bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effects of chain‐length and unsaturation on affinity and selectivity at muscarinic receptors
Authors: Barlow R.B. , Holdup D.W. , Harris Georgina , Veale M.A. , Williams Alex 
Published: July 2012

Lengthening the chain in diphenylacetylcholine decreases affinity for muscarinic cholinoceptors in guinea‐pig ileum. Diphenylacetoxypropyldimethylamine and its quaternary trimethylammonium salt are roughly equiactive: the dimethylamine and the piperidine have some selectivity for ileum compared with atria, but are not as active nor as selective as 4‐diphenylacetoxy‐N‐methylpiperidine (4‐DAMP) methobromide (MeBr). With the weaker diphenylacetoxybutyl compounds the base is more active than the quaternary salt.
The diphenylacetoxybutyl‐, cis‐butenyl and trans‐butenyl compounds have similar affinities. The quaternary salts are less active than the tertiary bases, but they are less selective than the butynyl analogues studied in earlier work.
1,1‐Diphenyl‐1‐hydroxy‐2,4‐hexadiynyl dimethylamine and its trimethylammonium salt are inactive in concentrations below 100 μm, as are the (+)‐camphor‐sulphonyl ester of 4‐hydroxy‐N‐methyl piperidine and its methiodide. The (±)‐phenylcyclopentylacetyl ester of 4‐hydroxy‐N‐methylpiperidine methobromide is more active than its cyclohexyl analogue and than 4‐DAMP MeBr but it is less selective than 4‐DAMP MeBr.
The high selectivity of p‐fluoro‐hexahydrosila‐diphenidol is confirmed but this compound has relatively low affinity (for ileum log K = 7.8).
The results indicate steric constraints to binding at muscarinic receptors which could be used to check molecular modelling of the receptor based on its known amino acid sequence. The group binding the charged nitrogen is probably at the mouth of a cavity which can accommodate two large rings (as in 4‐DAMP MeBr) but with a depth less than about 7 Å so that the rod‐like hexadiynes cannot fit. Differences between types of receptor may only involve small changes in geometry secondary to differences in amino acids not directly involved in binding and the production of selectivity depends upon finding substituents which interfere with binding more at one type of receptor than at another.
Subclassification of β‐adrenoceptors responsible for steroidogenesis in primary cultures of bovine adrenocortical zona fasciculata/reticularis cells
Authors: Lightly E.R.T. , Walker S.W. , Bird I.M. , Williams B.C. 
Published: July 2012

Forty eight hour primary cultures of purified bovine adrenocortical zona fasciculata/reticularis cells secreted hydrocortisone in response to stimulation with β‐adrenoceptor agonists. The observed order of potency was isoprenaline > noradrenaline > dobutamine > salbutamol > BRL37344.
Salbutamol acted as a partial agonist on these cells hence suggesting the presence of a β1‐adrenoceptor.
Schild analysis of the hydrocortisone response to isoprenaline showed that the selective β1‐antagonist practolol and the selective β2‐antagonist ICI118,551 gave pA2 values of 6.85 and 7.17, respectively. These values were in close agreement with corresponding pA2 values previously obtained for the β1‐adrenoceptor.
We conclude that β1‐adrenoceptors are responsible for mediating catecholamine‐stimulated hydrocortisone secretion from primary cultures of bovine zona fasciculata/reticularis cells.
The effects of anticholinesterases on the latencies of action potentials in mouse skeletal muscles
Authors: Kelly S.S. , Ferry C.B. , Bamforth J.P. 
Published: July 2012

The purpose of this investigation was to determine the long‐term effects of a single dose of persistent anticholinesterases on muscle action potentials evoked by nerve stimulation.
Action potentials (APs), elicited by stimulation of the phrenic nerve, were recorded intracellularly in muscle fibres of mouse diaphragm. The time between stimulus and AP was measured and the variability of this latency was calculated during trains of APs. At the beginning of trains of APs there was an increase in latency, and this delay was also measured.
Within 3 h of subcutaneous injection, a single dose (500 nmol kg−1) of the anticholinesterase, ecothiopate produced about 90% reduction in the acetylcholinesterase activity of homogenates of mouse diaphragm muscle, but five days after injection, this activity was not different from values in untreated animals. The initial delay of APs and the variability of latencies were increased four fold and two fold respectively, remained at these maxima from the 1st to the 5th day after ecothiopate, and returned to the values in untreated animals between 15 and 27 days after ecothiopate.
These effects of ecothiopate on AP latency were dose‐dependent and were also seen in extensor digitorum longus and soleus muscles.
Other anticholinesterases used were BOS (pinacolyl S‐(2‐trimethylaminoethyl)methylphosphonothioate), a quaternary compound, and diisopropyl fluorophosphate, a tertiary compound, which had effects similar to those of ecothiopate; the greater duration of the effects of this compound may be related to the greater duration of reduction in cholinesterase activity.
Ecothiopate had no effect on the delay or variability of latencies of endplate potentials which were recorded in cut‐fibre preparations 5 days later.
It is concluded that the effects of ecothiopate on the latencies of indirectly‐evoked muscle APs are postjunctional, may not be related to the degree of reduction in cholinesterase activity at the time of recording, and are not directly linked to necrosis.
Effects of neuropeptide Y and calcitonin gene‐related peptide on sheep coronary artery rings under oxygenated, hypoxic and simulated myocardial ischaemic conditions
Authors: Kwan Y.W. , Wadsworth R.M. , Kane K.A. 
Published: July 2012

