bluuebunny/crossref_metadata_2025_split huggingface dataset:
Similar effects of ethanol and flumazenil on acquisition of a shuttle‐box avoidance response during withdrawal from chronic ethanol treatment
Authors: Criswell Hugh E. , Breese George R. 
Published: July 2012

Acquisition of a two‐way shuttle‐box avoidance response is facilitated by ethanol. This facilitated acquisition of an avoidance response to ethanol was attenuated during withdrawal from chronic‐ethanol diet intake (i.e. tolerance developed by ethanol). The deficit in the avoidance task after chronic ethanol treatment could be overcome by increasing the dose of ethanol.
Flumazenil, a benzodiazepine antagonist, also facilitated acquisition of the avoidance response in control rats. This response to flumazenil was significantly reduced during withdrawal from chronic‐ethanol treatment. This reduced avoidance responding during withdrawal also could be overcome by increasing the dose of flumazenil.
The benzodiazepine‐inverse agonist, RO 15–4513, produced a deficit in avoidance responding that was antagonized by both ethanol and flumazenil in a dose‐related manner.
To determine whether flumazenil has the properties of a benzodiazepine agonist, it was established that, unlike the benzodiazepine chlordiazepoxide, flumazenil did not enhance the ethanol‐induced deficit in the aerial righting reflex. Additionally, flumazenil blocked the action of chlordiazepoxide in this procedure, consistent with the benzodiazepine antagonist action of flumazenil.
Data collected are consistent with the hypothesis that an endogenous substance with the properties of a benzodiazepine‐inverse agonist antagonizes the anticonflict actions of acutely administered ethanol during withdrawal from chronic‐ethanol exposure.
Use of the endothelin antagonists BQ‐123 and PD 142893 to reveal three endothelin receptors mediating smooth muscle contraction and the release of EDRF
Authors: Warner Timothy D. , Allcock Graham H. , Corder Roger , Vane John R. 
Published: July 2012

We have compared the receptors mediating the contractions of rings of rat thoracic aorta or rabbit pulmonary artery and rat stomach strips in response to the endothelin/sarafotoxin (ET/SX) family of peptides and to those mediating endothelium‐dependent vasodilatations within the isolated perfused mesentery of the rat. To discriminate ETA receptors from ETB receptors we have used the criteria that ET‐1 is more active than SX6c on ETA receptors, and that the ET/SX peptides are equiactive on ETB receptors. We have also assessed the effects of the ETA receptor‐selective antagonist BQ‐123, and the non‐selective ET receptor antagonist PD 142893 on the responses of each preparation to the ET/SX peptides.
ET‐1‐induced constrictions of the rat thoracic aorta (EC50 3 × 10−10m), a prototypic ETA receptor‐mediated response, or isolated perfused mesentery of the rat were antagonized by BQ‐123 (10−5 m) or PD 142893 (10−5 m). SX6c did not constrict either the rat isolated perfused mesentery or the rat thoracic aorta. Thus, ETA receptors mediate these constrictions.
ET‐1 and SX6c were approximately equipotent in constricting rabbit pulmonary artery rings (EC50s 3–6 × 10−10 m). Neither BQ‐123 (10−5 m) nor PD 142893 antagonized the contractions induced by ET‐1. These effects suggest mediation by ETB receptors but PD 142893 (10−5 m) did give a 3 fold antagonism of constrictions induced by SX6c.
SX6c was more potent than ET‐1 in contracting the rat stomach strip (threshold concentrations 10−10 and 3 × 10−10 m). Contractions to ET‐1 or SX6c were unaffected by BQ‐123 (10−5 m), again indicative of ETB receptor‐mediated events. PD 142893 (10−5 m) was ineffective against ET‐1 but produced a 3 fold antagonism of SX6c.
In the rat isolated perfused mesentery ET‐1 or SX6c (0.3–300 pmol) were equipotent in producing dose‐related vasodilatations that were unaffected by BQ‐123 (10−6 m), indicative of an ETB receptor‐mediated response. In contrast to the other ETB‐mediated responses, PD 142893 (10−6 m) strongly antagonized these vasodilatations.
