bluuebunny/crossref_metadata_2025_split huggingface dataset:
The effects of siguazodan, a selective phosphodiesterase inhibitor, on human platelet function
Authors: Murray Kenneth J. , England Paul J. , Hallam Trevor J. , Maguire Joanne , Moores Kitty , Reeves Martin L. , Simpson Alec W. M. , Rink Timothy J. 
Published: July 2012

The effects of siguazodan (SK&F 94836) a selective phosphodiesterase (PDE) inhibitor with inotropic and vasodilator activity, were studied on human platelets.
Siguazodan selectively inhibited the major cyclic AMP‐hydrolysing PDE in human platelet supernatants. The inhibited enzyme has been variously termed cyclic GMP‐inhibited PDE or PDE‐III.
In platelet‐rich plasma (PRP), siguazodan inhibited U46619‐induced aggregation more potently than that induced by ADP and collagen. Treatment of the PRP with aspirin had no effect on the potency of siguazodan.
In washed platelets, siguazodan increased cyclic AMP levels and reduced cytoplasmic free calcium ([Ca2+]i). ADP decreased the ability of siguazodan to raise cyclic AMP and this may explain its lower potency in inhibiting responses to ADP.
Siguazodan has anti‐platelet actions over the same concentration range that it is an inotrope and vasodilator.
5‐Hydroxytryptamine and arachidonic acid metabolites modulate extensive platelet activation induced by collagen in cats in vivo
Authors: De Clerck F. , Loots W. , Somers Y. , Beetens J. , Wouters L. , Wynants J. , Janssen P.A.J. 
Published: July 2012

The pathways contributing to the platelet adhesion/aggregation reaction elicited by collagen microfibrils, administered to cats in vivo, were analysed.
The intra‐aortic infusion of collagen (100 μg kg−1 in 1 min) caused an extensive activation of platelets, as evidenced by the time‐dependent drop of free platelet numbers in whole blood, and the increases of 5‐hydroxyindoles (5‐HI), 5‐hydroxytryptamine (5‐HT) and thromboxane B2 (TXB2) levels in plasma, prepared from effluent venous blood sampled from the inferior caval vein.
5‐HT2 receptor blockade with ketanserin (0.63 mg kg−1 i.v., 10 min) and cyclo‐oxygenase inhibition with aspirin (10 mg kg−1 i.v., 10 min) slightly attenuated the peak reduction of free platelets in whole blood in response to collagen without affecting changes in plasma 5‐HI. Aspirin, but not ketanserin, reduced the collagen‐induced changes in plasma TXB2, prostaglandin E2 (PGE2) and 6K‐PGF1α.
Dual TXA2 synthetase inhibition/TXA2‐prostaglandin endoperoxide receptor antagonism with ridogrel (5 mg kg−1 i.v., 10 min) halved the drop in free platelets, reduced the release of platelet 5‐HI, inhibited the increase in plasma TXB2 and elevated that of 6K‐PGF1α and PGE2 in response to collagen.
Combined treatment with ketanserin and aspirin reduced the collagen‐induced drop of free platelets and the release of platelet 5‐HI to a similar extent as ridogrel alone; plasma prostanoids were affected as with aspirin alone.
Combined administration of ketanserin and ridogrel virtually eliminated the collagen‐induced platelet adhesion/aggregation response and release of 5‐HI; prostanoids were affected as with ridogrel alone.
The results indicate that the interplay between 5‐HT and arachidonic acid metabolites is causally involved in the platelet reaction to activation induced by collagen in cats in vivo.
Regulation of the synthesis and metabolism of striatal dopamine after disruption of nerve conduction in the medial forebrain bundle
Authors: Commissiong John W. , Slimovitch Caroline , Toffano Gino 
Published: July 2012

