bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effects of the δ‐opioid receptor antagonist naltrindole on antinociceptive responses to selective δ‐agonists in post‐weanling rats
Authors: Crook T.J. , Kitchen I. , Hill R.G. 
Published: July 2012

Antagonism, by the selective δ‐opioid receptor antagonist naltrindole, of the antinociceptive effects of [d‐Pen2, d‐Pen5] enkephalin (DPDPE), [d‐Ser2, Leu5, Thr6] enkephalin (DSLET) and d‐Ala2 deltorphin I (DELT I) has been studied in 25 day old rats.
Antinociception was measured by the 50°C tail immersion test following i.p. administration of agonists and/or antagonists.
Dose‐related antinociception was observed with DPDPE, DSLET and DELT I and ED75 doses were computed (0.66 mg kg−1, 0.65 mg kg−1, 0.032 mg kg−1 respectively) and used for antagonism studies.
Naltrindole (0.01 mg kg−1) significantly attenuated the antinociceptive effects of DPDPE and DSLET with 0.1 mg kg−1 producing complete reversal of the effects of the ED75 dose. In contrast, naltrindole at 0.01 and 0.1 mg kg−1 did not alter antinociceptive responses to DELT I. Naltrindole at 1 mg kg−1 significantly attenuated DELT I antinociception.
Naloxone (1 mg kg−1) produced equivalent degrees of antagonism of the antinociceptive effects of DPDPE, DSLET and DELT I. ICI 174,864 (1 mg kg−1) also antagonized antinociception with a differential degree of attenuation (DSLET > DPDPE > DELT I).6 Naltrindole (1 mg kg−1) had no effect on the antinociception induced by the selective μ‐agonist alfentanil (60 μgkg−1). Naltrindole, naloxone or ICI 174,864 had no effect on nociceptive latencies.7 The differential antagonism by naltrindole of the effects of three selective δ‐agonists suggests δ‐receptor heterogeneity. Further, the lower sensitivity of response to DELT I suggests that this agent may exert its antinociceptive effects at a different δ receptor subtype from DPDPE or DSLET.
Inhibition by phosphoramidon of the regional haemodynamic effects of proendothelin−2 and −3 in conscious rats
Authors: Gardiner S.M. , Kemp P.A. , Bennett T. 
Published: July 2012

Regional haemodynamic studies were carried out in conscious, Long Evans rats, chronically‐instrumented with pulsed Doppler flow probes and intravascular catheters.
In the first experiment, proendothelin‐2 and −3 (0.1 and 1.0 nmol kg−1, i.v. boluses) were found to cause dose‐dependent pressor, bradycardic, and renal and, particularly, mesenteric vasoconstrictor effects. The hindquarters showed an initial vasodilatation (which was not dose‐dependent) followed by a vasoconstriction (which was dose‐related). The pressor and renal and mesenteric vasoconstrictor effects of proendothelin‐3 were greater than those of proendothelin‐2.
In the second experiment, it was demonstrated that phosphoramidon (10 μmol kg−1, i.v. bolus) abolished the pressor, bradycardic, and hindquarters vasoconstrictor effects of proendothelin‐2 (1.0 nmol kg−1), and inhibited significantly the renal and mesenteric vasoconstrictor actions of this peptide. Phosphoramidon had similar effects on the responses to proendothelin‐3 (1.0 nmol kg−1), although a slight pressor effect of this peptide remained in the presence of phosphoramidon.
In the third experiment, it was found that phosphoramidon had no significant effect on the pressor or vasoconstrictor responses to endothelin‐2 or −3 (0.1 nmol kg−1).
Collectively, the results indicate that the haemodynamic effects of proendothelin‐2 and −3 in vivo in conscious rats are probably due to their conversion to endothelin‐2 and −3, respectively, by an enzyme(s) that is inhibited by phosphoramidon. There appears to be no obvious difference between proendothelin‐2, proendothelin‐3 and proendothelin‐1 in this respect.
Endothelium‐dependent and ‐independent effects of exogenous ATP, adenosine, GTP and guanosine on vascular tone and cyclic nucleotide accumulation of rat mesenteric artery
Authors: Vuorinen Pauli , Pörsti Ilkka , Metsä‐Ketelä Timo , Manninen Vesa , Vapaatalo Heikki , Laustiola Kai E. 
Published: July 2012

