bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effect of selective agonists and antagonists on atrial adenosine receptors and their interaction with Bay K 8644 and [3H]‐nitrendipine
Authors: Borea Pier Andrea , Caparrotta Laura , de Biasi Mariella , Fassina Giuliana , Froldi Guglielmina , Pandolfo Luisa , Ragazzi Eugenio 
Published: July 2012

(−)‐N6‐phenylisopropyladenosine (R‐PIA) and N6‐cyclohexyladenosine (CHA), highly selective agonists at A1‐adenosine receptors, 5′‐N‐ethyl‐carboxamidoadenosine (NECA), a non‐selective agonist at A1 and A2 receptors, and 2‐phenylaminoadenosine (CV‐1808), a selective A2 agonist, were compared in spontaneously beating and electrically driven atria. R‐PIA, CHA and NECA inhibited contraction in both preparations. CV‐1808 was not effective up to 500 nM.
1,3‐Dipropyl‐8‐cyclopentylxanthine (DPCPX), a new selective A1 receptor antagonist, competitively inhibited the effects of the adenosine agonists, at low concentrations (IC50 < 1 nm).
CHA and NECA were able to inhibit the positive inotropic effect of Bay K 8644 both in spontaneously beating and in electrically driven atria.
R‐PIA, CHA and NECA (agonists), 8‐phenyltheophylline (PT) and DPCPX (antagonists), failed to influence [3H]‐nitrendipine binding on microsomal membranes from guinea‐pig atria and ventricles in a range of concentrations from 1 nM to 100 μm.
The data support the existence of A1 receptors in atrial tissue. No evidence for a direct interaction between adenosine analogues and Bay K 8644 was found at the level of slow calcium channels. Adenosine analogues appear to antagonize the effects of Bay K 8644 indirectly by activation of A1 receptors.
Inhibitory effect of a selective thromboxane A2receptor antagonist, EP 092, on platelet aggregation in whole bloodex vivoandin vivo
Authors: Booth R.F.G. , Honey A.C. , Lad N. , Tuffin D.P. , Wade P.J. 
Published: July 2012

The inhibitory effect of a selective prostaglandin H2(PGH2)/thromboxane A2receptor antagonist, EP 092, on platelet aggregatory responses in whole bloodex vivo(guinea‐pig: Rhesus monkey) and intravascular aggregationin vivo(rabbit) has been investigated.Collagen (0.1–10.0 μgml−1) caused a concentration‐dependent decrease in single platelet count in samples of both guinea‐pig and Rhesus monkey citrated whole blood incubatedex vivo. EP 092 administered to guinea‐pigs by intravenous (0.1–3.0 mg kg−1) or oral (1.0–10.0 mg kg−1) routes significantly inhibited the platelet responses to collagen (ED50values 1.3 ± 0.2 and 1.4 ± 0.2 mg kg−1respectively). Similar potency against collagen‐induced whole blood aggregation was observed in Rhesus monkey blood samples following EP 092 given orally (ED500.9 ± 0.3 mg kg−1).The duration of action of EP 092 against collagen aggregatory responsesex vivoin both guinea‐pigs and Rhesus monkeys was between 3 and 6h following oral administration at 3.0 mg kg−1.The inhibitory activity demonstrated by EP 092 against collagen‐induced aggregation of Rhesus monkey whole bloodex vivowas not accompanied by any significant reduction in thromboxane A2formation except at the highest dose tested (10 mg kg−1).The intravascular aggregatory response induced by collagen or thrombin in the anaesthetized rabbit was significantly inhibited by an intravenous infusion of EP 092 (10 mg kg−1). EP 092 appeared less potent and its effect was of shorter duration in this preparation compared with its inhibitory effect onex vivoaggregation, being evident immediately after infusion of drug but not after a further 30 min.It is concluded that collagen‐induced platelet aggregatory responses in guinea‐pig and Rhesus monkey whole bloodex vivoand rabbitin vivoexhibit a thromboxane‐dependent component which can be inhibited in a dose‐related fashion by pretreatment with the thromboxane antagonist EP 092. In the rabbit, moreover, the data support the possibility of a role for thromboxane in the intravascular aggregatory response to thrombin.
Affinity of muscarinic receptor antagonists for three putative muscarinic receptor binding sites
Authors: Delmendo Ronald E. , Michel Anton D. , Whiting Roger L. 
Published: July 2012