After physical (knife‐cut) or chemically‐mediated (tetrodotoxin 300 nm, 1.5 μl; 1.0 μl min−1) interruption of nerve conduction in the nigrostriatal tract, there was a marked increase in the synthesis and metabolism of dopamine in the isolated dopaminergic nerve terminals of the striatum. The effect peaked at 4 h post‐transection, at which time 3,4‐dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) were increased by 300% and 700% respectively (DOPAC: 27 ± 13 vs 80 ± 17 nmol g−1; HVA: 6.66 ± 3.57 vs 54 ± 18 nmol g−1). The increases in dopamine content and metabolism are secondary to an increase in the rate of synthesis on the lesioned side, versus the intact, control side.
In both experimental situations, haloperidol (1.0 mg kg−1, i.p.) retained its known ability to induce a significant increase in DOPAC and HVA in the striatum, despite the interruption of nerve conduction in the nigrostriatal tract.
Six days after cutting the left nigrostriatal tract, dopamine in the left striatum was reduced to <5% of the control value, and DOPAC and HVA were not detectable. In the denervated, left striatum, the synthesis of dopamine (from injected l‐DOPA), and its metabolism to DOPAC and HVA, occurred to the same degree as in the intact right side. In these DOPA‐treated rats, haloperidol (1.0 mg kg−1, i.p.) caused a further increase in DOPAC and HVA in the intact striatum, but not in the denervated striatum.
Under non‐stressful conditions, using a combination of anaesthetic treatments, electrical stimulation (400 μA, 0.4 ms, 15 Hz, 15 min) of the nigrostriatal tract did not increase DOPAC or HVA in the striatum on the stimulated side.
It is concluded (a) that there is a significant presynaptic, and/or local circuit mechanism capable of activating the synthesis and metabolism of dopamine in the isolated, striatal, dopaminergic nerve terminals. Furthermore, haloperidol can act directly on the striatal, dopaminergic nerve terminal, to cause an increase in the synthesis and metabolism of striatal dopamine. (b) After degeneration of the striatal dopaminergic nerves, the denervated striatum retains the ability to synthesize (from l‐DOPA) and metabolize dopamine, to the same degree as the intact, innervated, contralateral striatum. (c) When stress is minimized, and release of dopamine is induced by electrical stimulation of the medial forebrain bundle, the catabolism of dopamine (to DOPAC and HVA) during the release‐uptake cycle may not be a significant factor under physiological conditions. (d) When dopamine synthesis is increased in the striatum, the normal blood concentration of tyrosine is adequate to sustain the increased synthesis, and precursor availability is not a limiting factor. (e) These results suggest that some of the basic concepts about the neurochemical/neurophysiological regulation of monoaminergic neurones may require further re‐evaluation.
The actions of human atrial natriuretic factor on hepatic arterial and portal vascular beds of the anaesthetized dog
Authors: Withrington P.G. , Dhume V.G. , Croxton R. , Gerbes A.L. 
Published: July 2012

The vascular actions of atrial natriuretic factor (ANF) have been assessed with other vasoactive agents on the hepatic arterial and portal vascular beds of the anaesthetized dog.
Intra‐arterial bolus injections of ANF (0.1–50 nmol) caused graded increases in hepatic arterial blood flow representing a vasodilatation of relatively short duration. Vasoconstriction was never observed.
The maximum increase in hepatic arterial blood was the same for ANF and isoprenaline (Iso) i.e. approximately 60–70% increase over control flow.
On a molar basis, ANF was less potent than Iso although over the higher dose range (10−9−10−7 mol) its vasodilator activity exceeded that of the endogenous vasodilator adrenaline.
Intraportal bolus injections (1.0–50 nmol) of ANF did not alter portal inflow resistance since no changes in portal inflow pressure occurred when the portal circuit was perfused at constant inflow volume.
This differential action of ANF on the hepatic arterial and portal vascular beds may provide a change in total liver blood flow in favour of the arterial component.
ANF, by altering hepatic haemodynamics to favour formation of trans‐sinusoidal fluid exchange, may provide a temporary expansion of the extravascular fluid reservoir to buffer any increased venous pressure. However, chronically elevated plasma levels of ANF would encourage the formation of ascitic fluid.
Acetylcholinesterase activity in regions of mouse brain following acute and chronic treatment with a benzodiazepine inverse agonist
Authors: Appleyard M.E. , Taylor S.C. , Little H.J. 
Published: July 2012

