bluuebunny/crossref_metadata_2025_split huggingface dataset:
Alkylation with β‐funaltrexamine suggests differences between μ‐opioid receptor systems in guinea‐pig brain and myenteric‐plexus
Authors: Franklin T.G. , Traynor J.R. 
Published: July 2012

The effects of pre‐incubation with β‐funaltrexamine (β‐FNA) on the binding of [3H]‐[d‐Ala2, MePhe4, Gly‐ol5]enkephalin ([3H]‐DAMGO) to homogenates of guinea‐pig brain and myenteric‐plexus longitudinal muscle have been studied.
β‐FNA pretreatment of brain homogenates in Tris‐HCl buffer reduced the amount of [3H]‐DAMGO binding. This was principally due to a reduction in the maximal number of binding sites measurable. However, approximately 30% of sites labelled by 1 nm [3H]‐DAMGO were insensitive to 1 μm β‐FNA. Similar findings were obtained when the alkylation was performed in brain homogenates prepared in Krebs solution buffered with HEPES.
β‐FNA pretreatment of whole myenteric‐plexus longitudinal muscle strips caused an increase in the IC50 values of μ‐agonists, but not of κ‐agonists. However, the binding of [3H]‐DAMGO to homogenates of myenteric‐plexus longitudinal muscle was not altered by pre‐incubation with β‐FNA in Tris‐HCl buffer. On the other hand when the pretreatment was carried out in whole tissue in Krebs solution, or in homogenates in the presence of NaCl and Gpp(NH)p, a marked reduction in [3H]‐DAMGO binding was observed.
These results suggest that a low affinity form of the μ‐opioid receptor is the physiologically relevant site for β‐FNA alkylation in the myenteric‐plexus and that differences exist between μ‐receptor systems in guinea‐pig myenteric plexus and brain.
Modification of the rat uterine response to oestrogen and tamoxifen by thromboxane antagonists
Authors: Kerr M.B. , Marshall K. , Senior J. 
Published: July 2012

The thromboxane receptor antagonists EP092, AH23848 and BM 13.505 were used to investigate the role of thromboxane in the uterotrophic response to oestradiol and tamoxifen.
The parameters examined were uterine blood flow (measured by the microsphere technique), uterine wet and dry weights and the concentrations of cytosolic and nuclear oestrogen receptors.
Only EP092 potentiated the hyperaemic response to oestrogen but all three thromboxane antagonists inhibited oestradiol‐stimulated uterine growth. This inhibition was accompanied by a decrease in nuclear oestrogen receptor concentration.
The uterotrophic response to tamoxifen was unaffected by the thromboxane antagonists.
The mechanism by which the thromboxane antagonists may be exerting their growth inhibitory effect is discussed, although, whether this effect can be attributed to blockade of thromboxane receptors or to some other mechanism is not clear from this study.
Enhanced contractility of the rat stomach during suppression of angiotensin converting enzyme by captopril in vitro
Authors: Rani R. , Rao K.S. 
Published: July 2012

Intragastric pressure (IGP) was used as an index, of the effect of serosal application of captopril (SQ 14,225; d‐3‐mercapto‐2‐methylpropanoyl‐l‐proline) on the contractility of rat stomach in vitro.
Captopril, at concentrations > 0.3 μm, enhanced the spontaneous gastric motility (GM) in a concentration‐dependent manner whereas concentrations < 0.3 μm selectively potentiated 4 nm bradykinin (BK)‐evoked gastric contractions without significantly affecting the spontaneous GM.
The kallikrein inhibitor, aprotinin (100 u ml−1), markedly antagonized the enhanced GM to 1.4 μm captopril and BK (4 nm)‐evoked contractions, without affecting the contractions evoked by angiotensin 1 (10 nm) and acetylcholine (0.4 μm). The angiotensin II antagonist, saralasin (50 μm) failed to mimic aprotinin.
The enhanced GM to captopril was markedly inhibited by tetrodotoxin (1 μm), and partially inhibited by atropine (1 μm).
These results indicate that in vitro, captopril (> 0.3 μm) enhances gastric contractility through kininase/ACE inhibitory action, presumably by increasing the concentration of undegraded tissue kinins and substance P. This motor response seems to be predominantly due to activation of the cholinergic neurones but non‐cholinergic excitatory neurones are also involved.
Influence of acute and chronic chlorimipramine treatment on the 5‐HT receptor‐mediated modulation of acetylcholine release from the cerebral cortex of freely moving guinea‐pigs
Authors: Siniscalchi Anna , Bianchi Clementina , Beani Lorenzo 
Published: July 2012

