bluuebunny/crossref_metadata_2025_split huggingface dataset:
Gastric damage following local intra‐arterial administration of reactive oxygen metabolites in the rat
Authors: Esplugues J.V. , Whittle B.J.R. 
Published: July 2012

The effects of reactive oxygen metabolites on the rat gastric mucosa following close‐arterial infusion into the left gastric artery have been determined by macroscopic and histological assessment.
Local intra‐arterial infusion of hydrogen peroxide (0.6‐1.3 μmol kg−1 min−1) induced mucosal injury, characterised by areas of pronounced disruption and haemorrhage, which was prevented by concurrent intravenous administration of catalase.
Local infusion of the superoxide generating system xanthine‐oxidase and hypoxanthine likewise induced extensive haemorrhagic damage and necrosis of the mucosa. Prolonged incubation of this mixture (10 min) before administration, significantly reduced the degree of injury, indicating the lability of the products so formed.
The gastric mucosal injury induced by the superoxide generating system was inhibited by concurrent local infusion of superoxide dismutase (96 u kg−1 min−1), as was the associated increase in mucosal permeability to radiolabelled albumin.
Administration of catalase did not inhibit the gastric mucosal damage induced by infusion of xanthine oxidase‐hypoxanthine, yet augmented the protective effects of a low dose of superoxide dismutase (46 u kg−1 min−1 i.a.).
These findings directly confirm that reactive oxygen metabolites can induce extensive gastric mucosal injury, supporting their role in the pathogenesis of gastric damage following ischaemia and hypotensive shock.
Postnatal changes in response to adenosine and adenine nucleotides in rat duodenum
Authors: Furukawa Kyoko , Nomoto Teruko 
Published: July 2012

The effects of adenosine and adenine nucleotides were studied in rat duodenum from postnatal day 1 to day 70. The mechanical activity of duodenal segments was recorded through an isotonic transducer connected to a polygraphic recorder.
In rat duodenal segments, adenosine‐5′‐triphosphate (ATP, 10−4m) and adenosines‐5′‐diphosphate (ADP, 10−4m) produced a contractile response on postnatal day 1. This response increased with age, peaking on day 7, followed by a gradual decrease and was non‐existent by day 21. In contrast, a relaxant response to ATP and ADP was apparent on day 21, and continued to increase up to day 70.
The contraction caused by ATP was inhibited by indomethacin or the P2y‐purinoceptor antagonist, reactive blue‐2 but not by tetrodotoxin or hyoscine. Thus, it may be mediated by production of prostaglandin through the P2y‐purinoceptor. The relaxation produced by ATP was inhibited by reactive blue‐2 but not by tetrodotoxin, guanethidine or the P1‐purinoceptor antagonist, 8‐phenyltheophylline indicating that ATP acts on smooth muscle directly through the P2y‐purinoceptor. The pD2 for the contractile response to ATP was 5.15 on day 7 and that for the relaxant response, 6.64 on day 70.
Adenosine (10−4m) and adenosine‐5′‐monophosphate (AMP, 10−4m) elicited no response before day 14. On day 14, both adenosine and AMP produced a small relaxant response which increased with age. The relaxation produced by adenosine was inhibited by 8‐phenyltheophylline but not by tetrodotoxin or guanethidine, indicating that it is mediated by an action on the P1‐purinoceptor of smooth muscle.
It is evident from these results that in neonatal rat, a contractile response to ATP and ADP occurs initially in the duodenum, followed by a relaxant response to adenosine and AMP on day 14 and to ADP and ATP on day 21.
The smooth muscle of rat duodenum may tentatively be concluded to contain separate purinoceptors for adenosine and AMP (P1) and ADP and ATP (P2) and the responses to P1‐ and P2‐agonists change during the course of development.
Inhibition of neurally‐evoked transmitter release by calcium channel antagonists in rat parasympathetic ganglia
Authors: Seabrook Guy R. , Adams David J. 
Published: July 2012