The effects of calcitonin gene‐related peptide (CGRP) and neuropeptide Y (NPY) were examined on sheep circumflex (2–2.5 mm o.d.) coronary artery rings, with and without endothelium, under oxygenated, hypoxic and simulated ischaemic conditions. The interaction between the vasoconstrictor effects of NPY and the thromboxane mimetic, U46619, was also studied.
Ischaemia was simulated by modification of the composition of the physiological salt solution by increasing potassium and H+, including lactate and reducing glucose and Po2.
Hypoxia alone and simulated ischaemia increased the maximum vasodilatation produced by CGRP. CGRP (30 nm) abolished and markedly reduced the contraction that was induced by hypoxia and simulated ischaemia respectively.
Hypoxia increased and simulated ischaemia reduced the contractile response to NPY in endothelium intact rings. When the endothelium was removed, NPY caused a contraction under ischaemic conditions only. The hypoxic and ischaemic‐induced contractions were augmented by NPY (30 nm).
In the rings containing endothelium, NPY enhanced the contraction caused by U46619 during hypoxia only. In endothelium‐denuded preparations, NPY increased or partially restored the contraction caused by U46619.
These results show that the responsiveness of coronary artery rings isolated from sheep to either CGRP or NPY is modified by hypoxia or simulated myocardial ischaemia.
Effects of torbafylline, pentoxifylline and buflomedil on vascularisation and fibre type of rat skeletal muscles subjected to limited blood supply
Authors: Hudlická Olga , Price Susan 
Published: July 2012

Blood flow (measured by radio‐labelled microspheres), fibre composition and capillary/fibre ratio were estimated in rat fast twitch skeletal muscles (tibialis anterior and extensor digitorum longus) five weeks after unilateral ligation of the common iliac artery in animals treated with either saline, torbafylline, pentoxifylline or buflomedil.
The resting blood flow was lower in muscles with limited blood supply than in their contralateral controls; this difference became statistically insignificant after treatment. Capillary/fibre ratio was similar in all muscles with either intact or limited blood supply and did not change after administration of any of the drugs.
The percentage of glycolytic fibres was not changed by ligation, but it decreased significantly in animals treated with torbafylline. This may improve performance in muscles with limited blood supply.
Investigation of the selectivity of α, β‐methylene ATP in inhibiting vascular responses of the rat in vivo and in vitro
Authors: Dalziel H.H. , Gray G.A. , Drummond R.M. , Furman B.L. , Sneddon P. 
Published: July 2012

The proposal that α,β‐methylene adenosine 5′‐triphosphate (mATP) inhibits pressor responses in the pithed rat by selective desensitization of P2x‐purinoceptors was examined by comparing the selectivity of its inhibitory effect on vascular responses in vitro and in vivo.
In isolated ring preparations of rat femoral and tail artery, which had been denuded of endothelium, mATP markedly reduced the contractile response to exogenous ATP but had no effect on the response of the arteries to exogenous noradrenaline (NA).
In the pithed rat a substantial proportion of the pressor response to sympathetic nerve stimulation was resistant to α‐adrenoceptor blockade, suggesting a non‐adrenergic component to the sympathetic vasoconstriction.
In the pithed rat, repeated administration of desensitizing doses of mATP attenuated the pressor response to sympathetic nerve stimulation by approximately 80%, suggesting that a component of the sympathetic vasoconstriction is mediated by ATP acting on vascular P2x‐purinoceptors. However, the same mATP treatment also attenuated, to a similar degree, the pressor responses to intravenous NA, angiotensin II and vasopressin, indicating that the desensitization procedure was non‐selective.
These results demonstrate that while mATP can be used to desensitize selectively P2x‐purinoceptors in vitro, its attenuation of the sympathetic nerve‐mediated pressor response in vivo is non‐selective.
Rapid tolerance to the hypotensive effects of glyceryl trinitrate in the rat: prevention by N‐acetyl‐l‐ but not N‐acetyl‐d‐cysteine
Authors: Newman Christopher M. , Warren John B. , Taylor Graham W. , Boobis Alan R. , Davies Donald S. 
Published: July 2012

