with a lower affinity than prazosin, HV723 or WB4101. The pA2 values for yohimbine were similar in groups I and II (the values greater than 6.5), which were greater than those in group III (values less than 6.4).
The α1‐adrenoceptors in group II were selectively affected by chlorethylclonidine, resulting in an irreversible attenuation of noradrenaline responses in the dog carotid artery and a persistent contraction in the rat thoracic aorta.
Nifedipine either produced no effect or a slight inhibition of α1‐adrenoceptor‐mediated contractions in all the blood vessels; these effects were not correlated to the above groups.
These results suggest that α1 ‐adrenoceptors of blood vessels can be divided into three subtypes (designated as α1H, α1L and α1N) by antagonist affinity and their susceptibility to chloroethylclonidine but not to nifedipine: the characteristics of each subtype are summarized in Table 3. Subtypes α1H, α1L and α1N may be predominantly involved in the contractile responses to noradrenaline or phenylephrine of the blood vessels in groups II, III and I, respectively.
Evaluation of the effect of azapropazone on neutrophil migration in anaesthetized swine using a multichamber blister suction technique
Authors: Mousa S.A. , Brown R. , Chan Y. , Hsieh J. , Smith R.D. 
Published: July 2012

The purpose of this study was to determine the in vivo inhibitory efficacy of azopropazone on neutrophil migration. The effects of azapropazone given at a dose of 100 mg kg−1 i.v. every 2 h on the neutrophil migration into skin inflammation sites (blister fluid) as well as into an autologous serum (± chemoattractant) placed above the blister surface (2nd chamber) were determined.
Azapropazone treatment schedule maintained blood levels at 70–100 μg ml−1 throughout the time course (360 min) of the experiment.
Azapropazone significantly inhibited (48 ± 6%) neutrophil migration into the blister fluid (as evident from the decrease in myeloperoxidase activity).
Azapropazone significantly inhibited the neutrophil migration into the autologous serum either with (65 ± 5%) or (35 ± 6%) without the chemoattractant, formyl‐methionyl‐leucyl‐phenylalanine (FMLP). The chemoattractant, FMLP, markedly increased neutrophil migration into the autologous serum by approximately 1.5 to 2 times the non‐FMLP treated group. Azapropazone was more efficacious in inhibiting the neutrophil migration in the presence of FMLP than in its absence.
We conclude that azapropazone is an effective inhibitor of neutrophil migration into topically inflamed sites in anaesthetized swine.
Phorbol esters inhibit smooth muscle contractions through activation of Na+ ‐K+ ‐ATPase
Authors: Sasaguri Toshiyuki , Watson Stephen P. 
Published: July 2012

The role of protein kinase C (PKC) in agonist‐induced contractions of guinea‐pig ileum longitudinal smooth muscle has been investigated.
The phorbol esters, phorbol 12,13‐dibutyrate (PDBu), phorbol 12,13‐diacetate (PDA) and phorbol 12‐myristate 13‐acetate (PMA), relaxed tissues precontracted by submaximal concentrations of carbachol, histamine or substance P.
This inhibitory action of the phorbol esters was reversed following the application of ouabain, a specific inhibitor of Na+‐K+‐ATPase. Similarly, pretreatment with ouabain inhibited the ability of phorbol esters to relax tissues precontracted by the above agonists.
The slow relaxation of the tonic component of contraction induced by submaximal concentrations of carbachol and histamine, and all concentrations of substance P, was abolished in the presence of ouabain.
In Na+‐loaded tissues, PDBu and carbachol caused a concentration‐dependent increase of Na+‐K+‐ATPase activity, assessed by ouabain‐sensitive 86Rb+‐uptake. Extrusion of Na+, assessed by the cellular content of the ion, was also stimulated by PDBu (the effect of carbachol was not investigated).
We conclude that phorbol esters inhibit the tonic component of contractions induced by submaximal concentrations of these agonists through activation of Na+‐K+‐ATPase. We suggest that PKC may exert feedback control over the tonic component of agonist contractions through stimulation of the pump.
Vasopressin and stress‐induced antinociception in the mouse
Authors: Hart S.L. , OluyomiXY1 A.O. 
Published: July 2012

Arginine vasopressin produced antinociception in the hot‐plate test after intracerebroventricular injection (0.5 μg) and in the acetic acid abdominal constriction test after intraperitoneal injection (0.1 mg kg−1).
The antinociception produced by arginine vasopressin was sensitive to deamino(CH2)5Tyr(Me) arginine vasopressin (0.5 μg i.c.v.; 0.1 mg kg−1 i.p.) but not to naloxone (5 μg i.c.v.; 2 mg kg−1 i.p.)
Arginine vasopressin when administered by the intracerebroventricular route, but not by the intraperitoneal route, produced characteristic behaviour which was sensitive to deamino(CH2)5Tyr(Me) arginine vasopressin (0.5 μg, i.c.v.).
A 3 min swim at 20°C produced antinociception on the hot‐plate which was sensitive to naloxone (0.4 mg kg−1, i.p.) but not to deamino(CH2)5Tyr(Me) arginine vasopressin (0.5 μg, i.cv.).
The reduction in the number of acetic acid‐induced abdominal constrictions produced by a 30 s swim at 30°C was not sensitive to either naloxone (2 mg kg−1, i.p.) or deamino(CH2)5Tyr(Me) arginine vasopressin (0.1 mg kg−1, i.p.).
Arginine vasopressin, at high doses, is antinociceptive in the mouse but does not appear to mediate stress‐induced antinociception in this species.
Changes in preganglionic sympathetic nerve function following chronic morphine treatment in rats
Authors: Leung Christopher M.K. , Dai Soter , Ogle Clive W. 
Published: July 2012

