bluuebunny/crossref_metadata_2025_split huggingface dataset:
Neurotransmission in pig renal artery: the actions of angiotensin II and dopamine
Authors: Ferguson D.R. , Randall M.D. 
Published: July 2012

Electrical stimulation of pig renal arteries causes contractions which are potentiated in the presence of angiotensin II (5 × 10−8 m).
The potentiation is followed by a long‐lasting inhibitory phase which is mimicked by dopamine and 2‐amino‐6,7,dihydroxy‐1,2,3,4,‐tetrahydronaphthalene (ADTN), but blocked by sulpiride (5 × 10−8 m).
Release of noradrenaline from renal artery rings by 25 mM K+ was measured by h.p.l.c. and found to be increased by 5 × 10−8m angiotensin II. As this was done in the presence of 1 × 10−6 m desmethylimipramine it was concluded that the increase was due to increased neuronal release of noradrenaline, not inhibition of neuronal uptake.
The experiments indicate that dopamine is present in the artery wall and produces its effects through DA2‐receptors.
The classification of prostaglandin DP‐receptors in platelets and vasculature using BW A868C, a novel, selective and potent competitive antagonist
Authors: Giles Heather , Leff P. , Bolofo Mary L. , Kelly M.G. , Robertson A.D. 
Published: July 2012

BW A868C, a novel compound, behaved as a simple competitive antagonist in a human washed platelet aggregation assay. Anti‐aggregatory concentration‐effect curves to BW 245C were displaced in a parallel manner. The shifts accorded with a Schild plot slope of unity and a pKB of 9.26.
Inhibition of platelet aggregation by prostaglandin D2 (PGD2) was antagonized with a similar potency, as were the relaxation effects of BW 245C and PGD2 in the rabbit jugular vein. BW A868C can, therefore, be classified as a DP‐receptor antagonist.
Actions of BW A868C at other prostaglandin receptors (IP, EP1, EP2, TP and FP) were excluded at concentrations up to 1,000 times higher than the DP‐receptor affinity.
Analyses of BW 245C‐ and PGD2‐mediated effects were complicated by additional agonist receptor interactions which were revealed by BW A868C. In rabbit jugular vein a resistant phase of agonism was detectable, indicating that both agonists exerted effects through another receptor (possibly EP2). Also, PGD2, in addition to its anti‐aggregatory effect on platelets, demonstrated a pro‐aggregatory action in the presence of BW A868C.
The contractile effects of PGD2 in guinea‐pig tracheal strips were resistant to 10 μm BW A868C indicating that they were not mediated through DP‐receptors.
To our knowledge this is the first account of a well‐classified competitive antagonist at the DP‐receptor. Its potency and selectivity make it an important new tool in prostanoid receptor classification and identification.
The antagonism by BW A868C of PGD2 and BW245C activation of human platelet adenylate cyclase
Authors: Trist D.G. , Collins B.A. , Wood J. , Kelly M.G. , Robertson A.D. 
Published: July 2012

In glycerol‐lysed human platelets, prostaglandin D2 (PGD2) and the hydantoin BW245C both activate adenylate cyclase in a biphasic manner. These activations are qualitatively different from those of carbacyclin, iloprost and prostaglandin E2 (PGE2) whose E/[A] curves can be adequately described by rectangular hyperbolae.
Prostaglandin E1 (PGE1) had E/[A] curves of slope significantly lower than that expected for a rectangular hyperbola.
The selective PGD2 antagonist BW A868C shifts the first phase of the PGD2 and BW245C E/[A] curves but has no effect on the second phase.
Applying a two‐receptor model enables a pKB to be derived for BW A868C of 9.11.
BW A868C has no effect on carbacyclin, iloprost, prostacyclin, PGE1 and PGE2 at a concentration 1,000 fold that of its KB against PGD2 and BW245C.
These results indicate that PGD2 and BW245C are capable of activating adenylate cyclase in human platelets through the DP‐receptor and by another mechanism as yet uncharacterized.
Binding of [3H]‐muscimol to GABAA sites in the guinea‐pig urinary bladder: biochemical assay and autoradiography
Authors: Erdö S.L. , Mione M.C. , Amenta F. , Wolff J.R. 
Published: July 2012