Excitatory postsynaptic potentials (e.p.s.ps) were recorded from the submandibular parasympathetic ganglia of newborn rats (10–20 days old), by intracellular microelectrode recording and a suction electrode to deliver stimulus trains to the lingual nerve (15 stimuli at 0.1, 0.3, 1, 3, and 10 Hz, 22°C). Only evoked responses without voltage‐dependent action potentials were analyzed (observed at membrane potentials negative to −70 mV), and e.p.s.p. amplitudes were determined for the plateau responses during each train (5‐15th response).
Cadmium, an inorganic calcium channel antagonist, reduced e.p.s.p. amplitudes in a dose‐dependent manner (Kd 74 μm, P < 0.01). Nickel (1–300 μm) did not attenuate the amplitude of evoked responses.
Verapamil (0.1–30 μm), a phenylamine, had no significant effects upon e.p.s.p. amplitudes at any frequency examined. Higher concentrations of verapamil (100 μm) blocked neurally evoked responses in a manner consistent with the antagonism of voltage‐sensitive sodium currents.
Diltiazem, a benzothiazepine, reduced e.p.s.p. amplitudes in a dose‐dependent manner, the depression being accentuated at high stimulation frequencies (80% block at 30 μm and 10 Hz). The pure (−)‐cis enantiomer of diltiazem (10–30 μm) was without effect.
Amlodipine, a 1,4‐dihydropyridine, did not antagonize synaptic transmission at any stimulus frequency examined (10–30μm, 0.1–10 Hz, n = 3).
Amiloride, a potassium‐sparing diuretic, depressed the amplitudes of evoked responses in a dose‐dependent manner (one‐site Kd 31 μm, P < 0.005), although the extent of the block was alleviated with high stimulus frequencies. The effects of 30 μm amiloride were unlikely to be of postsynaptic origin as both the amplitudes of miniature e.p.s.ps, and the iontophoretic potentials induced by exogenous acetylcholine, were not attenuated by treatment with this compound. The amiloride derivative, 3′,4′‐dichlorobenzamil was ineffective in reducing the amplitude of e.p.s.ps (30–100 μm).
ω‐Conotoxin GVIA, a marine neurotoxin, which depressed whole cell calcium currents recorded from cultured rat parasympathetic cardiac neurones (up to 90% block at 10 nm), was ineffective at blocking synaptic transmission in submandibular ganglia (0.1–1 μm).
The differential effects of these calcium channel antagonists upon synaptic transmission in rat parasympathetic ganglia, suggest that either more than one type of calcium channel may be involved in transmitter release, or that the presynaptic calcium channels possess pharmacological sensitivities different from those of channel types described in neuronal cell bodies.
Inhibitory effects of AH 21–132 in guinea‐pig isolated ileum and taenia caeci
Authors: Small R.C. , Boyle J.P. , Elliott K.R.F. , Foster R.W. , Watt A.J. 
Published: July 2012