Thus, ETA receptors mediate constrictions of the rat thoracic aorta and rat isolated perfused mesentery whereas ETB receptors mediate constrictions of the rabbit pulmonary artery and rat stomach strip and endothelium‐dependent dilatations within the mesentery. However, within the group of ETB receptor‐mediated responses, endothelium‐dependent vasodilatations are sensitive to PD 142893, whereas contractions of the isolated smooth muscle preparations are not. Thus, the receptor present on the endothelium responsible for the release of nitric oxide in response to the ET/SX peptides is most probably different from that present on smooth muscle that mediates BQ‐123‐insensitive contractions.
Characterization of endothelin receptors mediating the effects of the endothelin/sarafotoxin peptides on autonomic neurotransmission in the rat vas deferens and guinea‐pig ileum
Authors: Warner Timothy D. , Allcock Graham H. , Mickley Emma J. , Vane John R. 
Published: July 2012

To characterize the receptors mediating the effects of the endothelin/sarafotoxin family of peptides on the responses to electrical stimulation of the rat vas deferens (RVD) and guinea‐pig ileum (GPI) we have used endothelin‐1 (ET‐1), ET‐3, sarafotoxin 6b (SX6b) and SX6c as agonists and the endothelin‐receptor antagonists BQ‐123 (ETA receptor selective) and PD 142893 (non‐selective).
In the RVD, ET‐1 and SX6b increased the twitches induced by field stimulation starting at a threshold concentration of 10−10 m while the threshold concentration for ET‐3 was 3 × 10−9 m. SX6c (up to 3 × 10−8 m) did not potentiate the twitches. SX6b produced significantly (P < 0.05) greater potentiations than ET‐1 at concentrations of 3 × 10−9 m and higher, and 10−7 m ET‐3 also produced a significantly greater effect than ET‐1 at the same concentration. Thus, at threshold the rank order of peptides was ET‐1 = SX6b > ET‐3 >> SX6c, and at concentrations of 3 × 10−8 m and higher, SX6b > ET‐3 > ET‐1 >>> SX6c.
In the presence of BQ‐123 or PD 142893 (10−5 m) the threshold concentrations for ET‐1 to augment the twitches were increased 30 fold. In the same conditions neither SX6b nor ET‐3 potentiated the responses. The relative activities of the endothelin/sarafotoxin peptides and the effectiveness of the endothelin receptor antagonists are consistent with postjunctional ETA receptors mediating these effects.
In the transmurally stimulated GPI the endothelin/sarafotoxin peptides produced two effects; an increase in the basal tension of the tissues and an inhibition of the twitch responses. To increase the basal tension the peptides had the order of potency ET‐1 > SX6b >> ET‐3 = SX6c. These direct effects of ET‐1 or SX6b were strongly antagonized (100 fold) by either BQ‐123 (10−5 m) or PD 142893 (10−5 m). Thus, ETA receptors mediate contractions of the GPI induced by these peptides.
The endothelin/sarafotoxin peptides were approximately equipotent at depressing twitches of the GPI in response to transmural stimulation (EC50S, 4 × 10−11 to 1.5 × 10−10 m). The depressions induced by ET‐1 were unaffected by either BQ‐123 (10−5 m) or PD 142893 (10−5 m). BQ‐123 produced a small (three fold) antagonism of the inhibitory effects of ET‐3 or SX6c. These results indicate that a receptor of the ETB type mediates the inhibitory effects of the endothelin/sarafotoxin peptides on neurotransmission in the GPI.
Thus, both ETA receptors and ETB receptors mediate the effects of the endothelin/sarafotoxin peptides on neurotransmission.
Role of oxygen radicals and arachidonic acid metabolites in the reverse passive Arthus reaction and carrageenin paw oedema in the rat
Authors: Boughton‐Smith N.K. , Deakin A.M. , Follenfant R.L. , Whittle B.J.R. , Garland L.G. 
Published: July 2012

The role of arachidonic acid metabolites and oxygen radicals in carrageenin‐induced rat paw oedema and dermal reverse passive Arthus reaction (RPA) have been investigated.