The specific binding of [3H]‐muscimol, a γ‐aminobutyric acidA receptor (GABAA) agonist, to whole membranes of the guinea‐pig urinary bladder was examined. In addition, the distribution of specific muscimol binding sites within the bladder was visualized by autoradiography.
It was demonstrated that in a frozen‐thawed whole membrane preparation of the organ the specific binding of [3H]‐muscimol is reproducible, reversible and saturable.
Saturable binding was of a single component with an equilibrium dissociation constant (Kd) of 12 nM and a maximal density (Bmax) of about 80 fmol mg−1 protein.
In displacement experiments with several model compounds, [3H]‐muscimol binding sites showed the characteristics of a GABAA receptor site.
Autoradiographic experiments revealed uneven distribution of specifically bound [3H]‐muscimol in the bladder. The density of binding sites was high in clusters within the smooth muscle layers of the bladder fundus and of the urethra, while the apex and the neck were not specifically labelled.
The present findings show that GABAA type receptor sites in the guinea‐pig urinary bladder may be labelled by [3H]‐muscimol in a specific and reproducible manner. Moreover, the localization of these binding sites is consistent with the presence of GABAA receptors in only a sub‐population of vesical ganglia.
Characterization of 5‐HT receptors mediating contraction of canine and primate basilar artery by use of GR43175, a selective 5‐HT1‐like receptor agonist
Authors: Connor H.E. , Feniuk W. , Humphrey P.P.A. 
Published: July 2012

The aim of this study was to characterize the 5‐hydroxytryptamine (5‐HT) receptor which mediates contraction of canine and primate isolated basilar artery by use of a variety of selective 5‐HT agonists and antagonists.
5‐HT, α‐methyl 5‐HT and the selective 5‐HT1‐like receptor agonists, GR43175 and 5‐carboxamidotryptamine (5‐CT), each caused contraction of canine and primate basilar artery with a rank order of agonist potency of 5‐CT ≥ 5‐HT > GR43175 > α‐methyl 5‐HT. The 5‐HT1‐like receptor agonists, GR43175 and 5‐CT, produced maximum effects which were less than that produced by 5‐HT or α‐methyl 5‐HT.
In canine basilar artery, ketanserin (0.1–1 μm) caused some depression of the maximum effect of 5‐HT but produced little or no shift of the concentration‐effect curve. The contractile effects of GR43175 were not modified by ketanserin (1 μm), MDL72222 (1 μm) or cyanopindolol (1 μm). However, the effects of 5‐HT and GR43175 were specifically antagonized by methiothepin (0.1 μm); the mean agonist concentration‐ratios were 33 and 48 respectively.
In primate basilar artery, ketanserin (1 μm) again caused a small depression of the 5‐HT maximum response but had no effect against GR43175‐induced contractions. In contrast, methiothepin (0.1 μm) antagonized both 5‐HT‐ and GR43175‐induced contractions; the mean agonist concentration‐ratios were 35 for both.
These results demonstrate that a large component of the effects of 5‐HT in canine and primate basilar artery is produced by stimulation of a 5‐HT1‐like receptor. This receptor can be characterized by the high potency of the novel, selective agonist, GR43175, and susceptibility to blockade by methiothepin. However, there also appears to be a population of 5‐HT2 receptors in these pre‐pAarations which contribute to the contractile effects of 5‐HT.
Modulation of the GABAA receptor complex by steroids in slices of rat cuneate nucleus
Authors: Turner J.P. , Simmonds M.A. 
Published: July 2012