Summary
. The effects of exogenous guanosine 5′‐triphosphate (GTP) and guanosine on vascular tone and cyclic nucleotide accumulation of noradrenaline‐precontracted endothelium‐intact and endothelium‐denuded rat mesenteric artery rings were compared with the effects of the known purinoceptor agonists adenosine 5′‐triphosphate (ATP) and adenosine.
. GTP (10 μm−1 mm) dose‐dependently relaxed endothelium‐intact mesenteric artery rings by producing a rapid initial response followed by sustained relaxation resembling the relaxant response to acetylcholine. GTP also slightly relaxed endothelium‐denuded artery rings. The acetylcholine‐ and GTP‐induced relaxations of endothelium‐intact rings were attenuated by NG‐nitro l‐arginine methyl ester (l‐NAME, 330 μm) which attenuation was reversed with l‐arginine (1 mm).
. Guanosine (10 μm−1 mm) relaxed both endothelium‐intact and ‐denuded artery rings in a dose‐dependent manner. The relaxations were more pronounced in endothelium‐intact preparations and were only slightly attenuated by l‐NAME (330 μm).
. ATP (1 μm−1 mm) and adenosine (10 μm−1 mm) dose‐dependently relaxed endothelium‐intact and ‐denuded artery rings. The responses were more pronounced in endothelium‐intact vascular preparations.
. GTP (100 μm) and guanosine (100 μm) increased guanosine 3′:5′‐cyclic monophosphate (cyclic GMP) accumulation in both endothelium‐intact and ‐denuded artery rings corresponding to the relaxations observed. The concentrations of adenosine 3′:5′‐cyclic monophosphate (cyclic AMP) were not affected.
. ATP (100 μm) increased cyclic GMP concentration of endothelium‐intact artery rings. The concentrations of cyclic AMP were not affected by ATP (100 μm) and adenosine (100 μm) in endothelium‐intact and ‐denuded vascular preparations.
. These results provide evidence that exogenous GTP and guanosine relax precontracted endothelium‐intact and ‐denuded rat mesenteric artery rings by increasing cyclic GMP accumulation. The response to GTP of endothelium‐intact rings can mainly be explained by the release of endothelium‐derived relaxing factor (EDRF), but that of guanosine is only partly due to EDRF, and is a combination of endothelium‐dependent and ‐independent effects. The endothelium‐independent response of GTP and guanosine is a direct, unknown effect on smooth muscle and guanylate cyclase.
Decreased inhibition by gravidin of arachidonate release from transformed compared to nontransformed cells
Authors: Wilson Theresa , Ralph Raymond K. , Ganendren Ranjini 
Published: July 2012

Summary
. Gravidin (a phospholipase A2 inhibitor) reduced the release of arachidonic acid from human lymphocytes by 51% at 10−8 m.
. Under normal culture conditions, nanomolar gravidin caused a significant reduction in the release of free arachidonic acid from human lymphocytes or nontransformed fibroblasts but in transformed cells, nanomolar gravidin was ineffective.
. Inhibition of arachidonate release appeared to be related to rate of growth as inhibitory effects of gravidin on Jurkat cells and HL‐29 cells could be observed if the cells were cultured under conditions where DNA synthesis was low.
. The reported disparate effects of lipocortin on cell phospholipase A2 activity may be reconciled if DNA synthesis is investigated.
Characterization of the P1‐purinoceptors mediating contraction of the rat colon muscularis mucosae
Authors: Bailey S.J. , Hickman D. , Hourani S.M.O. 
Published: July 2012