AH 21–132 is being investigated as a potential chemotherapeutic agent for bronchial asthma. The present experiments were designed to determine whether AH 21–132 shares the activity of theophylline as an antagonist at adenosine A1 receptors and to assess its potency as a relaxant in intestinal smooth muscle.
In the transmurally‐stimulated guinea‐pig ileum, theophylline (1 mm), but not AH 21–132 (1 and 10 μm), antagonized twitch depression induced by adenosine. Higher concentrations (100 μm and 1 mm) of AH 21–132 themselves had a depressant effect. Neither theophylline (1 mm) nor AH 21–132 (1 and 10 μm) antagonized twitch depression induced by noradrenaline.
AH 21–132 (100 μm and 1 mm) depressed maximum contractions of ileum induced by both acetylcholine (ACh) and histamine.
In ileum treated with hyoscine (1 μm), AH 21–132 (>10 μm) caused a concentration‐dependent depression of the log concentration‐effect curve for potassium chloride.
Simultaneous extracellular electrophysiological and mechanical recording from taenia caeci showed that AH 21–132 (100 μm‐1 mm) inhibited spontaneous tension waves and their associated bursts of electrical spike activity.
Intracellular electrophysiological recording from taenia caeci showed that the mechano‐inhibitory effect of 1 mM AH 21–132 was accompanied by abolition of spontaneous spike activity. Following spike abolition, the membrane potential assumed a value very close to that observed during periods of electrical quiescence prior to drug exposure.
AH 21–132 inhibited the activity of cyclic AMP‐dependent and cyclic GMP‐dependent phosphodiesterases derived from homogenates of ileal smooth muscle. The effective concentration ranges were 0.1–1000 μm and 1–1000 μm, respectively. Theophylline, too, inhibited these enzymes but in each case was less potent than AH 21–132.
It is concluded that AH 21–132 is devoid of antagonist activity at adenosine A1 receptors which modulate ACh release from intramural cholinergic nerves in the ileum. At concentrations greater than 10 μm, AH 21–132 has a relaxant effect on intestinal smooth muscle characterized by suppression of spontaneous action potentials but by minor change in resting membrane potential. AH 21–132 previously has been reported to depress the spontaneous tone of trachealis muscle with an EC50 value of less than 10 μm and the present experiments therefore show that this agent is much less potent in inhibiting intestinal muscle. This potency difference cannot be attributed to a tissue‐related difference in the potency of AH 21–132 as an inhibitor of cyclic AMP‐ or cyclic GMP‐dependent phosphodiesterases.
Inhibition of platelet‐activating factor‐ and zymosan‐activated serum‐induced chemotaxis of human neutrophils by nedocromil sodium, BN 52021 and sodium cromoglycate
Authors: Bruijnzeel P.L.B. , Warringa R.A.J. , Kok P.T.M. 
Published: July 2012

Inflammatory cells such as eosinophils and neutrophils are thought to contribute actively to the pathogenesis of asthma since they infiltrate into the lung tissue. These cells are mobilized by lipid‐like and protein‐like chemotactic factors. As illustrative examples of both groups, platelet‐activating‐factor (Paf) and zymosan‐activated‐serum (ZAS) were used in this study. The inhibitory effects of nedocromil sodium, the Paf antagonist BN 52021 and sodium cromoglycate on Paf‐ and ZAS‐induced neutrophil chemotaxis were evaluated.
All tested drugs inhibited Paf‐induced neutrophil chemotaxis with approximately the same potency (IC50 ≅ 1 nm).
Nedocromil sodium and sodium cromoglycate were equally potent in inhibiting ZAS‐induced neutrophil chemotaxis (IC50 = 0.1–1 μm), whereas BN 52021 was considerably less potent (IC30=10 μm).
To find out whether the drugs tested could inhibit early events in cell activation, their capacity to inhibit Paf‐ and ZAS‐induced cytosolic free Ca2+‐mobilization was investigated. BN 52021, at a concentration of 100 μm, completely inhibited Paf‐induced Ca2+‐mobilization and inhibited ZAS‐induced Ca2+‐mobilization by about 50%. Nedocromil sodium and sodium cromoglycate were ineffective.
Activation of the human neutrophil 5‐lipoxygenase by exogenous arachidonic acid: involvement of pertussis toxin‐sensitive guanine nucleotide‐binding proteins
Authors: McColl Shaun R. , Krump Eric , Naccache Paul H. , Caon Adriana C. , Borgeat Pierre 
Published: July 2012