Several derivatives of pregnane and androstane that have hypnotic properties have been investigated for their ability to potentiate responses to the GABAA receptor agonist muscimol and to reduce the effect of the non‐competitive GABAA antagonist picrotoxin.
Depolarizing responses to muscimol in slices of rat cuneate nucleus were potentiated most potently by 3α‐hydroxy, 5α‐pregnane‐11,20‐dione (alphaxalone), which gave half‐maximal potentiation at 0.15 μm. The 5β isomer of alphaxalone had little effect up to 3 μm but in analogues lacking an 11‐keto substituent (pregnanolones), both the 5α‐ and 5β‐isomers potentiated with potencies 20 and 10 times lower, respectively, than that of alphaxalone. The a configuration of the 3‐hydroxy was essential in alphaxalone, the 3β‐hydroxy isomer being inactive. However, there was little difference between the potencies of the 3α‐ and 3β‐hydroxy configurations in the pregnanolones, although the maximal effects of the 30‐hydroxy isomers were rather lower than those of the 3α‐hydroxy isomers.
Reductions in the effect of picrotoxin as an antagonist of muscimol were caused most potently by the 3α‐hydroxy pregnanolones, with a ten fold reduction in picrotoxin potency at 1 μm concentrations of these steroids. Alphaxalone and its 5β‐isomer were about half as potent. Androsterone was about 10 times less potent and the 3β‐hydroxy pregnanolones were ineffective.
This difference in the structure‐activity relationships for steroidal potentiation of muscimol and reduction in picrotoxin antagonism of muscimol is reminiscent of an analogous distinction found with the barbiturates.
5‐HT1‐like receptors mediate 5‐hydroxytryptamine‐induced contraction of human isolated basilar artery
Authors: Parsons Andrew A. , Whalley Eric T. , Feniuk Wasyl , Connor Helen E. , Humphrey Patrick P.A. 
Published: July 2012

The 5‐hydroxytryptamine (5‐HT) receptor mediating contraction of endothelium denuded human basilar artery has been characterized in vitro.
5‐HT and a variety of 5‐HT agonists contracted human isolated basilar artery with a rank order of agonist potency, 5‐carboxamidotryptamine (5‐CT) > 5‐HT = methysergide > GR43175 > 8‐OHDPAT > 2‐methyl‐5‐HT. The maximum response produced by these agonists differed.
None of the agonists relaxed human basilar artery when tone was elevated with prostaglandin F2α, indeed further contraction was seen.
The contractile responses of human basilar artery to 5‐HT and the selective 5‐HT1‐like agonist GR43175 were highly reproducible whilst those to 5‐CT were not.
The contractile response to both 5‐HT and GR43175 was resistant to antagonism by ketanserin and GR38032, thus excluding activation of 5‐HT2 and 5‐HT3 receptors. The contractile action of 5‐HT and GR43175 was also not antagonized by (±)‐cyanopindolol, excluding the activation of receptors similar to 5‐HT1A and 5‐HT1B recognition sites identified in ligand binding studies.
In marked contrast, methiothepin was a potent antagonist of the contractile actions of both 5‐HT and GR43175, with a pA2 value of 8.8 against both agonists. Methiothepin (100 nm) had no effect on the contractile response to the thromboxane A2‐mimetic U46619.
We conclude that 5‐HT and GR43175 contract the human isolated basilar artery by activating the same receptor type. This receptor appears identical to the 5‐HT1‐like receptor causing contraction of the dog isolated saphenous vein and cerebral blood vessels from the dog and primate.
Involvement of 5‐HT2 receptors in the behaviours produced by intrathecal administration of selected 5‐HT agonists and the TRH analogue (CG 3509) to rats
Authors: Fone K.C.F. , Johnson J.V. , Bennett G.W. , Marsden C.A. 
Published: July 2012