A range of muscarinic receptor antagonists were examined for affinity at the M1 muscarinic binding site, present in rat cerebrocortical membranes and the M2 muscarinic binding sites of rat cardiac and submaxillary gland membranes.
The results obtained were consistent with the presence of three classes of muscarinic binding site.
Both the M1 binding site, labelled by [3H]‐pirenzepine ([3H]‐Pir) in rat cerebrocortical membranes, and the M2 gland binding site, labelled by [3H]‐N‐methyl scopolamine ([3H]‐NMS) in rat submaxillary gland membranes, displayed higher affinity for pirenzepine, dicyclomine, 4‐diphenylacetoxy‐N‐methylpiperidine methiodide (4‐DAMP) and cyclohexylphenyl (2‐piperidinoethyl) silanol (CPPS) than did the M2 binding sites of cardiac membranes labelled by [3H]‐NMS.
The M2 cardiac sites displayed higher affinity for methoctramine, himbacine and AF‐DX 116 than did either the M1 binding site of cerebrocortical membranes or the M2 gland binding site present in rat submaxillary gland membranes.
The M1 and M2 gland binding sites could only be distinguished by considering the absolute affinity of compounds for these two sites. Thus, all compounds, with the exception of 4‐DAMP, displayed between a 2 and 8 fold higher affinity for the M1 than for the M2 gland binding site. There were no antagonists with higher M2 gland than M1 affinity.
Pharmacological characterization of postjunctional α‐adrenoceptors in cerebral arteries from the sheep
Authors: Gaw A.J. , Wadsworth R.M. 
Published: July 2012

The responsiveness to noradrenaline was characterized in cerebral arteries from the sheep, since this species was large enough to permit a comparison of arteries from different parts of the cerebral vasculature.
Noradrenaline caused contraction of the basilar artery, middle cerebral artery and small pial arteries by stimulation of α1‐adrenoceptors.
The maximum contraction to noradrenaline was small in the basilar artery (28% of the 5‐hydroxytryptamine (5‐HT) maximum) but larger in the middle cerebral artery (78% of the 5‐HT maximum) and pial artery (92% of the 5‐HT maximum) of the sheep.
Cocaine (10 μm) potentiated noradrenaline‐induced contractions in the sheep middle cerebral artery but not in the sheep basilar artery.
The noradrenaline contraction, relative to the 5‐HT contraction, was not affected by removal of the endothelium in either the sheep basilar or middle cerebral artery.
The results showed a variation within the sheep cerebral vasculature in the response to noradrenaline which cannot be explained by regional differences in α‐adrenoceptor subtypes, noradrenaline uptake mechanisms or endothelial function.
Effects of receptor‐selective neurokinin agonists and a neurokinin antagonist on the electrical activity of spinal cord neurones in culture
Authors: Wienrich M. , Reuss K. , Harting J. 
Published: July 2012