The mechanism by which incubation of human peripheral blood neutrophils with exogenous arachidonic acid leads to 5‐lipoxygenase product synthesis was investigated.
Incubation of neutrophils with arachidonic acid caused a concentration‐ and time‐dependent synthesis of leukotriene B4, its Ω‐oxidation products, and 5‐hydroxyeicosatetraenoic acid.
The threshold concentration of arachidonic acid required for this effect was equal to, or greater than 3.3 μm and the synthesis increased with up to 33 μm arachidonic acid, the highest concentration used. Synthesis induced by arachidonic acid increased with time for up to 15 min and the major products detected were the Ω‐oxidation products of leukotriene B4.
Pre‐incubation of neutrophils with pertussis toxin inhibited the synthesis of 5‐lipoxygenase products induced by arachidonic acid by 75% or more, but had no effect on either arachidonic acid‐induced synthesis of the 15‐lipoxygenase product, 15‐hydroxyeicosatetraenoic acid, or activation of the 5‐lipoxygenase induced by the calcium ionophore A23187.
Pre‐incubation of neutrophils with granulocyte‐macrophage colony‐stimulating factor lead to enhanced leukotriene synthesis in response to arachidonic acid.
These results imply that exogenous arachidonic acid is not only used as a substrate, but also activates the 5‐lipoxygenase. Possible mechanisms of action are discussed.
3‐Aminopropylphosphinic acid—a potent, selective GABAB receptor agonist in the guinea‐pig ileum and rat anococcygeus muscle
Authors: Hills Judith M. , Dingsdale Rhona A. , Parsons Michael E. , Dolle Roland E. , Howson William 
Published: July 2012

3‐Aminopropylphosphinic acid, a γ‐aminobutyric acid (GABA) analogue, was tested for activity on guinea‐pig isolated ileum and rat isolated anococcygeus muscle preparations. The effects of 3‐aminopropylphosphinic acid were compared with those of GABA and baclofen.
In the electrically stimulated ileum, 3‐aminopropylphosphinic acid, like GABA and baclofen, caused a concentration‐dependent inhibition of the cholinergic twitch contraction, the IC50 value being 1.84 ± 0.23 μm (n = 12). Unlike GABA, but like baclofen, 3‐aminopropylphosphinic acid did not produce an initial contraction.
The inhibitory effects of 3‐aminopropylphosphinic acid and baclofen in the guinea‐pig ileum were not significantly antagonized by bicuculline (10 μm), phentolamine plus propranolol (both 1 μm), yohimbine (1 μm), naloxone (1 μm), impromidine (1 μm) or 8‐phenyltheophylline (10 μm). The inhibitory effects of 3‐aminopropylphosphinic acid, but not of baclofen, were however antagonized by phaclofen (500 μm). In addition the effects of 3‐aminopropylphosphinic acid were abolished by baclofen desensitization in the guinea‐pig ileum.
3‐Aminopropylphosphinic acid, GABA and baclofen reduced the twitch contraction evoked by electrical field stimulation in the rat anococcygeus muscle. The IC50 for 3‐aminopropylphosphinic acid inhibition of the anococcygeus contraction was 0.89 ± 0.15 μm (n = 8).
It is concluded that 3‐aminopropylphosphinic acid is a potent, selective GABAB agonist, being seven times more potent than baclofen in the guinea‐pig ileum and five times more potent than baclofen in the rat anococcygues muscle preparations.
Antagonism of responses to excitatory amino acids on rat cortical neurones by the spider toxin, argiotoxin636
Authors: Priestley T. , Woodruff G.N. , Kemp J.A. 
Published: July 2012

Several low molecular weight spider toxins have recently been shown to block potently glutama‐tergic neuromuscular transmission at the invertebrate neuromuscular junction. The aim of the present investigation was to evaluate the effects of one such toxin, argiotoxin636, on excitatory amino acid receptor‐mediated responses in mammalian neurones.
Membrane currents were recorded from rat cortical neurones after 2–6 weeks in cell culture, by the whole‐cell variant of the patch‐clamp technique. N‐methyl‐D‐aspartate (NMDA) and kainate were used as selective agonists for their respective receptor subtypes. α‐Amino‐3‐hydroxy‐5‐methyl‐4‐isoxazole‐propionic acid (AMPA) was used as a selective agonist for the quisqualate receptor subtype.
Responses to these agonists were characterised with respect to their concentration and voltage‐dependence. Argiotoxin636 (3–30 μm) was found to attenuate markedly responses to NMDA in an agonist‐ and voltage‐dependent manner. Thus, argiotoxin636 progressively reduced successive responses to NMDA when membrane potentials were voltage clamped between −40 mV to −100 mV. The more negative the membrane potential the more rapid the development of the block of inward current.
The antagonism of NMDA‐induced currents by argiotoxin636 could be reversed by clamping the membrane at positive potentials (+ 20 to + 60 mV) and reapplying NMDA.
Responses to AMPA and kainate were less affected by argiotoxin636, with an antagonist action only becoming evident at a concentration of 100 μm
These results suggest that argiotoxin636 is an open‐channel blocker of the NMDA activated ion‐channel in mammalian neurones. Furthermore, our results indicate at least a 30 fold selectivity for NMDA over the quisqualate‐ and kainate‐activated ion‐channels.
The effect of a single dose of oestradiol on tamoxifen‐induced uterine hyperaemia and growth in the rat
Authors: Marshall K. , Senior J. 
Published: July 2012