Chronic administration of the benzodiazepine inverse agonist FG 7142 has previously been shown to induce seizure activity in mice. In the present study we have investigated the effects of acute and chronic treatment with FG 7142 in mice on the levels of acetylcholinesterase activity in cortex, hippocampus, midbrain and striatum. We have also investigated the effects of acute and chronic stress in the form of handling (vehicle‐injection) on acetylcholinesterase levels.
A single dose of FG 7142 produced a marked elevation of total acetylcholinesterase activities in the hippocampus and midbrain when compared with vehicle‐injected control levels, but the levels were not different from those in unhandled animals.
Acute stress, in the form of vehicle‐injection produced decreases in cortical and hippocampal soluble acetylcholinesterase activity but FG 7142 had no effect upon these stress‐induced changes.
Total cortical and hippocampal acetylcholinesterase activities were increased by 56% and 16% respectively in the chronic FG 7142‐treated mice that exhibited seizure activity (compared with vehicle‐injected controls).
Soluble acetylcholinesterase activity in the midbrain was decreased to 82% of control levels only in animals that had undergone FG 7142‐induced kindling. Smaller or no changes in acetylcholinesterase activity in the midbrain were observed in chronically FG 7142‐treated animals that exhibited no seizure activity.
Mice that did not demonstrate seizure activity in response to chronic FG 7142 treatment showed alterations in the soluble acetylcholinesterase activities of the hippocampus and midbrain.
It is concluded that chronic treatment with the benzodiazepine inverse agonist FG 7142 produces alterations in the acetylcholinesterase activities of various brain regions, in a manner related to the kindling that can be produced by this treatment.
Chronic mild stress, in the form of repeated handling (vehicle injection), induced changes in brain activity with decreases in total activity occurring in the cortex and hippocampus, and an increase in soluble acetylcholinesterase activity occurring in the midbrain.
All these stress‐induced changes appeared to be prevented by administration of FG 7142 at the time of the stress. It would appear therefore that FG 7142 can prevent the effects of chronic stress on brain acetylcholinesterase activity.
Suramin is a slowly‐equilibrating but competitive antagonist at P2x‐receptors in the rabbit isolated ear artery
Authors: Leff P. , Wood B.E. , O'Connor S.E. 
Published: July 2012

The antagonist dynamics of suramin were investigated at P2x‐receptors in isolated rings of endothelium‐denuded ear artery from New Zealand White (NZW) rabbits.
α,β‐Methylene adenosine 5′‐triphosphate (ATP) concentration‐effect curves were constructed cumulatively in a paired curve design in the absence and presence of increasing concentrations of suramin, incubated for 45 min. The slope of the resulting Schild plot was significantly greater than unity (1.50 ± 0.08).
Assuming that slow equilibration by suramin explains the steep Schild plot, further experiments were conducted using short (15 min) and long (3 h) incubation times. The resulting Schild plot slopes were 1.66 ± 0.36 and 1.06 ± 0.13 respectively confirming the assumption. However, after 3 h incubation, suramin also caused depression of α,β‐methylene ATP curves.
In an attempt to minimize the depressant effect of suramin, a kinetic study was designed to calculate the minimum incubation times for each concentration of suramin used in the Schild analysis to achieve effectively complete equilibrium. Theoretically fractional occupancy for the antagonist is given by (r − 1)/r, where r is the dose‐ratio. A plot of (r − 1)/r against time allowed the apparent ‘on’ and ‘off’ rate constants to be calculated.
With the resulting rate constant estimates, an optimised antagonism study was carried out in which incubation times were chosen such that > 95% occupancy by suramin could be achieved without agonist curve depression at each concentration of suramin used.
Under these conditions, suramin fulfilled all criteria for simple competition: parallel rightward displacement of α,β‐methylene ATP curves and a Schild plot slope of unity (1.00 ± 0.09). The resulting pKB estimate was 4.79 ± 0.05. This estimate of affinity was shown to be independent of the agonist used in another experiment in which l‐β,γ‐methylene ATP was employed (pKB = 5.17).
Under the same conditions, suramin was found to have no effect on KCl‐induced contractions and only slight effects on phenylephrine‐ and histamine‐induced responses.
This analysis provides the first evidence that suramin is a genuine competitive P2x‐receptor antagonist.
The effects of 5‐HT on articular sensory receptors in normal and arthritic rats
Authors: Birrell G.J. , McQueen D.S. , Iggo A. , Grubb B.D. 
Published: July 2012

The effects of intra arterial (i.a.) injections of 5‐hydroxytryptamine (5‐HT, 1–100 μg) on the discharge of (a) identified articular high threshold mechanoreceptors and (b) unidentified chemosensitive receptors in the ankle joint have been studied electrophysiologically in anaesthetized normal and arthritic rats. Recordings were made from a fine branch of the medial plantar nerve.
5‐HT increased the mechanical responsiveness of high threshold nociceptive mechanoreceptors with C and Aδ fibre afferents in both normal and adjuvant‐arthritic rats. Receptors in arthritic joints were more sensitive to 5‐HT than were those from normal joints.
5‐HT produced a complex response from both types of articular receptors following i.a. injection. Two separate components were identified: (a) a fast transient burst of activity was obtained within 10 s of this injection in 66% of units from normal animals and 45% from arthritics, followed by (b) a delayed slow longer‐lasting excitation seen in 62% of the units examined from normals and 77% of units from arthritic rats.
Increased mechanoreceptor resonsiveness produced by 5‐HT was reduced or abolished by the 5‐HT3 receptor antagonists studied (MDL 72222, ICS 205–930, or GR 38032F, in single doses of 100 μg kg−1, i.a.).
Fast excitation showed marked tachyphylaxis and was antagonized by MDL 72222, ICS 205–930 or GR 38032F. It was unaffected by ketanserin (100 μg kg−1, i.a.). Delayed excitation was reduced or abolished by ketanserin but was unaffected by the 5‐HT3‐receptor antagonists.
Administration of MDL 72222, ICS 205–930 or GR 38032F caused short lasting (< 5 min) reductions in background activity from both types of unit recorded in arthritic rats, as well as in normal rats in which activity had increased following administration of 5‐HT. Ketanserin caused similar reductions in background activity in chemosensitive units, but had no effect on mechanoreceptors.
At least two types of receptor are involved in the actions of 5‐HT on articular sensory receptors with fine afferent fibres. Increased mechano‐responsiveness involves a 5‐HT3‐receptor as does fast excitation. Delayed excitation probably involves a 5‐HT2‐receptor. Endogenous 5‐HT appears not to play a crucial role in sensitization of high threshold mechanoreceptors in this model of chronic inflammation and arthritis, although its local release may potentiate the actions of other inflammatory mediators on sensory receptors in the ankle joint.
Endothelin and a Ca2+ ionophore raise cyclic GMP levels in a neuronal cell line via formation of nitric oxide
Authors: Reiser Georg 
Published: July 2012