Previous studies had shown that adenosine and adenine nucleotides including adenosine 5′‐triphosphate (ATP) caused contraction of the rat colon muscularis mucosae via P1 and P2Y‐purinoceptors respectively, and that the stable ATP analogue adenylyl 5′‐(β, γ‐methylene)diphosphonate (AMPPCP) had an unexpected direct action on the P1‐purinoceptors. The P1‐purinoceptors have now therefore been further characterized by use of the adenosine analogues 5′‐N‐ethylcarboxamidoadenosine (NECA) and N6‐cyclopropyladenosine (CPA) and the antagonist 1,3‐dipropyl‐8‐cyclopentylxanthine (DPCPX), which is selective for the A1 subtype. The P2‐purinoceptor antagonist suramin was also used, to investigate the selectivity of the P2 agonists.
The order of potency of P1 agonists for contraction was CPA > NECA > AMPPCP ≥ adenosine, and DPCPX (1 nm) caused greater than two fold shifts to the right of the log concentration‐response curves for each of these agonists, although the shifts were not always parallel and Schild analysis of the inhibition of the effect of adenosine resulted in a plot with a slope greater than unity. These results indicate that the P1‐purinoceptor mediating contraction is of the A1 subtype, as has been found in other tissues in which adenosine causes contraction.
The P2‐purinoceptor antagonist suramin (300 μm) had no effect on the responses to adenosine or to AMPPCP, but abolished contractions induced by the related stable ATP analogue adenosine 5′‐(α,β‐methylene)triphosphonate (AMPCPP). Contractions induced by ATP, which were not affected by DPCPX (10 nm) alone, were only partially inhibited by suramin (300 μm), revealing an A1 component to its action which could be blocked by DPCPX (10 nm).
In conclusion, these results show that the rat colon muscularis mucosae possesses contractile A1 receptors in addition to the previously characterized P2Y receptors, and confirms our finding that the stable ATP analogue, AMPPCP, has an unexpected direct action on these A1 receptors.
Evidence that nitric oxide does not mediate the hyperpolarization and relaxation to acetylcholine in the rat small mesenteric artery
Authors: Garland Christopher J. , McPherson Grant A. 
Published: July 2012

Acetylcholine caused a concentration‐dependent smooth muscle hyperpolarization and relaxation in rat small mesenteric arteries (diameter at 100 mmHg 250–450 mm) stimulated with noradrenaline (3 μm).
Nitric oxide (NO), generated from either NO‐gas or from acidified sodium nitrite, also induced smooth muscle hyperpolarization but only in the absence of active force. However, unlike the hyperpolarizations to acetylcholine, those to NO were abolished either by prior smooth muscle depolarization caused by noradrenaline, or by the K+ channel blocker, glibenclamide (3 μm).
Hyperpolarization and relaxation to acetylcholine were unaffected by prior exposure of the mesenteric artery to either the cyclo‐oxygenase inhibitor, indomethacin (10 μm), or the nitric oxide synthase inhibitor, NG‐nitro‐l‐arginine (l‐NNA, 100 μm).
Haemoglobin (1.5 μm), which binds and inactivates NO, blocked the hyperpolarizing and vasorelaxant response to NO, but did not alter either response to acetylcholine.
These data show that, in the rat small mesenteric artery, membrane hyperpolarizations to NO and acetylcholine are mediated by different mechanisms, and that the hyperpolarization induced by NO is not involved in the responses to acetylcholine. In addition, they provide evidence that the acetylcholine responses in this artery, which are endothelium‐dependent, are not mediated by the release of NO.
Effects of the P2‐purinoceptor antagonist, suramin, on human platelet aggregation induced by adenosine 5′‐diphosphate
Authors: Hourani S.M.O. , Hall D.A. , Nieman C.J. 
Published: July 2012