Indomethacin (10 mg kg−1, p.o.) inhibited carrageenin paw oedema when administered 30 min before, but not 2 h after carrageenin. BWB70C (10 mg kg−1, p.o.), a selective inhibitor of 5‐lipoxygenase, had no effect whether administered before or after carrageenin. Administration of both indomethacin and BWB70C had no greater anti‐inflammatory effect than indomethacin alone.
BW755C (20 mg kg−1, p.o.), which inhibits the cyclo‐oxygenase and lipoxygenase pathways of arachidonic acid metabolism, or superoxide dismutase‐polyethylene glycol conjugate (SOD‐PEG, 3000 u, i.v.) inhibited carrageenin paw oedema whether administered either 30 min before, or 2 h after carrageenin.
Pretreatment with dexamethasone (0.1 mg kg−1) or colchicine (2 mg kg−1), likewise suppressed carrageenin paw oedema.
BW755C (25–100 mg kg−1, p.o.) dose‐dependently reduced plasma leakage in the RPA, whereas indomethacin (5 mg kg−1, p.o.) or BWB70C either alone or in combination, did not.
SOD‐PEG (300–3000 u, i.v.) dose‐dependently inhibited plasma leakage in the RPA. In addition, the iron chelator and peroxyl radical scavenger, desferrioxamine (200 mg kg−1, s.c.) also inhibited plasma leakage.
Pretreatment with dexamethasone (0.1 mg kg−1) or colchicine (1 mg kg−1) reduced the plasma leakage in RPA, whereas MK‐886 (10 mg kg−1) had no effect.
These results indicate an important role for oxygen radicals but not arachidonic acid metabolites in the maintenance of carrageenin paw oedema and the plasma leakage in RPA. Furthermore, the results suggest that the anti‐inflammatory actions of BW755C can be dissociated from its effects on arachidonic acid metabolism and are attributed to its anti‐oxidant activity.
Electrophysiological actions of alfentanil: intracellular studies in the rat locus coeruleus neurones
Authors: Chiu T.H. , Yeh M.H. , Tsai S.K. , Mok M.S. 
Published: July 2012

The electrophysiological effects of alfentanil on 156 neurones of the rat locus coeruleus were investigated by use of intracellular recordings from the in vitro brain slice preparation.
Bath application of alfentanil (5–100 nm) reversibly decreased the firing rate of all neurones tested in a dose‐dependent manner, with an IC50 4.1 nm.
Based on inhibition of the spontaneous firing rate, alfentanil was 22 times more potent than morphine.
At 100 nm, alfentanil produced a complete inhibition of firing of all neurones tested (n = 62); the inhibition was accompanied by a membrane hyperpolarization 17.0 ± 0.8 mV (range 6.1–30.3 mV, n = 62) and a reduction in input resistance 26.4 ± 1.7% (range 6.5−53%, n = 51).
The effects of alfentanil were antagonized by naloxone, with a dissociation equilibrium constant of 2.7 ± 0.4 nm (n = 6).
The reversal potential for the alfentanil‐induced hyperpolarization was −; 110 ± 2 mV (n = 9), which is approximately the potassium equilibrium potential.
The alfentanil‐induced hyperpolarization was blocked by caesium chloride and barium chloride.
These results indicate that alfentanil binds to μ‐opioid receptors on the cell membrane of neurones of the locus coeruleus. This leads to opening of the inward‐going rectification potassium channels, resulting in the observed hyperpolarization of the membrane.
A pharmacological analysis of receptors mediating the excitatory response to 5‐hydroxytryptamine in the guinea‐pig isolated trachea
Authors: Lucchelli Adele , Santagostino‐Barbone Maria Grazia , Barbieri Annalisa , Tonini Marcello 
Published: July 2012

Experiments were carried out to characterize the receptors mediating the indirect excitatory response to 5‐hydroxytryptamine (5‐HT) in the guinea‐pig isolated trachea.