A new model of tolerance to the hypotensive effect of organic nitrates has been developed in the rat.
The fall in mean arterial pressure (MAP) in response to bolus doses of sodium nitroprusside (NP) (4 μg kg−1) and glyceryl trinitrate (GTN) (10 μg kg−1) was recorded both before and after a 60 min infusion of either 0.9% saline, NP (20 μg kg−1 min−1) or GTN (40 μg kg−1 min−1).
The hypotensive effects of NP or GTN were unchanged following saline infusion, but were reduced in both cases by approximately 40% following the infusion of NP.
Infusion of GTN for 60 min virtually abolished the hypotensive effect of a GTN bolus (i.e. nitrate tolerance), whilst the effect of a NP bolus was reduced only to a similar extent (30%) as after an infusion of NP. This latter effect is attributed to a degree of non‐specific cross‐tolerance between GTN and NP.
Co‐treatment of a group of rats with N‐acetyl‐l‐cysteine (l‐NAC) prevented the development of nitrate tolerance, confirming the role of thiols in this phenomenon, whereas N‐acetyl‐d‐cysteine (d‐NAC) did not.
The stereospecificity in the effect of NAC in preventing this specific tolerance to GTN suggests that the interaction between GTN and NAC and/or cysteine involves an enzyme‐dependent step.
NAC was unable to prevent the non‐specific cross‐tolerance to NP which followed infusion of GTN, suggesting that the mechanism does not directly involve NAC and/or cysteine.
Evidence for noradrenergic‐purinergic cotransmission in the hepatic artery of the rabbit
Authors: Brizzolara Antonia L. , Burnstock Geoffrey 
Published: July 2012

Transmural electrical field stimulation produced a transient contraction of the isolated hepatic artery of the rabbit that was frequency‐dependent up to 64 Hz. A contraction was rarely evoked at a stimulation frequency of less than 8 Hz and never at 4 Hz or less. All contractions were abolished in the presence of tetrodotoxin.
Neurogenic contractions were partially inhibited by prazosin. After desensitization of the P2X‐purinoceptor with α,β‐methylene ATP, contractions in response to electrical stimulation were significantly reduced at all frequencies tested (4–64 Hz). In most cases, contractions were abolished by a combination of both drugs.
In vessels treated with 6‐hydroxydopamine, no nerve‐mediated contractile responses were observed.
In arteries from reserpine‐treated rabbits, nerve stimulation evoked contractions that were resistant to prazosin. After desentization of the P2X‐purinoceptor with α,β‐methylene ATP, no neurogenic contractile response remained.
The tissue contracted to exogenously applied noradrenaline and α,β‐methylene ATP. There was an increase in sensitivity to noradrenaline in 6‐hydroxydopamine‐treated vessels compared with control vessels, but no difference in potency to α,β‐methylene ATP was detected. The potency of noradrenaline and α,β‐methylene ATP was not significantly affected by reserpine treatment.
In control tissues, fluorescence histochemistry demonstrated the presence of noradrenergic nerve fibres. Noradrenaline‐containing nerves were not observed in 6‐hydroxydopamine‐treated or reserpine‐treated vessels.
It is concluded that noradrenaline and ATP are cotransmitters in the sympathetic nerves supplying the hepatic artery of the rabbit. In contrast to other vessels, the hepatic artery requires a relatively high frequency of stimulation to evoke contractions and the purinergic component is not frequency‐dependent. The significance of this finding in terms of the physiological demands of blood flow to the liver are discussed.
Characterization of cholecystokinin octapeptide‐stimulated endogenous dopamine release from rat nucleus accumbens in vitro
Authors: Marshall F.H. , Barnes S. , Pinnock R.D. , Hughes J. 
Published: July 2012

The effect of cholecystokinin sulphated octapeptide (CCK8S) on endogenous dopamine release was examined in rat striatal and nucleus accumbens slices, by high performance liquid chromatography (h.p.l.c.) with electrochemical detection.
CCK8S was shown to increase dopamine release from slices of nucleus accumbens but not striatum in a dose‐dependent manner between 0.1 and 10 μm.
Pentagastrin was without effect on dopamine release at doses up to 10 μm.
The dopamine release produced in the presence of CCK8S was abolished by preincubation of the slice with 1.0 or 10.0 nm L‐364,718 (the CCKA‐selective antagonist) while 1 μm L‐365,260 (the CCKB‐selective antagonist) had no action.
These results suggest that the CCK8S‐evoked release of dopamine from the nucleus accumbens is mediated by a CCKA‐receptor.
Tolbutamide excites rat glucoreceptive ventromedial hypothallamic neurones by indirect inhibition of ATP‐K+ channels
Authors: Ashford M.L.J. , Boden P.R. , Treherne J.M. 
Published: July 2012