Rat spinal cord neurones grown in tissue culture were used to examine the electrophysiological effects of the neurokin in (NK)‐selective agonists (pGlu6, Pro9) substance P(6–11) (septide; NK1, 10−6 m.) and (pGlu5, MePhe8, MeGly9)SP(1–7) (DiMe‐C7; NK3, 10−6 m.). In addition, the effect of the neurokinin antagonist (D‐Arg1, D‐Pro2, D‐Trp7,9, Leu11)SP (10−5 m.) on the neurokinin‐evoked responses was investigated.
Neurokinin‐evoked responses consisted of an increase in neuronal activity with or without long‐lasting (mean: 50s) depolarizations of the membrane potential of up to 25mV. The latter also occurred in the presence of tetrodotoxin (10−7 m.) (direct response).
In a number of spinal cord neurones (n = 17) only septide induced a membrane depolarization while DiMe‐C7 elicited no response. On the other hand, in 2 neurones a response was exclusively evoked by DiMe‐C7.
The neurokinin antagonist (D‐Arg1, D‐Pro2, D‐Trp7,9, Leu11)SP had no effect of its own but blocked the septide‐ and DiMe‐C7‐induced depolarizations. It had no effect on the glutamate (10−5 m.)‐evoked depolarization.
It is concluded that by the use of neurokinin receptor‐selective agonists, subpopulations of spinal cord neurones in primary dissociated cell culture can be differentiated which express the NK1 or the NK3 receptor. Cells expressing only the NK1 receptor outnumber those expressing only the NK3 receptor subtype. Both receptors can be blocked by the neurokinin antagonist (D‐Arg1, D‐Pro2, D‐Trp7,9, Leu11)SP.
Effects of hypoxia, elevated K+ and acidosis on the potency of verapamil, diltiazem and nifedipine in the guinea‐pig isolated papillary muscle
Authors: Robertson M.J. , Lumley P. 
Published: July 2012

The effects of the structurally diverse calcium channel blockers verapamil, nifedipine and diltiazem were investigated on the force of contraction of guinea‐pig, electrically stimulated papillary muscles in vitro.
Calcium channel blocking potency was assessed either as a direct negative inotropic effect or as the ability of the drugs to antagonise the positive inotropic effects of added calcium (Ca2+). By either method, the rank order of potency was found to be nifedipine > verapamil > diltiazem.
Various factors which mimic some of the consequences of acute ischaemia in vivo, namely low pH, hypoxia and elevated K+, in combination, but not singly, enhanced the negative inotropic potency of verapamil and to lesser extent that of diltiazem, but not that of nifedipine.
Whilst the various interventions, especially in combination, produced a profound negative inotropic effect themselves, this was not responsible per se for the potentiation of the negative inotropic effects of verapamil and diltiazem, since the negative inotropic effects of nifedipine and dinitrophenol were not potentiated under the ‘ischaemic’ conditions.
By use of antagonism of the positive inotropic action of exogenous Ca2+ as an alternative measure of potency, the differential influence of ‘ischaemia’ on calcium channel blocker potency was confirmed. The effect of verapamil was potentiated some 9 fold, that of diltiazem about 2 fold, and that of nifedipine was unchanged.
The differential effect of ‘ischaemia’ on the potencies of the calcium channel blockers was unexpected. Verapamil (but not nifedipine) is thought to bind to the calcium channel at a specific site not easily accessible from the extracellular space. ‘Ischaemic’ conditions may cause membranal perturbations which allow verapamil easier access to its binding site thus increasing its negative inotropic potency.
Ryanodine reveals multiple contractile and relaxant mechanisms in vascular smooth muscle: simultaneous measurements of mechanical activity and of cytoplasmic free Ca2+ level with fura‐2
Authors: Hisayama Tetsuhiro , Takayanagi Issei , Okamoto Yu 
Published: July 2012