Acetylcholine (ACh) release from the cerebral cortex of freely moving guinea‐pigs, implanted with epidural cups, was studied.
A single dose of chlorimipramine (Cl‐Imip, 10 mg kg−1, s.c.), reduced the cortical ACh release both in normal and in chronically (10 mg kg−1 daily, s.c., for 14 days) Cl‐Imip‐treated guinea‐pigs; the 5‐HT3 antagonist MDL 72222 (1 mg kg−1, s.c.) antagonized this effect.
A single dose of Cl‐Imip significantly reduced the effect of the 5‐HT1A agonist 8‐hydroxy‐2‐(di‐n‐propylaminotetralin) (8‐OH‐DPAT, 0.1 mg kg−1, s.c.), which nearly doubled the cortical ACh release in control animals. MDL 72222 restored to normal the response to 8‐OH‐DPAT reduced by the antidepressant.
A single dose of Cl‐Imip did not change the inhibitory, MDL 72222‐sensitive, effect induced by the 5‐HT3 agonist 2‐methyl‐5‐hydroxytryptamine (2‐methyl‐5‐HT, 500 μg, i.c.v.).
In chronically Cl‐Imip‐treated guinea‐pigs, the facilitatory effect of 8‐OH‐DPAT was no longer present, while the inhibitory, MDL 72222‐sensitive, effect of 2‐methyl‐5‐HT was maintained.
These results indicate that the 5‐HT1A receptor‐mediated increase in ACh release is reduced by prolonged Cl‐Imip treatment, while the 5‐HT3 receptor‐mediated inhibition of ACh release is unaffected. The relevance of these findings to the antidepressant mechanism of Cl‐Imip is discussed.
A comparison of excitotoxic lesions of the basal forebrain by kainate, quinolinate, ibotenate, N‐methyl‐d‐aspartate or quisqualate, and the effects on toxicity of 2‐amino‐5‐phosphonovaleric acid and kynurenic acid in the rat
Authors: Winn Philip , Stone Trevor W. , Latimer Mary , Hastings Michael H. , Clark Andrew J.M. 
Published: July 2012

It has been suggested that an NMDA1 receptor subtype might be activated by N‐methyl‐d‐aspartate (NMDA) and ibotenate and an NMDA2 subtype by NMDA or quinolinate, and that the NMDA2 site might be more susceptible to blockade by kynurenic acid.
Experiments were carried out to examine the ability of 2‐amino‐5‐phosphonovaleric acid (AP5) and kynurenic acid to antagonize the neurotoxic properties of kainate, ibotenate, NMDA, quinolinate and quisqualate injected into the rat basal forebrain.
Following histological analysis of the injection sites, lesion volume was assessed parametrically. Each of the toxins except quisqualate was found to make lesions of parvocellular neurones within the basal forebrain with a relative order of potency: kainate ≫ quinolinate > ibotenate = NMDA.
Equimolar doses of AP5 abolished the toxicity produced by quinolinate and NMDA; toxicity to kainate and ibotenate was attenuated to ∼40% of the toxin‐alone condition.
The antagonistic properties of kynurenate were dose‐dependent: equimolar kynurenate had no effect on quinolinate but attenuated the actions of ibotenate, kainate and NMDA; 2 × equimolar kynurenate had no effect on quinolinate or ibotenate but attenuated the toxicity of kainate and NMDA; and 3 × equimolar kynurenate had no effect on the toxicity of kainate or ibotenate, attenuated the actions of NMDA and abolished the toxic action of quinolinate.
The results are discussed in terms of the actions of the various toxins at different receptors, differentially sensitive to AP5 and kynurenate.
Effects of tacrine, velnacrine (HP029), suronacrine (HP128), and 3,4‐diaminopyridine on skeletal neuromuscular transmission in vitro
Authors: Braga M.F.M. , Harvey A.L. , Rowan E.G. 
Published: July 2012