The sulphonylureas, tolbutamide (0.1–10 mm) and glibenclamide (0.1–100 μm) were shown not to inhibit ATP‐K+ channel currents when applied to inside‐out membrane patches excised from rat cultured cerebral cortex or freshly‐dispersed ventromedial hypothalmic nucleus (VMHN) neurones.
Saturable binding sites for [3H]‐glibenclamide, with similar affinity constants are present in rat cerebral cortex and hypothalamic membranes. The density of binding sites was lower in the hypothalamus than cortex.
Intracellular recordings from glucoreceptive VMHN neurones in hypothalamic slices were obtained. In the absence of glucose, tolbutamide (0.1 mm) depolarized these cells, increased membrane resistance and elicited action potentials.
Tolbutamide (0.1 mm) inhibited ATP‐K+ channel currents and induced action current activity in cell‐attached recordings from glucoreceptive VMHN neurones.
Glibenclamide (10–500 nm) had no effect per se on glucoreceptive VMHN neurones but did antagonize the actions of tolbutamide.
It is concluded that the hypothalamic (and perhaps cortical) sulphonylurea receptors are not directly coupled to ATP‐K+ channels.
Spinal effects of four injectable anaesthetics on nociceptive reflexes in rats: a comparison of electrophysiological and behavioural measurements
Authors: Hartell N.A. , Headley P.M. 
Published: July 2012

To assess the direct spinal contributions to the depression of reflexes caused by general anaesthetics, the intravenous potency of four injectable anaesthetics has been compared in two preparations: in decerebrate, spinalised rats, using a novel preparation requiring little surgical intervention, and in intact rats with chronically implanted i.v. cannulae.
Methohexitone (1–8 mg kg−1 i.v.), alphaxalone/alphadolone (0.5–8 mg kg−1 i.v.), alpha‐chloralose (20–80 mg kg−1 i.v.) and ketamine (0.5–16 mg kg−1 i.v.) all produced a dose‐dependent depression of single motor unit activity evoked by controlled noxious mechanical stimuli in decerebrate, spinalised animals.
The sedative and motor effects brought about by equivalent doses to those used in the electrophysiological experiments were assessed in intact rats. Methohexitone, alphaxalone/alphadolone and alpha‐chloralose all caused similar levels of behavioural sedation at the doses that caused depression of spinal reflexes. Ketamine required relatively much higher doses to cause sedation.
To determine whether background anaesthesia modulated the potency with which these compounds affected spinal reflex activity, depressant effects in decerebrate, unanaesthetized rats were compared with those in animals maintained under anaesthesia with either alpha‐chloralose or the steroid mixture of alphaxalone/alphadolone. The presence of either of these two agents as maintenance anaesthetics did not influence the effectiveness with which other compounds depressed nociceptive responses. However, additional doses of the maintenance anaesthetics were less effective than the same doses tested in decerebrate animals.
All the anaesthetics tested produced a significant depression of spinal reflex responses to noxious stimuli at doses well below those required for anaesthesia. Whilst the presence of maintenance anaesthetics appears not to distort pharmacological tests of other agents, there may nonetheless be a biasing of the samples of cells recorded.
Characterization of histamine H3‐receptors in guinea‐pig ileum with H3‐selective ligands
Authors: Hew R.W.S. , Hodgkinson C.R. , Hill S.J. 
Published: July 2012