5‐HT caused concentration‐dependent contractions of tracheal strips, and the resulting concentration‐response curve was biphasic in nature. The first phase was obtained with agonist concentrations in the range of 0.01–3 nm and achieved a maximum which was 30% of the total 5‐HT response, while the second phase was in the range 10 nm–1 μm.
Atropine (0.1 μm) and tetrodotoxin (TTX: 0.3 μm) significantly reduced both phases of the 5‐HT curve. Morphine (10 μm), which can act to inhibit neuronal acetylcholine release, abolished the first phase and reduced the second phase. This suggests that the first phase is mainly neurogenic (cholinergic) in nature, while the second phase is in part neurogenic and in part due to direct activation of the effector cells.
The 5‐HT2A receptor antagonist, ketanserin (0.01, 0.1 μm) markedly depressed the first phase and shifted the second phase to the right in a parallel manner, with some depression of the 5‐HT response maximum. The less selective (5‐HT1/5‐HT2A) antagonist, methiothepin (0.1 μm) mimicked the action of ketanserin, albeit with less potency. Concomitant administration of ketanserin and methiothepin (each at 0.1 μm) produced an antagonism similar to that caused by ketanserin (0.1 μm) alone.
The 5‐HT3 receptor antagonists, ondansetron (0.1 μm) and granisetron (0.01 μm) slightly but significantly inhibited the first phase of the 5‐HT curve without altering the second phase. SDZ 205,557 (0.3 μm), a 5‐HT4 receptor antagonist, was ineffective.
Our results suggest that neural 5‐HT2A and, to a lesser extent, 5‐HT3 receptor subtypes mediate the first phase of the 5‐HT curve in the guinea‐pig trachea. The second phase is mediated by 5‐HT2A receptors, which are probably located at both the neural and muscular level. No evidence for the participation of 5‐HT1 receptors in the 5‐HT response has been obtained.
Peripheral and central adrenoceptor modulation of the behavioural effects of clozapine in the paw test
Authors: Prinssen Eric P.M. , Ellenbroek Bart A. , Cools Alexander R. 
Published: July 2012

In rats, the atypical neuroleptic, clozapine, has been found to increase the hindlimb retraction time but not the forelimb retraction time, in the paw test. These parameters have predictive validity for the antipsychotic efficacy and extrapyramidal side‐effects of drugs, respectively. The present study analysed to what extent drugs acting on adrenoceptors affect the behavioural effect of clozapine in the paw test.
The α1‐adrenoceptor agonist, ST 587 but not the peripherally working α1‐agonist, methoxamine, decreased the effect of clozapine on the hindlimb retraction time. The α1‐antagonist phenoxybenzamine increased this effect of clozapine, and blocked the effect of ST 587 on clozapine at low doses. Only the combination of phenoxybenzamine with clozapine produced an increase in forelimb retraction time.
The α1‐adrenoceptor agonist, clonidine, decreased the effect of clozapine on the hindlimb retraction time. This effect was neither antagonized by the α1‐antagonist rauwolscine nor by the α1‐antagonist phenoxybenzamine. Rauwolscine or the peripherally working α2‐antagonist L‐659,066 did not influence the effect of clozapine on the hindlimb retraction time. The forelimb retraction time was not affected by any of the drug combinations.
In contrast to the β2‐adrenoceptor agonist, clenbuterol, which was ineffective, the peripherally acting β‐agonist, (−)‐isoprenaline, increased the effects of clozapine on the hindlimb retraction time. The β‐antagonist, (−)‐propranolol as well as the peripherally acting β‐antagonist, nadolol decreased this effect of clozapine. Low doses of the peripherally acting β1‐antagonist, atenolol, as well as low doses of the β2‐antagonist, ICI‐118,551, decreased the effect of clozapine. A low dose of nadolol blocked the effect of (−)‐isoprenaline on clozapine. Only the combination of clenbuterol with clozapine produced an increase in forelimb retraction time.
It is concluded that blockade of central α1‐adrenoceptors plays an important role in the effect of clozapine on the hindlimb retraction time. Furthermore, the effect of clozapine on the hindlimb retraction time is strongly modulated by peripheral β1 and/or β2‐adrenoceptors. Given the predictive validity of the paw test, the presented data suggest that the α1‐adrenoceptor antagonist properties of clozapine are important for its therapeutic effects, but not for its lack of extrapyramidal side‐effects.