The effect of oestradiol on tamoxifen ‐ (single doses of each agent) induced responses in the uterus of the mature ovariectomized rat was investigated. The parameters examined were uterine blood flow (measured by the microsphere technique), weight and oestrogen receptor concentrations.
Initially the addition of oestradiol to the tamoxifen regimen produced a reduction in uterine blood flow and dry weight which was reflected by a reduction in nuclear oestrogen receptor. However, as the tamoxifen response became more established from 48 h onwards the addition of oestradiol produced an additive effect. These changes were not mirrored by increases in nuclear oestrogen receptor.
The results suggest that tamoxifen and oestradiol may, in part, act via different mechanisms; the role of possible mediatory systems such as histamine release and eosinophil migration is discussed. Heterogeneous control systems may also be involved in the early and late uterine response.
Nitroglycerin relaxes canine coronary arterial smooth muscle without reducing intracellular Ca2+ concentrations measured with fura‐2
Authors: Yanagisawa Teruyuki , Kawada Mitsuo , Taira Norio 
Published: July 2012

Changes in cytoplasmic Ca2+ concentration ([Ca2+]i) were measured simultaneously with force by a microfluorometric method using a calcium indicator, fura‐2, in canine coronary arterial smooth muscle cells.
Depolarization by high (30–90 mm) KCl‐physiological salt solution (PSS) produced concentration‐dependent increases in force and [Ca2+]i.
The KCl‐induced increase in [Ca2+]i was abolished by Ca2+‐free conditions and almost abolished by verapamil 10−5m, suggesting that it was entirely due to the increased Ca2+ influx through voltage‐dependent Ca2+ channels.
The [Ca2+]i‐force relationship in the presence of verapamil was not distinguishable from that of control.
Nitroglycerin produced a concentration‐dependent, reversible contraction of the coronary artery that had been contracted by high KC1‐PSS, without reduction of the increased [Ca2+]i.
The KCl‐induced increase in [Ca2+]i was not affected by nitroglycerin and in the presence of nitroglycerin it was abolished by 10−5m verapamil suggesting that it was caused by the influx of extracellular Ca2+.
The [Ca2+]i‐force curve was shifted to the right by nitroglycerin.
It is likely that nitroglycerin relaxes the coronary arterial smooth muscle by reducing the amount of myosin light chain phosphorylation even in the presence of raised [Ca2+]i produced by increased Ca2+ influx following depolarization.
Effects of endothelin on the mechanical activity and cytosolic calcium levels of various types of smooth muscle
Authors: Sakata K. , Ozaki H. , Kwon S.‐C. , Karaki H. 
Published: July 2012