The effects of suramin, a trypanocidal drug which has been reported to be a P2‐purinoceptor antagonist on smooth muscle, were investigated in human platelets, where adenosine 5′‐diphosphate (ADP) induces aggregation by acting on a subtype of purinoceptors which has been called P2T.
Suramin (100 μm) had no inhibitory effect on ADP‐induced platelet aggregation in plasma, even after 40 min incubation in the presence of bacitracin, a peptidase inhibitor, and did not affect the ability of adenosine 5′‐triphosphate (ATP) (40 μm) to inhibit competitively ADP‐induced aggregation. This lack of effect of suramin on platelets in plasma is probably due to its extensive binding to plasma proteins.
In washed platelets, suramin (50–400 μm) acted as an apparently competitive antagonist, causing parallel shifts to the right of the log concentration‐response curve to ADP. No depression of the maximal response to ADP was observed at concentrations of suramin (50–150 μm) for which full log concentration‐response curves to ADP could be obtained, but the slope of the Schild plot was around 2, indicating that this antagonism was not simply competitive. The apparent pA2 value for suramin, taken from this Schild plot, was 4.6.
Suramin (200–400 μm) also noncompetitively inhibited aggregation induced by U46619 (a thromboxane receptor agonist) or by 5‐hydroxytryptamine in the presence of adrenaline (100 μm), and caused a depression of the maximal response to these agonists. This nonspecific effect of suramin may explain the high Schild plot slope obtained against ADP.
These results provide evidence that the ADP receptor on human platelets is indeed similar to the P2‐purinoceptors responding to adenine nucleotides on smooth muscle and other tissues, and show that suramin cannot distinguish between the proposed subtypes of the P2‐purinoceptors.
4‐Aminopyridine and low Ca2+ differentiate presynaptic inhibition mediated by neuropeptide Y, baclofen and 2‐chloroadenosine in rat hippocampal CA1 in vitro
Authors: Klapstein Gloria J. , Colmers William F. 
Published: July 2012

Presynaptic inhibition is mediated by several receptors at the stratum radiatum‐CA1 synapse of rat hippocampus. We tested whether the same mechanism is activated by neuropeptide Y (NPY), baclofen and 2‐chloroadenosine (2‐CA), reasoning that if the receptors all activated the same process, then they should all respond to indirect manipulations of transmitter release in the same manner.
The effects on presynaptic inhibition by the potassium channel blocker, 4‐aminopyridine (4‐AP) and low extracellular concentrations of Ca2+ in the presence of 4‐AP were compared using evoked population excitatory postsynaptic potentials (p.e.p.s.p.) responses in the rat hippocampal slice in vitro.
Log concentration‐effect relationships for the inhibition of excitatory transmission were constructed for all 3 drugs in normal saline, and in the presence of 30 and 100 μm 4‐AP. 4‐AP reduced the inhibition mediated by all three substances, 100 μm 4‐AP was only slightly more effective than 30 μm.
Lowering extracellular Ca2+ from 1.5 to 0.75 mm in the presence of 30 μm 4‐AP restored the presynaptic inhibition caused by all effective concentrations of NPY and baclofen. By contrast, inhibition caused by 2‐CA was not restored by lowering Ca2+, except at concentrations of 2‐CA greater than 10 μm.
The results are consistent with the hypothesis that presynaptic NPY Y2 and GABAB receptors both inhibit transmitter release by the inhibition of voltage‐dependent Ca2+ influx, but that the A1 adenosine receptor may activate a different presynaptic mechanism.
Interaction of pinaverium (a quaternary ammonium compound) with 1,4‐dihydropyridine binding sites in rat ileum smooth muscle
Authors: Feron Olivier , Wibo Maurice , Christen Marie‐Odile , Godfraind Théophile 
Published: July 2012