The effects of ryanodine on changes in cytoplasmic Ca2+ level ([Ca2+]i) and muscle tension induced by maximum concentrations of phenylephrine (Phe; 1μm), prostaglandin F2α (PGF2α, 10 μm), caffeine (Caf, 30 mm) and isoprenaline (Iso, 1 μm) were examined in rat aortic strips using fura‐2.
In normal media, Phe and PGF2α produced a phasic contraction, followed by a tonic one. Caf elicited only a transient contraction. When the preparation was treated with 10 μm ryanodine, an increase in [Ca2+]i was induced accompanied by a nicardipine (1 μm)‐resistant contraction which was [Ca2+]o‐dependent.
In Ca2+‐free solution, the three stimulants elicited transient increases in [Ca2+]i. Transient contractions to Phe and Caf were accompanied by changes in [Ca2+]i. The transient increase in [Ca2+]i induced by PGF2α was not accompanied by a corresponding contraction.
Sustained contractions were induced by Phe and PGF2α in the absence of external Ca2+, while the increase in [Ca2+]i was reduced. A larger maximum contraction was induced by PGF2α than by Phe.
Ryanodine abolished both the Caf‐ and Phe‐induced [Ca2+]i transient increases and the corresponding contractions, but had no substantial effect on the PGF2α‐induced [Ca2+]i transient increase. Ryanodine had no influence on the sustained contractions induced by Phe and PGF2α.
Iso relaxed both sustained contractions almost completely, without any detectable change in [Ca2+]i. Treatment of the preparation with ryanodine had no effect on the concentration‐response curves for Iso in relaxing the 0.1 μm Phe‐ or 40 mm K+‐induced precontraction.
It is suggested that Phe and Caf mobilize Ca2+ from a ryanodine‐sensitive Ca2+ store and that PGF2α releases Ca2+ from a ryanodine‐insensitive Ca2+ store. The former contributes to the transient contraction through a Ca2+‐dependent process, while the latter seems not to be directly associated with the contraction. The sustained contraction under Ca2+‐free conditions might involve a Ca2+‐independent process or a change in the sensitivity of the contractile filaments to Ca2+.
In addition to lowering cytoplasmic Ca2+ concentration, it is suggested that Iso counteracts the apparently Ca2+‐independent process. The ryanodine‐sensitive Ca2+ store plays no substantial role in active relaxation by Iso, although it does play a major role in the maintenance of cytoplasmic Ca2+ in a quiescent muscle.
Pharmacological profile of a tachykinin antagonist, spantide, as examined on rat spinal motoneurones
Authors: Yanagisawa Mitsuhiko , Otsuka Masanori 
Published: July 2012

The pharmacological profile of a tachykinin antagonist, [d‐Arg1, d‐Trp7,9, Leu11] substance P (spantide), was studied on motoneurones of the isolated spinal cord of the newborn rat. For this purpose, potentials were recorded from a lumbar ventral root extracellularly and drugs were bath‐applied in the presence of tetrodotoxin (TTX).
Neurokinin A (NKA), a NK2‐receptor selective agonist, induced concentration‐dependent depolarizations, which were antagonized by spantide. Analyses of concentration‐response curves suggested a competitive type antagonism with a pA2 of 6.5.
Depolarizations induced by acetyl‐Arg6‐septide, a NK1‐receptor selective agonist, were also antagonized by spantide with a pA2 of 6.5.
Spantide (0.5–16 μm) had no depolarizing action on the ventral root in the presence of TTX.
Spantide antagonized the depolarizing action of substance P (SP) when SP was applied at low concentrations (0.1–0.3 μm) or by short duration pulses in artificial cerebrospinal fluid containing TTX, but much higher concentrations of spantide (4–10 μm) were needed to exert an antagonistic action against SP than against acetyl‐Arg6‐septide or NKA.
Thyrotrophin‐releasing hormone, l‐glutamate, GABA, and noradrenaline, also induced depolarizations of the ventral root in the presence of TTX but the responses to these agonists were not depressed by spantide (16 μm).
These results suggest that there is a subtype of tachykinin receptors on neonatal rat spinal motoneurones to which NKA, acetyl‐Arg6‐septide and spantide bind competitively with high affinity. The present results also suggest the existence on rat motoneurones of another class or other classes of tachykinin receptors that are less sensitive to the antagonistic action of spantide.
Evidence that central 5‐HT1A‐receptors play a role in the von Bezold‐Jarisch reflex in the rat
Authors: Bogle Richard G. , Pires Jose G.P. , Ramage Andrew G. 
Published: July 2012