The effects of tacrine (9‐amino‐1,2,3,4‐tetrahydroacridine), velnacrine (HP029, 9‐amino‐1,2,3,4‐tetrahydroacridin‐1‐ol maleate), suronacrine (HP128, 9‐benzylamino‐1,2,3,4‐tetrahydroacridin‐1‐ol maleate), and 3,4‐diaminopyridine on neuromuscular transmission were compared on isolated nerve‐muscle preparations.
Tacrine, HP029, and 3,4‐diaminopyridine augmented responses of chick biventer cervicis preparations to nerve stimulation, with tacrine and HP029 increasing responses to exogenously applied acetylcholine. HP128 blocked responses to nerve stimulation and to carbachol, but increased responses to acetylcholine.
In mouse diaphragm preparations that were partially paralysed by tubocurarine or low calcium solutions, tacrine, HP029, and 3,4‐diaminopyridine reversed the twitch block. HP128 deepened the block.
In mouse triangularis sterni preparations, tacrine and HP029 prolonged the decay phase of endplate potentials and miniature endplate potentials, but had no effect on quantal content at 36°C; above 10 μm, they reduced endplate potential amplitude. 3,4‐Diaminopyridine increased quantal content without affecting the time course of the endplate potentials. HP128 (1–10 μm) had no effect on amplitude or time course of endplate potentials, but reduced their amplitude at higher concentrations.
Extracellular recording of nerve terminal currents from triangularis sterni preparations revealed that 3,4‐diaminopyridine and HP128 had a selective blocking action on the waveform associated with K+ currents, tacrine reduced and prolonged the K+‐related waveform, and HP029 had nonselective blocking actions only seen at high concentrations.
Tacrine and HP029 behave predominantly as anticholinesterase agents, while HP128 has weaker anticholinesterase actions that are masked by cholinoceptor blockade. Tacrine and HP128, but not HP029, have some blocking actions on K+ currents of mouse motor nerve terminals.
Characterization of Gaddum's substance R
Authors: Douglas G.J. , Williams K.I. , Flower R.J. 
Published: July 2012

When the isolated small intestine of the rat is perfused via the mesenteric artery, an oxytocic principle (Gaddum's substance R) is released which is detectable in the perfusate after 30 min and is present in samples collected 8 h later.
The oxytocic activity of substance R is lost after boiling but is unaffected by treatment with thioglycolate. Furthermore, atropine, methysergide and indomethacin failed to antagonize uterine contractions to substance R.
Neither substance R nor urinary kallikrein alone induce a contraction of the guinea‐pig isolated ileum. However, in the presence of kininogen both substance R and urinary kallikrein produce a slow and prolonged contraction of the guinea‐pig ileum.
The oxytocic and kininogenase properties of both substance R and urinary kallikrein are inhibited by Trasylol.
Soy bean trypsin inhibitor (SBTI) selectively inhibited both the oxytocic and the kininogenase activities of substance R but not those of urinary kallikrein.
Gel filtration of substance R resolved a single peak of oxytocic activity with an estimated molecular weight of 40 kDa.
We conclude that substance R is a kininogenase enzyme which may be distinguished from plasma kallikrein by its molecular weight and from urinary kallikrein by its susceptibility to SBTI. The exact nature of this enzyme remains to be elucidated.
Effect of hyperosmolarity on human isolated central airways
Authors: Jongejan R.C. , de Jongste J.C. , Raatgeep R.C. , Stijnen T. , Bonta I.L. , Kerrebijn K.F. 
Published: July 2012