The behavioural effects of the intrathecal injection of a thyrotrophin‐releasing hormone (TRH) analogue l‐orotyl‐l‐histidyl‐prolineamide (CG 3509, 0.5 μg), the non‐selective 5‐HT1 and 5‐HT2 receptor agonist 5‐methoxy‐N,N′‐dimethyltryptamine (5‐MeODMT, 2–100 μg) and the selective 5‐HT2 receptor agonist 2,5‐dimethoxy‐α,4‐dimethyl‐benzene ethamine hydrochloride (DOM, 2–25 μg) were compared with the response of systemically administered 5‐MeODMT (2 mg kg−1, i.p.) in rats, to establish whether the agonist‐induced behaviours were mediated by bulbospinal 5‐HT1 or 5‐HT2 receptors.
Intrathecal injection of 5‐MeODMT or DOM produced dose‐related back muscle contractions (a previously undocumented behaviour) and wet‐dog shakes which were both markedly attenuated by ritanserin pretreatment (1 mg kg−1, i.p.) indicating the involvement of 5‐HT2 receptors. In contrast, reciprocal forepaw treading, flat body posture and Straub‐tail were evoked by 5‐MeODMT but not by DOM indicating that these behaviours were not produced by 5‐HT2 receptor activation alone. However, as ritanserin pretreatment reduced the reciprocal forepaw treading induced by intrathecal 5‐MeODMT, this behaviour may be facilitated by 5‐HT2 receptor activation.
Intrathecal 5,7‐dihydroxytryptamine (5,7‐DHT, 2 × 150 μg) treatment decreased thoraco‐lumbar spinal cord 5‐HT (‐95%) and potentiated the back muscle contractions produced by intrathecal DOM injection without altering the wet‐dog shake behaviour. None of the components of the 5‐HT syndrome produced by 5‐MeODMT (2 mg kg−1, i.p.), with the exception of a small increase in wet‐dog shakes, was significantly altered by intrathecal 5,7‐DHT (which reduced thoraco‐lumbar spinal cord 5‐HT by 84%). Taken together these data suggest that the only 5‐HT agonist‐induced behaviour mediated by the activation of 5‐HT2 receptors located postsynaptic to bulbospinal 5‐hydroxytryptaminergic (5‐HTergic) neurones was back muscle contractions.
The wet‐dog shake and forepaw licking behaviors produced by intrathecal CG 3509 (0.5 μg) were attenuated when ritanserin was administered intrathecally 30 min before, but not when it was given at the same time as CG 3509 and neither behaviour was altered by intrathecal 5,7‐DHT. This suggests that bulbospinal 5‐HTergic neurones are not involved in the production of these TRH analogue‐induced behaviours and that the 5‐HT2 receptors which mediate these behaviours are not located in the spinal cord.
Estimation of affinities and efficacies for κ‐receptor agonists in guinea‐pig ileum
Authors: Leff P. , Dougall I.G. 
Published: July 2012

Ethylketocyclazocine (EKC) and U50,488H have been employed widely as κ‐receptor agonists in the study of opioid receptor systems. However, the quantification of their agonism in terms of affinities and relative efficacies has not been investigated.
In this study, operational model‐fitting was used to analyse the effects of irreversible receptor alkylation by β‐chlornaltrexamine (β‐CNA) on the /c‐receptor mediated effects of EKC and U50,488H in the isolated, coaxially stimulated ileum of the guinea‐pig.
EKC produced monophasic inhibitory concentration‐effect curves which were readily amenable to analysis. In contrast U50,488H produced biphasic curves characterized by a higher potency phase of agonism that was susceptible to antagonism by 16‐methylcyprenorphine (RX8008M) and a lower potency phase that was apparently non‐opioid in nature.
Analysis of the κ‐receptor‐mediated effects of both agonists indicated that EKC has fifteen fold higher affinity than U50,488H and that the two agonists possess similar intrinsic efficacies.
Effects of tetrodotoxin on relaxation of pig duodenal circular muscle induced by C‐terminal fragments of cholecystokinin
Authors: Kimura Ikuko , Kondoh Takashi , Kimura Masayasu 
Published: July 2012