Actions of two new antagonists showing selectivity for different sub‐types of metabotropic glutamate receptor in the neonatal rat spinal cord
Authors: Jane D.E. , Jones P.L.St.J. , Pook P.C‐K. , Tse H‐W. , Watkins J.C. 
Published: July 2012

The presynaptic depressant action of l‐2‐amino‐4‐phosphonobutyrate (l‐AP4) on the monosynaptic excitation of neonatal rat motoneurones has been differentiated from the similar effects produced by (1S,3R)‐1‐aminocyclopentane‐1,3‐dicarboxylate ((1S,3R)‐ACPD), (1S,3S)‐ACPD and (2S,3S,4S)‐α‐(carboxycyclopropyl)glycine (l‐CCG‐I), and from the postsynaptic motoneuronal depolarization produced by (1S,3R)‐ACPD, by the actions of two new antagonists, α‐methyl‐l‐AP4 (MAP4) and α‐methyl‐l‐CCG‐I (MCCG). Such selectivity was not seen with a previously reported antagonist, (+)‐α‐methyl‐4‐carboxyphenylglycine (MCPG).
MAP4 selectively and competitively antagonized the depression of monosynaptic excitation produced by l‐AP4 (KD 22 μm). At ten fold higher concentrations, MAP4 also antagonized synaptic depression produced by l‐CCG‐I but in an apparently non‐competitive manner. MAP4 was virtually without effect on depression produced by (1S,3R)‐ or (1S,3S)‐ACPD.
MCCG differentially antagonized the presynaptic depression produced by the range of agonists used. This antagonist had minimal effect on l‐AP4‐induced depression. The antagonism of the synaptic depression effected by (1S,3S)‐ACPD and l‐CCG‐I was apparently competitive in each case but of varying effectiveness, with apparent KD values for the interaction between MCCG and the receptors activated by the two depressants calculated as 103 and 259 μm, respectively. MCCG also antagonized the presynaptic depression produced by (1S,3R)‐ACPD.
Neither MAP4 nor MCCG (200–500 μm) significantly affected motoneuronal depolarizations produced by (1S,3R)‐ACPD. At the same concentrations the two antagonists produced only very weak and variable effects (slight antagonism or potentiation) on depolarizations produced by (S)‐α‐amino‐3‐hydroxy‐5‐methylisoxazole‐4‐propionic acid (AMPA) and N‐methyl‐d‐aspartate (NMDA).
It is concluded that MAP4 is a potent and selective antagonist for those excitatory amino acid (EAA) receptors on neonatal rat primary afferent terminals that are preferentially activated by l‐AP4, and that MCCG is a relatively selective antagonist for different presynaptic EAA receptors that are preferentially activated by (1S,3S)‐ACPD and (perhaps less selectively) by l‐CCG‐I. These receptors probably comprise two sub‐types of metabotropic glutamate receptors negatively linked to adenylyl cyclase activity.
Contribution of both nitric oxide and a change in membrane potential to acetylcholine‐induced relaxation in the rat small mesenteric artery
Authors: Waldron Gareth J. , Garland Christopher J. 
Published: July 2012

Acetylcholine stimulated repolarization and relaxation in isolated segments of rat small mesenteric artery (D100 = 325 ± 9 μm) in which the smooth muscle cells were depolarized and contracted by submaximal concentrations of noradrenaline (0.75–2.5 μm). There was no significant difference either in the time taken to initiate relaxation or hyperpolarization, or for these parameters to reach maximum in response to acetylcholine.
The nitric oxide synthase inhibitor, NG‐nitro l‐arginine methyl ester (l‐NAME, 100 μm) reduced the pD2 for acetylcholine‐induced relaxation from 7.5 to 7 and depressed the maximum relaxation from 89% to 68% in tissues stimulated with noradrenaline. The pD2 for smooth muscle repolarization in these experiments was also reduced (7.4 to 6.6) but the maximum change in membrane potential in response to acetylcholine was unaltered. The increase in potential now clearly preceded relaxation by 3.7 s (to initiation) and 4.7 s (to maximum).