We studied the effect of hyperosmolarity on human isolated airways because a better understanding of the effect of hyperosmolarity on the human airway wall may improve insight into the pathophysiology of hyperosmolarity‐induced bronchoconstriction in asthma.
In cartilaginous bronchial rings dissected from fresh human lung tissue, hyperosmolar Krebs‐Henseleit buffer (450 mosm, extra sodium chloride added) evoked a biphasic response: a rapid relaxation phase (peak after 5.0 ± 0.3 min) followed by a slow contraction phase (peak after 25.4 ± 0.8 min).
With the histamine (H1) receptor antagonist mepyramine, the contraction phase was reduced to 41.2% of the control value (P < 0.001), with atropine to 50.0% (P < 0.01), with the local anaesthetic lignocaine to 48.7% (P < 0.05) and with mepyramine together with atropine to 19.2% (P < 0.001).
With the inhibitor of neutral metalloendopeptidase, phosphoramidon, the contraction phase increased to 128.0% of the control value (P < 0.05) and after removal of the epithelium to 131.8% (P < 0.05).
Indomethacin, the leukotriene C4/D4 (LTC4/D4) antagonist FPL 55712 or the blocker of nerve conduction, tetrodotoxin, had no effect on the contractile phase.
The relaxation phase was not altered by any of these drugs nor by epithelial denudation. The relaxation phase was also unchanged in the presence of α‐chymotrypsin, which degrades muscle relaxing peptides such as vasoactive intestinal peptide.
Hyperosmolar buffer slightly increased the sensitivity and maximal response to methacholine as well as the cholinergic twitch to electric field stimulation.
We conclude that hyperosmolarity releases acetylcholine, histamine and neuropeptides in the human airway wall in sufficient quantities to contract airway smooth muscle. This release itself or its effect on airway muscle is modulated by the airway epithelium. The mechanism of the relaxation phase may be an unknown smooth muscle relaxing substance or a direct effect on the airway muscle, related to ion fluxes.
The contribution of Rb‐permeable potassium channels to the relaxant and membrane hyperpolarizing actions of cromakalim, RP49356 and diazoxide in bovine tracheal smooth muscle
Authors: Longmore J. , Bray K.M. , Weston A.H. 
Published: July 2012

Cromakalim (1 and 10 μm), RP49356 (5 and 50 μm) and diazoxide (100 and 300 μm) produced full relaxation of smooth muscle strips pre‐contracted with 25 mm KCl. These agents caused membrane hyperpolarization and increased 42K and 86Rb efflux. The time taken to achieve the maximum change in each of these parameters (tmax) was less for the higher concentration levels of cromakalim, RP49356 and diazoxide than for the lower concentration levels.
Calculation of permeability (P) changes showed that cromakalim (1 and 10 μm) produced a greater rise in PK than PRb, although the PRb:PK ratio was simiiar at both concentration levels. Similarly RP49356 produced a greater change in PK than PRb. However, in contrast to cromakalim, this difference was more marked at the higher concentration (50 μm) and was reflected by a differential effect of the two concentrations of RP49356 on the PRb:PK ratio. Diazoxide (100 and 300 μm) produced similar changes in PK and PRb.
For cromakalim (1 and 10 μm) the tmax for the electrical and mechanical effects and also the profile of change in these parameters corresponded to changes in both PK and PRb. For RP49356 (5 μm), changes in tension and membrane potential were related to both changes in PK and PRb, whereas at 50 μm these responses more closely corresponded to changes in PK. For diazoxide (100 and 300 μm) the electrical and mechanical effects corresponded to changes in both PK and PRb.
The results show that changes in 42K and 86Rb efflux induced by cromakalim, RP49356 and diazoxide are good indicators of changes in membrane PK and PRb evoked by these agents. Furthermore, it is concluded that the K channels involved in the mechanical and electrical effects of cromakalim are represented by the opening of a single population through which Rb can pass less easily than K, whilst the K channels associated with actions of diazoxide are equally permeable to both K and Rb. In contrast, the relaxant and membrane hyperpolarizing actions of RP49356 may involve the opening of more than one group of K channels which differ in their permeability to Rb.
5‐Hydroxytryptamine‐induced bronchoconstriction in the guinea‐pig: effect of 5‐HT2 receptor activation on acetylcholine release
Authors: Macquin‐Mavier Isabelle , Jarreau Pierre‐Henri , Istin Nathalie , Harf Alain 
Published: July 2012