The vasoconstrictor peptide endothelin‐1 caused a fast, transient rise in guanosine 3′:5′‐cyclic monophosphate (cyclic GMP) levels in a neuronal cell line (mouse neuroblastoma x rat glioma hybrid cells 108CC15). The mechanism of activation of guanylate cyclase by endothelin‐1 was investigated. The endothelin‐1‐induced rise depended on the release of internal Ca2+.
The stimulation of cyclic GMP synthesis induced by endothelin‐1 was suppressed after preincubating the cells in medium containing haemoglobin (IC50 3 μm). Similarly, pretreatment of the cells with the l‐arginine analogues, l‐canavanine (IC50 60 μm) or NG‐monomethyl‐l‐arginine (IC50 2.5 μm), inhibited the cyclic GMP response to endothelin‐1. Therefore, endothelin‐1 activates guanylate cyclase most probably via formation of nitric oxide, which is released from l‐arginine.
The Ca2+ ionophore ionomycin induced a transient rise in cyclic GMP levels, which was also suppressed by preincubation in the presence of either haemoglobin or the l‐arginine analogues l‐canavanine or NG‐monomethyl‐l‐arginine. Therefore, we conclude that ionomycin can activate guanylate cyclase by a mechanism involving nitric oxide formation, similar to that induced by endothelin‐1.
The alkaloid veratridine, which activates Na+ channels and also causes influx of Ca2+ induced a transient rise of cyclic GMP levels in the neuronal cell line. This stimulation was blocked by pretreating the cells with l‐canavanine, NG‐monomethyl‐l‐arginine or haemoglobin.
Loading the cells with the Ca2+ chelator BAPTA suppresed the cyclic GMP response to application of endothelin‐1, ionomycin, or veratridine. Thus, in the neuronal cell line a rise in cytosolic Ca2+ activity seems to be sufficient to stimulate the nitric oxide forming enzyme which synthesizes the activator of soluble guanylate cyclase.
Electrophysiological and arrhythmogenic effects of platelet activating factor during normal perfusion, myocardial ischaemia and reperfusion in the guinea‐pig
Authors: Flores Nicholas A. , Sheridan Desmond J. 
Published: July 2012

Platelet activating factor (PAF) is often used to study the effects of platelet activation. While direct myocardial electrophysiological effects of PAF have been described in superfused myocardial tissue, little is known about its actions on the whole heart.
The cellular electrophysiological and arrhythmogenic effects of PAF (10−11 m, 10−10 m and 10−9 m) were studied during normal perfusion, global myocardial ischaemia and reperfusion in Langendorff‐perfused guinea‐pig hearts at 32°C.
PAF (10−9 m) increased the incidence of ventricular fibrillation during ischaemia and reduced action potential duration (APD) during normal perfusion and early myocardial ischaemia (10−9 m and 10−10 m). PAF also reduced refractory period (RP) during normal perfusion (10−9 m) and early ischaemia (10−9 m and 10−10 m). PAF prevented recovery of APD (10−9 m) and RP (10−9 m and 10−10 m) during reperfusion. PAF at a concentration of 10−11 m had no electrophysiological effects.
PAF (10−9 m) increased the QRS width of the electrocardiogram during late ischaemia while 10−10 m PAF raised pacing threshold during late ischaemia.
Perfusion pressure was increased, and developed tension decreased by 10−9 m PAF.
These results demonstrate that PAF has direct myocardial electrophysiological effects in the whole heart which occur during normal perfusion and are capable of augmenting the effects of myocardial ischaemia, but are independent of the presence of platelets.
Bradykinin‐induced plasma exudation in guinea‐pig airways: involvement of platelet activating factor
Authors: Rogers Duncan F. , Dijk Sas , Barnes Peter J. 
Published: July 2012