In the presence of noradrenaline and a raised potassium concentration (25 mm), the repolarization to acetylcholine was markedly attenuated. Simultaneous tension measurements also revealed a marked reduction in the maximal relaxation to acetylcholine, but the pD2 was unchanged at 7.4.
The residual relaxation recorded in the absence of marked repolarization (in the presence of noradrenaline and 25 mm potassium) was abolished by the addition of 100 μm l‐NAME.
Nitric oxide gas in solution (0.2–2.2 μm; NOg) relaxed artery segments precontracted with noradrenaline. The magnitude of relaxation to NOg was not altered in the presence of noradrenaline and 25 mm potassium.
These data provide additional evidence that acetylcholine‐evoked endothelium‐dependent increases in membrane potential provide a major mechanism for smooth muscle relaxation in the mesenteric artery. They also show that voltage‐dependent and independent (initiated by NO) mechanisms can both contribute to relaxation, and suggest that NO may modulate the increase in membrane potential or the release of a hyperpolarizing factor.
Effects of cyclic GMP and analogues on neurogenic transmission in the rat tail artery
Authors: Ouedraogo Sylvin , Tschöpl Martin , Stoclet Jean‐Claude , Bucher Bernard 
Published: July 2012

The effects of membrane permeable analogues of guanosine 3′:5′‐cyclic monophosphate (cyclic GMP), and of the NO donor, 3‐morpholinosydnonimine‐N‐ethylcarbamide (SIN‐1) were investigated on [3H]‐noradrenaline release and neurogenic vasoconstriction in electrical field stimulated rat tail arteries.
Two 8‐substituted analogues of cyclic GMP (8‐bromoguanosine 3′:5′‐cyclic monophosphate; 8‐bromo‐cyclic GMP and 8‐(4‐chlorophenylthio)‐guanosine 3′:5′‐cyclic monophosphate; 8‐pCPT‐cyclic GMP) concentration‐dependently enhanced stimulation‐induced [3H]‐noradrenaline release. These prejunctional effects were antagonized by the cyclic AMP‐dependent protein kinase (PKA) inhibitor N‐[2‐((3‐(4‐bromophenyl)‐2‐propenyl)‐amino)‐ethyl]‐5 isoquinolinesulphonamide dihydrochloride (H‐89; 100 nm) but not by the cyclic GMP‐dependent protein kinase (PKG) inhibitors, Rp‐8‐bromoguanosine 3′:5′‐cyclic monophosphorothioate (Rp‐8‐bromo‐cyclic GMPS; 10 μm) or Rp‐8‐(4‐chlorophenylthio)‐guanosine 3′:5′‐cyclic monophosphorothioate (Rp‐8‐pCPT‐cyclic GMPS; 10 μm).
β‐Phenyl‐1,N2‐ethenoguanosine 3′:5′‐cyclic monophosphate (PET‐cyclic GMP) had no effect on stimulation‐induced [3H]‐noradrenaline release but concentration‐dependently decreased the stimulation‐induced vasoconstriction.
The two 8‐substituted cyclic GMP derivatives, PET‐cyclic GMP and SIN‐1, both decreased stimulation‐induced vasoconstriction. In addition, SIN‐1 relaxed rat tail arteries precontracted with phenylephrine (1 μm). The SIN‐1 concentration‐relaxation curve was shifted in parallel manner to the right by Rp‐8‐bromo‐cyclic GMPS (10 μm) and Rp‐8‐pCPT‐cyclic GMPS (10 μm) with no change in the maximum effect, showing that the relaxation was mediated by a cyclic GMP/PKG‐dependent mechanism.
It is concluded that PKA activation is involved in the noradrenaline release enhancing effect of the two 8‐substituted cyclic GMP analogues, whereas a cyclic GMP/PKG‐operated pathway accounts for the inhibitory effects of the cyclic GMP and its analogues on vascular smooth muscle contraction.