The interaction of pinaverium bromide, a quaternary ammonium compound, with binding sites for (L‐type) calcium channel blockers was investigated in rat ileum smooth muscle.
Pinaverium inhibited [3H]‐(+)‐PN200–110 ([3H]‐(+)‐isradipine) specific binding to tissue homogenates incompletely (Ki 0.38 μm; maximal inhibition 80%). In contrast, binding to single cell preparations (obtained by collagenase treatment) and to saponin‐treated homogenates was completely inhibited. These data are compatible with the view that, in untreated homogenates, 20% of [3H]‐(+)‐isradipine binding sites are not accessible to pinaverium because it is associated with sealed inside‐out vesicles.
Pinaverium bromide increased the apparent KD of [3H]‐(+)‐isradipine binding to saponin‐treated homogenates but did not significantly affect the Bmax value. Moreover, the dissociation rate constant of [3H]‐(+)‐isradipine binding was not changed by pinaverium. These data suggest that pinaverium interacts with the dihydropyridine binding site in a competitive manner. However, in contrast to uncharged dihydropyridine calcium antagonists, pinaverium inhibited, rather than stimulated, [3H]‐diltiazem binding to rat brain membranes (at 30–37°C).
Although Bmax values of [3H]‐(+)‐isradipine were similar in homogenates prepared from tissue and cells (collagenase‐treated), the KD value was significantly higher in cell homogenates (166 vs 95 pm). Similarly, the Ki value of pinaverium was higher in cell preparations than in tissue homogenates (0.77 vs 0.38 μm). Thus, collagenase can significantly modify the dihydropyridine recognition site.
The competitive interaction of pinaverium, a permanently charged drug, with [3H]‐(+)‐isradipine bound to intact cells and its absence of interaction with [3H]‐(+)‐isradipine bound to sealed inside‐out vesicles imply that the dihydropyridine receptor lies near the external surface of the plasma membrane.
Effects of peptidase inhibition on angiotensin receptor agonist and antagonist potency in rabbit isolated thoracic aorta
Authors: Robertson Mark J. , Cunoosamy Mootoosamy P. , Clark Kenneth L. 
Published: July 2012

Experiments were performed with peptidase inhibitors on rabbit aortic strip preparations, to determine whether endogenous peptidase activity can influence the potency estimates for angiotensin receptor agonists and antagonists in this tissue.
Angiotensin II (A II) and angiotensin III (A III) both induced concentration‐related contractions of rabbit aortic strip preparations. A III was approximately 38 fold less potent than A II, and the gradient of the A III concentration‐response curve (1.00 ±0.04) was significantly more shallow than that (1.76 ± 0.05) of the A II curve.
Neither the aminopeptidase‐A and ‐M inhibitor, amastatin, nor the aminopeptidase‐B and ‐M inhibitor, bestatin, affected the potency of, or the maximum response to, A II. In contrast, the potency of A III was increased by both amastatin and bestatin. Amastatin had the most marked effect and at 10 μm caused approximately a 12 fold increase in the potency of A III (EC50 values, 102 nm and 8.6 nm in the absence and presence of amastatin, respectively), and also significantly steepened the gradient of the A III concentration‐response curve. Amastatin did not affect the position or shape of the concentration‐response curve to the α1‐adrenoceptor agonist, phenylephrine. Finally, the carboxypeptidase‐N inhibitor, d‐l‐mercaptomethyl‐3‐guanidine‐ethylpropanoic acid (MERGETPA) did not change the position or shape of the concentration‐response curves to either A II or A III.
In the presence of amastatin, the potency of the peptide angiotensin receptor antagonist, Ile7‐A III (100 nm − 1μm), was increased approximately 13 fold (pA2, with A II as the agonist, 7.0 ± 0.1 and 8.1 ± 0.1, in the absence and presence of amastatin, respectively). However, the potency of the non‐peptide angiotensin receptor antagonist, DuP 753 (30–300 nm), was little affected by amastatin (pA2, 8.2 ± 0.1 and 8.1 ± 0.1 in the absence and presence of amastatin, respectively).
The results of this study suggest that endogenous aminopeptidase activity in the rabbit thoracic aorta can profoundly affect estimates of the potency of peptide angiotensin receptor agonists and antagonists. A suitable aminopeptidase inhibitor should therefore be included in studies, using this tissue, which aim to classify angiotensin receptor subtype(s) based on the rank order of peptide angiotensin receptor agonist and/or antagonist potencies.
Actions of arginine polyamine on voltage and ligand‐activated whole cell currents recorded from cultured neurones
Authors: Scott Roderick H. , Sweeney Marva I. , Kobrinsky Evgeny M. , Pearson Hugh A. , Timms Graham H. , Pullar Ian A. , Wedley Susan , Dolphin Annette C. 
Published: July 2012