The effect of the selective histamine H3‐receptor agonist R‐(α)‐methylhistamine has been investigated on the contractile responses of the longitudinal smooth muscle of guinea‐pig ileum elicited by electrical field stimulation of acetylcholine release from myenteric nerve endings.
R‐(α)‐methylhistamine produced a concentration‐dependent (EC50 = 1.4 ± 0.2 × 10−8 m) inhibition of the response to electrical field stimulation which was insensitive to inhibition by mepyramine (1 μm) and tiotidine(2.4 μm).
This response to R‐(α)‐methylhistamine could be inhibited in a competitive fashion by a range of H3‐receptor antagonists including thioperamide (KB = 1.1 nm), impromidine (KB = 65 nm), nor‐burimamide (KB = 380 nm) and SKF 91486 (KB = 34 nm). Burimamide was also a potent inhibitor of this response but the Schild slope obtained (1.3) was significantly greater than unity.
The estimated KB values were all within a factor of three of those values reported for the histamine H3‐receptor mediating inhibition of histamine release in rat cerebral cortex.
These data suggest that the histamine receptor mediating inhibition of cholinergic neurotransmission by R‐(α)‐methylhistamine in guinea‐pig ileum is the same as the H3‐receptor present in rat cerebral cortex.
Evidence that the agonist action of dynorphin A(1–8) in the guinea‐pig myenteric‐plexus may be mediated partly through conversion to [Leu5]enkephalin
Authors: Dixon Diane M. , Traynor J.R. 
Published: July 2012

The agonist action of the opioid peptide dynorphin A(1–8) on the myenteric plexus‐longitudinal muscle of the guinea‐pig ileum has been characterized.
The endogenous opioid peptide dynorphin A(1–8) was rapidly degraded by slices of myenteric plexus‐longitudinal muscle of the guinea‐pig ileum.
A product of the degradation was the δ‐receptor preferring [Leu5]enkephalin. Levels of [Leu5]enkephalin were markedly increased in the presence of the peptidase inhibitors bestatin, thiorphan and captopril.
In the myenteric plexus dynorphin A(1–8) acted as a κ‐receptor agonist. In the presence of bestatin, thiorphan and captopril a μ‐receptor agonist effect was observed. This μ‐agonist action was lost in the presence of N‐[1‐(RS)‐carboxy‐2‐phenylethyl]Ala‐Ala‐Phe‐p‐aminobenzoate, an inhibitor of the endopeptidase enzyme EC 3.4.24.15.
The results suggest that formation of [Leu5]enkephalin from dynorphin A(1–8) may be an important conversion process. The enzyme responsible may be the Zn2+‐metalloendopeptidase, EC 3.4.24.15.
Actions of capsaicin on peripheral nociceptors of the neonatal rat spinal cord‐tail in vitro: dependence of extracellular ions and independence of second messengers
Authors: Dray A. , Bettaney J. , Forster P. 
Published: July 2012

We have tested the hypothesis that capsaicin‐induced activation, desensitization and impairment of peripheral nociceptor function is mediated by separate mechanisms. This was investigated by use of an in vitro preparation of the neonatal rat spinal cord with the functionally attached tail in which the cord and tail were separately superfused with physiological solution. Activation of peripheral fibres by noxious (capsaicin, bradykinin, 5‐hydroxytryptamine, heat, pinch) and innocuous (light brush) stimuli was assessed by recording the depolarization of a spinal ventral root (L3‐L5).
Brief administration of capsaicin produced dose‐related depolarizing responses (EC50 = 280 nm). These responses could be reproduced for many hours following the repeated application of capsaicin at a submaximal concentration. Prolonged application of 0.5–2.0 μm capsaicin induced a selective desensitization to subsequent brief administrations of capsaicin. Prolonged administration at 20–50 μm produced an additional non‐selective reduction in responses to all noxious stimuli without changing innocuous brush responses.
Removal of extracellular calcium from the tail superfusate did not reduce the response to capsaicin or prevent capsaicin‐induced desensitization. However, high concentrations of capsaicin no longer induced a non‐specific reduction of responses to other noxious stimuli. The response to a brief administration of capsaicin was unaffected by calcium channel blocking drugs including nifedipine, cadmium or ω‐conotoxin. On the other hand high extracellular calcium increased the incidence of the non‐selective reduction of responses to all noxious stimuli produced by high concentrations of capsaicin.
Replacement of extracellular sodium with choline blocked peripheral nerve conduction but did not prevent the desensitization produced by capsaicin. In addition, high concentrations of capsaicin were less effective in reducing the responsiveness to other noxious stimuli.
Neither capsaicin‐evoked responses nor capsaicin‐induced desensitization were affected by the administration of forskolin, dibutyryl cyclic AMP, nitroprusside, dibutyryl cyclic GMP, β‐12,13 phorbol dibutyrate, trifluoperazine, indomethacin, staurosporine or mepacrine, in the tail superfusate.
These data suggest that capsaicin‐induced activation, desensitization and impairment of peripheral nociceptors may be separable phenomena. Extracellular calcium is not required for capsaicin‐induced activation or desensitization but calcium as well as sodium are important for capsaicin‐induced impairment of nociceptive responses. Desensitization may occur independently of peripheral fibre activation and cannot be attributed to a central mechanism. Finally neither capsaicin‐induced activation nor desensitization require the participation of a second messenger.