The mechanisms by which cholecystokinin (CCK)‐C‐terminal peptides relax the isolated duodenal circular muscles of pigs were compared with mechanisms involving high potassium and electrical stimulation.
The relaxation (30%) induced by CCK‐8 0.263 nm was completely and non‐competitively blocked by tetrodotoxin (TTX) 0.313 μm, and was enhanced 2–2.5 times by mesaconitine 0.158 μm, tetraethylammonium (TEA) 0.597 mm and ouabain 0.136 μm.
The TTX sensitivity was greater for CCK‐8 and CCK‐6, than for CCK‐5 and CCK‐4.
High potassium (11.8–23.6 mm)‐induced, or electrically stimulated (0.3–30 Hz) relaxation showed similar characteristics except that they were not antagonized by the CCK antagonist P3‐I (168 μm).
Apamin (0.385–3.85 μm) enhanced relaxation induced by 10.6 mm K+, but did not affect relaxation induced by CCK‐8.
These results indicate that: (1) CCK‐8, K+, and transmural electrical stimulation relax duodenal circular muscles by releasing an endogenous inhibitory substance; (2) the latter two do not mediate the release of CCK; and (3) the mechanisms for relaxation by CCK‐4 are different from those of CCK‐8.
Vasoactive intestinal polypeptide and non‐adrenergic, non‐cholinergic inhibition in lower oesophageal sphincter of opossum
Authors: Daniel E.E. , Jager L.P. , Jury J. 
Published: July 2012

Field stimulation or vasoactive intestinal polypeptide (VIP) relaxed lower oesophageal sphincter (LOS) from North American opossum. Pretreatment with carbachol in Cl‐ion‐containing or Cl‐ion‐free Krebs solution or with 10−3 m 9‐aminoacridine abolished or markedly reduced relaxation due to VIP applied exogenously but not that elicited by field stimulation of non‐adrenergic, noncholinergic nerves.
Inhibitory junction potentials (7.5 ± 1.2 mV, n = 5) could be recorded in LOS strips with the sucrose gap technique. They lacked significant after‐depolarizations but were accompanied by decreased membrane resistance (61 ± 6%, n = 3). In these strips, VIP (10−6 m) produced small hyperpolarizations (2.1 ± 1.1 mV, n = 5) sometimes followed by membrane potential oscillations but no change in conductance.
Removal of external chloride depolarized the membranes (7.6 ± 1.7 mV) but did not prevent the hyperpolarization to VIP or the occurrence of inhibitory junction potentials. Restoration of external chloride repolarized the cells. It appears that an appreciable chloride conductance may be present in sphincter muscle cells and this may cause them to be more depolarized than non‐sphincter muscle.
We conclude that it is very unlikely that VIP is the inhibitory NANC neurotransmitter since it does not mimic the inhibitory junction potential.
Protein kinase C regulates the tonic but not the phasic component of contraction in guinea‐pig ileum
Authors: Sasaguri Toshiyuki , Watson Stephen P. 
Published: July 2012