Effects of porcine/human endothelin (endothelin‐1), a novel vasoconstrictor peptide, on various smooth muscles were examined.
In rat aorta, endothelin (1 pM‐30 nm) induced contraction in a concentration‐dependent manner. Removal of endothelium shifted the concentration‐response curve to the left. When added during the sustained contraction induced by 0.1 μm noradrenaline, endothelin (1 nm) induced a relaxation that was inhibited by removing endothelium or by methylene blue.
In rat aorta without endothelium, endothelin (1–30 nm) increased cytosolic Ca2+ level ([Ca2+]cyt) followed by contraction. Endothelin induced less contraction than high K+ at a given [Ca2+]cyt when the concentration of endothelin was lower (1–3 nm) and/or during the early phase of the contraction (< 10 min). In contrast, endothelin induced a greater contraction than KCl after prolonged exposure to high concentrations (> 10 nm).
The increase in [Ca2+]cyt due to endothelin was strongly inhibited by 10 μm verapamil or 0.3 μm nicardipine although muscle contraction was only partially inhibited.
In Ca2+‐free solution, endothelin (30 nm) induced a transient increase in [Ca2+]cyt and a slow increase in muscle tension. After a prolonged incubation in Ca2+‐free solution, endothelin (30 nm) still induced a slow increase in tension without changing [Ca2+]cyt. This contraction was inhibited by 1 μm sodium nitroprusside or 10 μm forskolin.
In canine trachea and guinea‐pig uterus, endothelin (30 nm) induced sustained contraction with an increase in [Ca2+]cyt. In the absence of external Ca2+, endothelin (30 nm) induced a sustained contraction in canine trachea without changing [Ca2+]cyt. In guinea‐pig vas deferens, taenia caeci and ileal longitudinal muscle, endothelin induced small increases in [Ca2+]cyt and tension.
In permeabilized smooth muscles, endothelin (30 nm) did not change the muscle tone.
These results suggest that endothelin acts on the endothelium and increases the synthesis or release of endothelium‐derived relaxing factor (EDRF). These results also suggest that endothelin acts directly on smooth muscle and increases [Ca2+]cyt by releasing Ca2+ from storage sites and increasing Ca2+ influx through the verapamil‐ and 1,4‐dihydropyridine‐sensitive pathway. Endothelin seems to decrease Ca2+‐sensitivity of contractile elements at lower concentrations and/or during the early phase of the contraction, whereas it increases Ca2+‐sensitivity at higher concentrations during the sustained phase of the contraction. Furthermore, endothelin induces a contraction that is not dependent on [Ca2+]cyt.
The influence of amine metabolizing enzymes on the pharmacology of tyramine in the isolated perfused mesenteric arterial bed of the rat
Authors: Elliott Jonathan , Callingham Brian A. , Sharman Dennis F. 
Published: July 2012

The pressor response to the infusion of tyramine (Tyr) into the isolated perfused mesenteric arterial bed of the rat has been studied at both a low and a high dose (0.2 and 2.0 μmol) and the effect of monoamine oxidase‐A (MAO‐A) and semicarbazide‐sensitive amine oxidase (SSAO) inhibition was examined. Very little MAO‐B activity is found in homogenates of this tissue when Tyr is used as substrate.
Inhibition of SSAO by treating rats with 1 mg kg−1 (E)‐2‐(3′,4′‐dimethoxyphenyl)‐3‐fluoroally lamine (MDL 72145) 1 h before dissection, had no significant effect on the maximum pressure attained or the area under the curve (AUC) of the response to both low and high doses of Tyr. Inhibition of MAO‐A, by inclusion of 10 μm clorgyline in the perfusing fluid, resulted in no significant potentiation at both low or high doses of Tyr. The inhibition of both these enzymes together substantially increased the AUC of the pressor response.
Cocaine (3 μm) significantly potentiated the responses to adrenaline (Ad). At this dose, cocaine significantly reduced the peak height and the AUC of the responses to both doses of Tyr.
Inhibition of extraneuronal uptake mechanisms with corticosterone (29 μm) did not potentiate the response to Ad and did not significantly alter the response to Tyr (low dose).
The effects of MDL 72145 and clorgyline on the directly acting amine, Ad, were studied. MDL 72145 caused a small but significant increase in the EC50 and in the maximum response to Ad, whilst clorgyline (10 μm) increased the EC50 value slightly and decreased the maximum response. When the two inhibitors were used in combination, a significant increase in the maximum response but with no change in the EC50 was seen.
These data indicate that the action of Tyr in this vascular bed is, at least, partly indirect. Inactivation of Tyr is effected by both MAO‐A and SSAO in the blood vessel wall. Inhibition of both enzymes seems to be necessary to achieve a significant potentiation of the pressor response. The effects of these enzyme inhibitors on directly acting amines may mask any potentiation of the response when MAO‐A or SSAO alone are inhibited.