The effects of intracisternal (i.c.) application of putative 5‐hydroxytryptamine (5‐HT)1Aantagonists on the reflex bradycardia evoked by injection of phenylbiguanide (i.v.) were investigated in anaesthetized, atenolol‐pretreated rats.Intracisternal application of spiperone (100 μg kg−1) reversibly attenuated the reflex bradycardia whilst the same dose given i.v. had no effect. The bradycardia was also attenuated by i.e. methiothepin (200 μg kg−1), (±)‐pindolol (100 μg kg−1) and buspirone (200 μ kg−1) but was not attenuated by antagonists selective for α1‐adrenoceptors (alfuzosin; 100 μg kg−1), 5‐HT2‐receptors (BW 501C67; 100 μg kg−1) or dopamine D2‐receptors ((−)−sulpiride; 100 μg kg−1) given i.e.It is concluded that the 5‐HT1A‐receptor antagonist action of intracisternally applied spiperone, methiothepin, (±)‐pindolol and buspirone is responsible for the ability of these drugs to attenuate reversibly the excitation of cardiac vagal motoneurones caused by activation of the von Bezold‐Jarisch reflex.
Relationship between endothelin‐1 binding site densities and constrictor activities in human and animal airway smooth muscle
Authors: Henry Peter J. , Rigby Paul J. , Self Glenn J. , Preuss Janet M. , Goldie Roy G. 
Published: July 2012

Endothelin‐1 (ET‐1) binding site densities and constrictor activities were compared in airway smooth muscle preparations of human, guinea‐pig, rat and mouse.
The mean contractile response to 0.3 μm ET‐1 (measured as the % maximum response to 10 μm carbachol, % Cmax ± s.e.mean) and the mean concentration of ET‐1 producing 30% (95% confidence limits) were respectively; 85.9 ± 5.4% and 3.4nm (2.4–5.0) for mouse trachea (n = 11), 88.8 ± 4.7% and 18.2 nm (11.2–25.2) for rat trachea (n = 6), 71.0 ± 7.1% and 35.2 nm (5.4–231) for human bronchus (n = 3), and 32.3 ± 3.0% and 241 nm (125–460) for guinea‐pig trachea (n = 6).
Light microscopic autoradiography revealed specific [125I]‐ET‐1 binding sites localized to the smooth muscle band, with very low levels of binding associated with cartilage, submucosal and epithelial cells.
Quantitative autoradiographic analyses of the concentration‐dependence of specific [125I]‐ET‐1 binding (0.1–2nm) to smooth muscle revealed similar dissociation constants but markedly different specific binding site densities for the various animal species. The order of densities of specific [125I]‐ET‐1 binding sites was rat trachea (69.0 ± 11.2 amol mm−2) > human bronchus (42.7 ± 17.5 amol mm−2) > mouse trachea (28.7 ± 2.6 amol mm−2) > guinea‐pig trachea (8.3 ± 1.8 amol mm−2).
A positive relationship between [125I]‐ET‐l binding site density and ET‐1 constrictor activity was observed in airway smooth muscle preparations from rat, human and guinea‐pig. The greater sensitivity of mouse trachea to the constrictor actions of ET‐1 was not dependent on the release of cyclo‐oxygenaseor epithelium‐derived constrictor substances, but may have been due to an inter‐species difference in the receptor‐effector system for ET‐1.
In vitro inhibition of intestinal motility by phenylethanolaminotetralines: evidence of atypical β‐adrenoceptors in rat colon
Authors: Bianchetti Alberto , Manara Luciano 
Published: July 2012