We have investigated the effect of phorbol esters and the down‐regulation of protein kinase C on contraction of guinea‐pig ileum longitudinal smooth muscle to carbachol and high K+.
Phorbol 12,13‐dibutyrate (PDBu) enhanced the phasic component and inhibited or enhanced, respectively, the tonic component of contraction to carbachol and high K+. In contrast, 4α‐phorbol, which does not activate protein kinase C, had no effect on these responses.
Exposure to phorbol 12‐myristate 13‐acetate (PMA; 1 μm) for up to 8 h induced a time‐dependent loss of [3H]‐PDBu binding sites, consistent with the down‐regulation of protein kinase C by this treatment.
The phasic component of contraction to carbachol or high K+ was unaffected following the down‐regulation of protein kinase C. The tonic component of contraction to carbachol was markedly enhanced by this treatment while that to high K+ was partially suppressed.
These data suggest that although the activation of protein kinase C can lead to potentiation of the phasic component of contraction to carbachol or high K+, this appears to have little physiological significance since the response is not altered in tissues in which protein kinase C has been down‐regulated. On the other hand, protein kinase C may limit the tonic contraction to carbachol but potentiate that to high K+.
Relations between structure and nicotine‐like activity: X‐ray crystal structure analysis of (−)−cytisine and (−)−lobeline hydrochloride and a comparison with (−)−nicotine and other nicotine‐like compounds
Authors: Barlow R.B. , Johnson O. 
Published: July 2012

Although (−)−cytisine is a rigid structure, it occurs in the crystal in two distinct but very similar conformations in which the pyridone ring is tilted relative to the charged nitrogen atom at much the same angle as the pyridine ring is in (−)−nicotine hydrogen iodide. The carbonyl group in the pyridone ring of (−)−cytisine, however, is on the side of the ring opposite to the pyridine nitrogen in (−)−nicotine.
The pKa of (−)−lobeline HCl at 25°C is 8.6 (approx), indicating that (−)−lobeline is at least 90% in the protonated form at physiological pH (7.6). It is probably the phenyl 2‐keto‐ethyl part of (−)−lobeline, rather than the phenyl 2‐hydroxy‐ethyl part, which interacts with the receptor.
The combination within one molecule of a charged (‘onium’) nitrogen atom lying out of the plane of, and some distance (4.5–6.5 Å) from, an aromatic ring is common to many compounds with nicotine‐like activity (e.g. nicotine, cytisine, choline phenyl ether bromide, dimethyl‐phenyl‐piperazinium (DMPP) iodide, coryneine iodide and m‐hydroxyphenylpropyl trimethyl ammonium iodide). In some molecules the aromatic ring can be replaced by an unsaturated group, such as carbonyl (e.g. acetylcholine) or double‐bonds (e.g. anatoxin).
Activity at nicotinic receptors appears to involve interactions between the positively charged nitrogen atom and a negatively charged group, probably close to cysteine residues 192 and 193 in the receptor. It is suggested that rather than specific groups in the molecule also being involved, activity at nicotinic receptors depends on interactions between a flat part of the drug containing double‐bonds, or systems of double bonds, and a planar area in the receptor, possibly tyrosine or phenylalanine residues.
Properties of the cromakalim‐induced potassium conductance in smooth muscle cells isolated from the rabbit portal vein
Authors: Beech D.J. , Bolton T.B. 
Published: July 2012

Single smooth muscle cells were isolated freshly from the rabbit portal vein and membrane currents were recorded by the whole‐cell or excised patch configurations of the patch‐clamp technique at room temperature.
Cromakalim (Ckm, 10 μm) induced a potassium current (ICkm) that showed no pronounced voltage‐dependence and had low current noise.
This current, ICkm, was inhibited by (in order of potency): phencyclidine > quinidine > 4‐aminopyridine > tetraethylammonium ions (TEA). These drugs inhibited the delayed rectifier current, IdK, which is activated by depolarization of the cell, with the same order of potency.
Large conductance calcium‐activated potassium channels (LKCa) in isolated membrane patches were blocked by (in order of potency) quinidine > TEA ≅ phencyclidine. 4‐Aminopyridine was ineffective. A similar order of potency was found for block of spontaneous transient outward currents thought to represent bursts of openings of LKCa channels.
The low current noise of ICkm at positive potentials, and its susceptibility to inhibitors indicated that it was not carried by LKCa channels, and that it may be carried by channels which underlie IdK. It was observed that when ICkm was activated, IdK was reduced. However, in two experiments, ICkm was much more susceptible to glibenclamide than IdK; possible reasons for this are discussed.