The bronchoconstrictor responses to 5‐hydroxytryptamine (5‐HT) were studied in the guinea‐pig to establish whether they are partly attributable to parasympathetic activation within the airways. 5‐HT dose‐response curves were constructed in anaesthetized and ventilated guinea‐pigs pretreated with saline, or by bilateral cervical vagotomy or vagotomy plus atropine 3 mg kg−1, i.v. Vagotomy had no effect on 5‐HT‐induced bronchoconstriction but vagotomy plus atropine significantly reduced it.
To determine whether parasympathetic activation within the airways resulted from pre‐ or postganglionic stimulation, 5‐HT dose‐response curves were constructed for two groups of vagotomized guinea‐pigs treated with hexamethonium 2 mg kg−1, or hexamethonium 2 mg kg−1, plus atropine 3 mg kg−1. Guinea‐pigs treated with hexamethonium plus atropine experienced significantly less 5‐HT‐induced bronchoconstriction than those treated with hexamethonium alone.
To characterize the subtype of 5‐HT receptors involved in the activation of the parasympathetic system by 5‐HT, dose‐response curves to 5‐HT were constructed for four groups of vagotomized guinea‐pigs treated with saline, 1 mg kg−1 of the 5‐HT3 antagonist ICS 205–930, or either 0.01 or 0.1 mg kg−1 of the 5‐HT2 antagonist ketanserin. ICS 205–930 enhanced 5‐HT‐induced bronchoconstriction but 0.01 mg kg−1 ketanserin inhibited it significantly and 0.1 mg kg−1 ketanserin abolished it. To confirm the involvement of 5‐HT2 receptors in these responses, we studied the effects in vagotomized guinea‐pigs of atropine on the bronchoconstriction induced by the 5‐HT2 agonist, α‐methyl‐5‐HT, infused at rates of 40 and 80 ng kg−1 s−1. At both rates, atropine significantly reduced the bronchoconstrictor responses to α‐methyl‐5‐HT.
The above results indicate that 5‐HT‐induced bronchoconstriction is indeed partly mediated by parasympathetic activation within the airways. This activation is mediated by stimulation of 5‐HT2 receptors which are probably located on the postganglionic parasympathetic nerve endings.
The effects of probucol on the progression of atherosclerosis in mature Watanabe heritable hyperlipidaemic rabbits
Authors: Daugherty Alan , Zweifel Ben S. , Schonfeld Gustav 
Published: July 2012

Probucol was administered to mature Watanabe heritable hyperlipidaemic (WHHL) rabbits (≅9 months old). Groups of WHHL rabbits were randomly selected and treated as follows: Group 1 killed at 9 months (n = 9); Group II placed on sham‐treated diet at 9 months and followed for 6 months (n = 8); Group III placed on probucol at 9 months and followed for 6 months (n = 8). Probucol was administered by mixing 1% wt/wt drug with standard laboratory diet.
Plasma concentrations of probucol increased to 93 ± 11 μg ml−1 in Group III during the initial 2 weeks and increased further to 149 ± 24 μg ml−1 at the end of the treatment period.
Plasma concentrations of total cholesterol, unesterified cholesterol and phospholipids were significantly reduced overall by probucol, while triglycerides were not affected.
No statistically significant differences were observed in the presence of oxidized products in low density lipoproteins (LDL) isolated from plasma of controls compared to probucol‐treated rabbits. However, LDL from probucol‐treated animals was resistant to oxidation in the presence of Cu2+ (3 μm).
Group I had aortic atherosclerosis covering 70 ± 5% of intimal area of thoracic aortae, that increased to 91 ± 3% in Group II. This was associated with cholesterol contents of aortae increasing from 1.4 ± 0.2 μg mg−1 in Group I to 2.7 ± 0.3 μg mg−1 in Group II. Probucol administration did not produce a statistically significant reduction of atherosclerotic lesion area (78 ± 7%). However, probucol treatment reduced cholesterol content to 1.9 ± 0.3 μg mg−1 (P < 0.01). Collagen content of aortae was not affected by probucol treatment.
Thus, while probucol did not promote regression, the drug did retard the continued deposition of cholesterol esters into atherosclerotic lesions of mature WHHL rabbits.
Separation of two pathways for calcium entry into chromaffin cells
Authors: Gandía Luis , Casado Luis‐Felipe , López Manuela G. , García Antonio G. 
Published: July 2012