The new compounds phenylethanolaminotetralines (PEAT), unlike the reference β‐adrenoceptor agonists isoprenaline (Iso), ritodrine (Ri) and salbutamol (Sal), produced half‐maximal inhibition of spontaneous motility of rat isolated proximal colon at substantially lower concentrations (EC50 2.7–30 nm) than those inducing β2‐adrenoceptor‐mediated responses (relaxation of guinea‐pig isolated trachea and rat uterus) and had virtually no chronotropic action (EC50 > 3 × 10−5 m.) on the guinea‐pig isolated atrium (a β1‐adrenoceptor‐mediated response).
The nonselective β‐adrenoceptor antagonists alprenolol and propranolol prevented the inhibition of rat colon motility by the PEAT with low and different potencies (pA2 values around 7.5 and 6.5 respectively). Conversely alprenolol and propranolol had a higher and similar potency (pA2 values around 9.0) in preventing typical β1‐ or β2‐responses (increase in atrial frequency by Iso or tracheal relaxation by Ri or Sal).
The selective β‐adrenoceptor antagonists CGP 20712A (β1) and ICI 118,551 (β2) either alone or in combination, did not prevent rat colon motility inhibition by the representative PEAT SR 58611A, which was also fully resistant to α‐adrenoceptor, acetylcholine, dopamine, histamine, opioid and 5‐hydroxytryptamine antagonists.
These results indicate that the PEAT are a new class of β‐adrenoceptor agonists and suggest that their preferential intestinal action may be accounted for by selectivity for atypical β‐adrenoceptors, abundant in the rat colon and distinct from the currently recognized β1 and β2 subtypes.
γ‐Aminobutyric acid inhibition of histamine‐induced inositol phosphate formation in guinea‐pig cerebellum: comparison with guinea‐pig and rat cerebral cortex
Authors: Crawford Melissa L.A. , Carswell Heather , Young J.M. 
Published: July 2012

γ‐Aminobutyric acid (GABA), 2mm, inhibited basal accumulation of [3H]‐inositol monophosphate ([3H]‐IP1) in lithium‐treated slices of guinea‐pig cerebellum preincubated with [3H]‐inositol. In contrast, 2mm GABA stimulated the accumulation of [3H]‐IP1 in rat cerebral cortical slices over a 60 min incubation period, but had no significant effect in slices of guinea‐pig cerebral cortex. The estimated IC50 for the inhibitory action of GABA in guinea‐pig cerebellar slices was 0.52 ± 0.12 mm.
GABA inhibited histamine‐induced [3H]‐IP1 accumulation in guinea‐pig cerebellar slices in a noncompetitive manner. The best‐fit value for the maximum level of inhibition was 74 ± 6%. The estimated IC50 for GABA was 0.77 ± 0.15 mm and was not significantly different from the IC50 for inhibition of the basal accumulation of [3H]‐IP1. The response to histamine in guinea‐pig and rat cerebral cortical slices was also inhibited by 2 mm GABA.
In guinea‐pig cerebellar slices 2mm GABA potentiated histamine‐induced [3H]‐inositol bisphosphate ([3H]‐IP2) accumulation, whereas in both guinea‐pig and rat cerebral cortex the effect was inhibition.
Isoguvacine and muscimol, GABAA‐selective agonists, and (−)−baclofen, GABAB‐selective, had no significant effect on basal or histamine‐stimulated accumulation of [3H]‐IPs in guinea‐pig cerebellar slices. (−)−Baclofen had only a weak inhibitory effect on [3H]‐IP1 accumulation in guinea‐pig‐cerebral cortex (16 + 6% inhibition with 10 μm (−)−baclofen), whereas in rat cerebral cortex (−)−baclofen mimicked the inhibitory effect of GABA.
Nipecotic acid (1 mm) had qualitatively similar effects to those of 2mm GABA in guinea‐pig cerebellar slices.
The competitive GABA uptake inhibitors SK&F 89976‐A, SK&F 100330‐A and SK&F 100561‐A were potent histamine H1‐receptor antagonists, as indicated by the inhibition of [3H]‐mepyramine binding to homogenates of guinea‐pig cerebellum and cerebral cortex.
GABA (2mm) caused a small inhibition (12 ± 3%) of [3H]‐inositol incorporation into total inositol phospholipids in guinea‐pig cerebellar slices, as in rat cerebral cortical slices, whereas 0.2 mm histamine caused a small stimulation (15 ± 4%). In the presence of both GABA and histamine, [3H]‐inositol incorporation was unchanged from basal (101 ± 5%).
GABA also inhibited [3H]‐IP1 formation induced by endothelin‐1 in guinea‐pig cerebellar slices and increased, but not significantly, the amount of [3H]‐IP2 accumulated. This, taken with the inhibitory effect on basal and histamine‐stimulated accumulation, suggests that the action of GABA in guinea‐pig cerebellar slices may be non‐selective and may not be exerted through a specific GABA receptor.