The effects of acute or chronic morphine treatment on the changes in blood pressure and pulse rate in response to ganglionic stimulation or blockade and to vagal stimulation, and of isolated atria to field stimulation or noradrenaline, were studied.
In pithed rats, intravenously injected hexamethonium significantly depressed the blood pressure responses to sympathetic nerve stimulation. The ganglionic blocking effects of hexamethonium were significantly greater in chronically morphine‐treated rats, but were not significantly affected by acute morphine administration in naive animals.
Intravenous administration of nicotine dose‐dependently increased blood pressure and pulse rate. The magnitudes of these changes were not significantly affected by acute or chronic morphine pretreatment.
Studies with rat isolated atrial preparations revealed that the changes in atrial contractile rate and force in response to noradrenaline or field stimulation were not influenced by either acute or chronic morphine treatment.
Cervical vagal stimulation produced voltage‐ or frequency‐dependent decreases in pulse rate and blood pressure. The responses were not significantly affected by chronic morphine treatment.
These findings suggest that the site of the changes in sympathetic function following prolonged exposure to the opiate appears to be on the preganglionic nerve fibres.
Modulation of seizure susceptibility in the mouse by the strychnine‐insensitive glycine recognition site of the NMDA receptor/ion channel complex
Authors: Singh L. , Oles R.J. , Tricklebank M.D. 
Published: July 2012

In order to determine whether the strychnine‐insensitive glycine modulatory site on the N‐methyl‐d‐aspartate (NMDA) receptor/ion channel complex is fully activated in vivo, the ability of the selective glycine receptor agonist, d‐serine, to modulate seizure susceptibility in the mouse has been examined.
d‐Serine (10–200 μg per mouse, i.c.v.) dose‐dependently increased the potency of NMDLA in inducing seizures in Swiss Webster mice by approximately 3 fold. l‐Serine was without significant effect.
The potency of pentylenetetrazol in inducing seizures was also enhanced by d‐, but not l‐serine, although the magnitude of the shift (1.6 fold) was considerably less than for NMDLA.
Similar doses of d‐serine were also able to block the anticonvulsant effect of the non‐selective glycine receptor antagonist, kynurenic acid, against seizures induced by NMDLA, but were without effect on the anticonvulsant effect of the competitive NMDA receptor antagonist, 3‐((+)‐2‐carboxypiperazin‐4‐yl)‐propyl‐1‐phosphonic acid (CPP).
d‐Serine completely antagonized the protective effect of the selective glycine receptor antagonist, 7‐chlorokynurenic acid, against sound‐induced seizures in DBA/2 mice, but was less effective in this model against the less selective antagonist, kynurenic acid.
The results indicate that in vivo, NMDA receptors are not maximally potentiated by endogenous glycine and suggest an important involvement of the glycine modulatory site on the NMDA receptor/ion channel complex in the pathophysiology of epilepsy.
Developmental changes in β‐adrenergic and cholinergic interactions on calcium‐dependent slow action potentials in rat ventricular muscles
Authors: Kojima Michio , Sada Hideaki , Sperelakis Nicholas 
Published: July 2012

Developmental changes in the effect of isoprenaline (Iso) and acetylcholine (ACh) interactions on Ca2+‐dependent slow action potentials (APs) were studied in the ventricular muscles of foetal (12–20 days post‐gestation), neonatal (0–20 days old), and adult (2–3 months old) rats. The slow APs were recorded at 0.2 Hz in partially depolarized preparations (an extracellular K+ concentration of 25 mm).
Iso (1 nm to 10 μm) began to increase the of the slow APs (an approximate indicator of Ca2+ current) on foetal day 18; its potentiating effect became greater with age and reached the adult level about 2 weeks after birth.
ACh (10 μm) abolished the Iso (1 μm)‐induced increased in the observed in the late foetal and neonatal periods.
The inhibitory effect of ACh on the was antagonized by atropine but not by pirenzepine, suggesting that ACh reduces Ca2+ current (in the presence of β‐adrenoceptor agonists) by stimulating muscarinic (M2) cholinoceptors.
These results suggest that developmental changes in the modulatory effects of β‐adrenoceptor and cholinoceptor agonists on Ca2+ channels occur from a few days before birth to 2 weeks after birth and that the functional coupling between muscarinic cholinoceptors and Ca2+ channels has already been established when the coupling between β‐adrenoceptors and Ca2+ channels starts to operate.