Toxins from invertebrates have proved useful tools for investigation of the properties of ion channels. In this study we describe the actions of arginine polyamine which is believed to be a close analogue of FTX, a polyamine isolated from the American funnel web spider, Agelenopsis aperta.
Voltage‐activated Ca2+ currents and Ca2+‐dependent Cl− currents recorded from rat cultured dorsal root ganglion neurones were reversibly inhibited by arginine polyamine (AP; 0.001 to 100 μm). Low voltage‐activated T‐type Ca2+ currents were significantly more sensitive to AP than high voltage‐activated Ca2+ currents. The IC50 values for the actions of AP on low and high voltage‐activated Ca2+ currents were 10 nm and 3 μm respectively. AP was equally effective in inhibiting high voltage‐activated currents carried by Ba2+, Sr2+ or Ca2+. However, AP‐induced inhibition of Ca2+ currents was attenuated by increasing the extracellular Ca2+ concentration from 2 mm to 10 mm.
The actions of AP on a Ca2+‐independent K+ current were more complex, 1 μm AP enhanced this current but 10 μm AP had a dual action, initially enhancing but then inhibiting the K+ current.
γ‐Aminobutyric acid‐activated Cl− currents were also reversibly inhibited by 1 to 10 μm AP. In contrast N‐methyl‐d‐aspartate currents recorded from rat cultured cerebellar neurones were greatly enhanced by 10 μm AP.
We conclude that at a concentration of 10 nm, AP is a selective inhibitor of low threshold T‐type voltage‐activated Ca2+ currents. However, at higher concentrations 1–10 μm AP interacts with ion channels or other membrane constituents to produce a variety of actions on both voltage and ligand gated ion channels.
Vasoconstriction of guinea‐pig submucosal arterioles following sympathetic nerve stimulation is mediated by the release of ATP
Authors: Evans R.J. , Surprenant A. 
Published: July 2012

The nature of the transmitter mediating vasoconstriction of guinea‐pig submucosal arterioles following sympathetic nerve stimulation was studied.
Prazosin (0.1 μm) abolished the response to exogenously applied phenylephrine (1 μm) but had no effect on constrictions of submucosal arterioles evoked by nerve stimulation (100 pulses at 10 Hz).
Vasoconstrictions and excitatory junction potentials elicited by nerve stimulation were potentiated by idazoxan (0.1 μm).
Following reserpine treatment, catecholamine fluorescence was absent in submucosal arterioles but nerve‐evoked vasoconstrictions were unaltered.
Vasoconstrictions and excitatory junction potentials recorded in response to sympathetic nerve stimulation, as well as constrictions evoked by exogenously applied ATP (3 μm), were abolished by the P2‐purinoceptor antagonist, suramin (100 μm). Suramin had no effect on the vasoconstriction in response to noradrenaline (3 μm), or the nicotinic excitatory postsynaptic potentials (e.p.s.ps) and noradrenergic inhibitory postsynaptic potentials (i.p.s.ps) recorded from submucosal neurones.
We conclude that postjunctional responses of submucosal arterioles following sympathetic nerve stimulation are mediated solely through the activation of P2X‐purinoceptors by ATP or a related purine nucelotide. The function of neurally released noradrenaline is to act through prejunctional α2‐adrenoceptors to depress transmitter release.