We studied the effect of bradykinin on plasma exudation in the airways of the anaesthetized guinea‐pig in vivo. Tissue content of extravasated Evans blue dye was used as an index of protein exudation in the larynx, trachea, main bronchi and intrapulmonary airways (i.p.a.).
Bradykinin increased the content of Evans blue in all tissues studied in a dose‐related manner. The response was greatest in the main bronchi and i.p.a., less in the trachea and least in the larynx. A dose of 47 nmol kg−1 was the lowest tested which caused significant (P > 0.001) plasma exudation with increases in leakage above control values of 256% in the larynx, 405% in the trachea, 394% in the main bronchi and 485% in intrapulmonary airways.
Leakage was significantly (P > 0.05) increased above control values by 1 min after bradykinin (47 nmol kg−1) in the main bronchi and intrapulmonary airways and was maximal in all airways 5 min after bradykinin. Although reduced by 15 min, the tissue content of dye was still significantly (P > 0.05) increased 2 h after bradykinin.
The prolonged tissue dye retention was due to a later phase of slow and maintained exudation preventing full clearance of dye after the initial response.
The initial phase of leakage was partially attenuated by the platelet activating factor (PAF) receptor antagonists WEB 2086 or BN 52021, by indomethacin or by inhibiting sensory nerve activation by opioid anaesthesia: it was not affected by mepyramine and cimetidine nor by the sulphidopeptide leukotriene receptor antagonists FPL 55712 or ICI 198,615. Adrenoceptor blockade of the anti‐leakage effects of endogenously‐released catecholamines significantly (P > 0.05) enhanced leakage.
The later phase of plasma leakage was completely inhibited by the PAF antagonists.
We conclude that, in guinea‐pig airways in vivo, the initial phase of bradykinin‐induced plasma exudation is mediated in part by PAF, sensory nerves and prostaglandins, whereas the later, prolonged phase of leakage is mediated exclusively by PAF. If bradykinin is generated in asthma, its potent and prolonged effects on plasma leakage may contribute significantly to airway oedema and may be involved in the development of bronchial hyperresponsiveness.
Effect of blockade of noradrenaline re‐uptake on evoked tritium overflow from mouse vasa deferentia and rat cortex slices
Authors: El‐Mas M. , Hughes I.E. 
Published: July 2012

In tissues previously incubated with [3H]‐noradrenaline exposure to cocaine (0.1 to 10 μm) or desmethylimipramine (0.01 to 1 μm) produced a concentration‐dependent increase (up to 2 fold) in electrically evoked (3 Hz, 2 ms, 20 mA, 120 s every 20 min) fractional overflow of tritium from rat brain cortex slices but not from mouse vas deferens (2.5 Hz, 2 ms, 400 mA, for 90s every 14 min).
Yohimbine and idazoxan (0.01 to 1 μm) increased fractional evoked overflow of tritium by up to 2 fold; in the presence of these drugs, cocaine (10 μm) produced an increase in both tissues (up to 3.5 fold over control).
In brain slice an increase in stimulation frequency (0.1, 0.5, 1, 3 and 6 Hz) decreased fractional evoked overflow of tritium per pulse but cocaine (10 μm) produced a significant enhancement at each frequency except 6 Hz. In vas deferens fractional tritium overflow per pulse changed little with increasing frequency and cocaine produced no effect.
In both tissues fractional evoked overflow of tritium was dependent on the stimulation current; cocaine (10 μm) increased fractional evoked overflow from brain slice at every current tested but was without effect in vas deferens.
Chromatographic separation of the released tritium showed there was little difference in the proportions of [3H]‐noradrenaline and 3H‐metabolites overflowing from the tissues. Cocaine increased the proportion of [3H]‐noradrenaline and decreased the proportion of [3H]‐DOPEG overflowing both at rest and during stimulation.
In brain slice an increase in electrically evoked overflow was produced by cocaine (10 μm) whether total tritium overflow (1.8 fold), overflow of [3H]‐noradrenaline (1.8 fold) or overflow of unlabelled noradrenaline (1.8 fold) was measured. Evoked overflow from vas deferens was unaffected when assessed by any of these three methods.
The mechanism responsible for this differential effect of cocaine is unclear but may involve differences in the physical relationship between release sites, reuptake sites and presynaptic autoreceptors.