The effects of various drugs on 45Ca + 40Ca uptake into cultured bovine adrenal chromaffin cells evoked by 1,1‐dimethyl‐4‐phenylpiperazinium (DMPP) or high K, were studied. In the presence of 1 mm external 40Ca, with 45Ca as a radiotracer, unstimulated cells took up an average of 0.13 fmol/cell 40Ca and 772 c.p.m./106 cells of 45Ca (n = 76). Upon stimulation with DMPP (100μm for 60s) or K (59 mm for 60s), Ca uptake increased to 0.92 and 1 fmol/cell, respectively.
Flunarizine behaved as a potent blocker of both DMPP‐ and K‐evoked Ca uptake (IC50 of 1.76 and 1.49 μm, respectively for DMPP and K). A similar picture emerged with Cd ions, though Cd exhibited an IC50 against K (1.86 μm) slightly lower than the IC50 against DMPP (8.14 μm).
Clear cut differences were observed with amiloride, guanethidine, nimodipine and nisoldipine which behaved as selective blockers of DMPP‐mediated Ca uptake responses: IC50 values to block DMPP effects were 290, 27, 1.1 and 1.63 μm respectively for amiloride, guanethidine, nimodipine and nisoldipine. Amiloride blocked K‐evoked Ca uptake by only 35% and guanethidine did not affect it. Nisoldipine inhibited K‐evoked Ca uptake only partially at low concentrations (about 30%); a second blocking component was observed at the highest concentration used (10 μm). At 10 μm, nimodipine blocked K‐evoked Ca uptake by 50%.
Thus, it seems that the nicotinic receptor mediated Ca uptake pathway can be pharmacologically separated from the K‐activated pathway. The results are compatible with the hypothesis that in cultured bovine adrenal chromaffin cells, stimulation of nicotinic receptors recruits a single type of Ca channel which is sensitive to flunarizine, Cd, amiloride, guanethidine, nimodipine and nisoldipine. The results also suggest that K depolarization might be recruiting in addition to this channel, another Ca channel which is highly sensitive to Cd and flunarizine, resistant to nisoldipine, nimodipine and amiloride, and insensitive to guanethidine.
Effects of brevetoxin‐B on motor nerve terminals of mouse skeletal muscle
Authors: Tsai M.C. , Chen M.L. 
Published: July 2012

The effects of brevetoxin‐B, a red tide toxin, on motor nerve terminal activity were assessed on mouse triangularis sterni nerve‐muscle preparations. The perineural waveforms were recorded with extracellular electrodes placed in the perineural sheaths of motor nerves.
At 0.11 μm, brevetoxin‐B increased the components of waveforms associated with sodium and potassium currents while it decreased the calcium activated potassium current and the slow calcium current of the nerve terminal. The fast calcium current and slow potassium current were not affected.
At 1.11 μm, brevetoxin‐B decreased all of the components of waveforms associated with sodium, potassium and calcium currents.
It is concluded that brevetoxin‐B affects sodium, potassium as well as calcium currents in the nerve terminal. The effects may contribute to its pharmacological actions on synaptic transmission.