11 results on '"Bland-Ward PA"'
Search Results
2. Fab-arm exchange.
- Author
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Broug E, Bland-Ward PA, Powell J, and Johnson KS
- Subjects
- Animals, Cell Line, Humans, Mice, Models, Immunological, Immunoglobulin Fab Fragments immunology, Immunoglobulin G immunology, Immunoglobulin G therapeutic use
- Published
- 2010
- Full Text
- View/download PDF
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3. Inhibition of C-fibre mediated sensory transmission in the rat following intraplantar formalin.
- Author
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Martindale J, Bland-Ward PA, and Chessell IP
- Subjects
- Action Potentials drug effects, Action Potentials physiology, Animals, Electric Stimulation methods, Fixatives pharmacology, Hindlimb, Injections, Male, Nerve Fibers, Myelinated drug effects, Nerve Fibers, Myelinated physiology, Neural Inhibition physiology, Posterior Horn Cells drug effects, Posterior Horn Cells physiology, Rats, Rats, Sprague-Dawley, Synaptic Transmission physiology, Formaldehyde administration & dosage, Formaldehyde pharmacology, Nerve Fibers drug effects, Nerve Fibers physiology, Synaptic Transmission drug effects
- Abstract
Using extracellular recordings from deep dorsal horn neurones in the anaesthetized rat, the effects of intraplantar (i.pl.) administration of formalin were examined. Phasic patterns of dorsal horn firing were observed which temporally concur with previously described behavioural responses following i.pl. formalin. However, unexpectedly, formalin abolished C-fibre mediated transmission, and significantly reduced responses to noxious mechanical stimulation, while electrically evoked A-fibre responses were unaffected. This suggests that whilst the first phase formalin response is mediated by direct afferent stimulation, the second phase behavioural response is dependant on a central hyperexcitability of the recipient second-order dorsal horn neurones, which may be maintained by peripheral input only from A-fibres. This study therefore provides further evidence for a centrally-mediated secondary component of the formalin model, and for the first time, describes loss of high-threshold C-fibre input to the spinal cord during this phase. more...
- Published
- 2001
- Full Text
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4. P2X receptors mediate ATP-induced primary nociceptive neurone activation.
- Author
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Bland-Ward PA and Humphrey PP
- Subjects
- Animals, Humans, Male, Neurons, Afferent physiology, Pain physiopathology, Synaptic Transmission physiology, Adenosine Triphosphate physiology, Neurons physiology, Nociceptors physiology, Receptors, Purinergic P2 physiology
- Abstract
ATP-gated P2X ion-channel receptors are localised throughout the mammalian nervous system and have been identified on neurones which participate in conduction of nociceptive information from the periphery to, and within, the CNS. This article briefly reviews recently published research describing the role that ATP and P2X receptors may play in pain perception, highlighting the importance of the P2X(3) receptor in this process. The P2X(3) receptor subunit is almost exclusively expressed on a subset of small and medium diameter sensory neurones innervating cutaneous and visceral tissue. Activation of P2X receptors present on the peripheral terminals of primary afferents results in neuronal depolarisation and, in conscious animals, leads to the manifestation of acute nociceptive behaviour. Recent animal studies have also shown that P2X(3) receptor expression is increased in sensory ganglia following acute neuronal injury, hinting that similar plasticity in the expression of this receptor subtype could underlie the mechanisms involved in a range of conditions characterised by sensory hypersensitivity in man. It is apparent from the evidence available that functional antagonists at specific P2X receptor subtypes could represent an important class of novel analgesic agents. more...
- Published
- 2000
- Full Text
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5. Acute nociception mediated by hindpaw P2X receptor activation in the rat.
- Author
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Bland-Ward PA and Humphrey PP
- Subjects
- Animals, Behavior, Animal drug effects, Bradykinin pharmacology, Hindlimb, Male, Pain chemically induced, Purinergic P2 Receptor Agonists, Rats, Adenosine Triphosphate analogs & derivatives, Adenosine Triphosphate pharmacology, Pain physiopathology, Receptors, Purinergic P2 physiology
- Abstract
1. The functional consequences of P2X receptor activation on peripheral sensory neurones have been investigated in vivo. Behavioural indices of acute nociception were monitored in the conscious rat following subplantar injection of adenosine 5'-triphosphate (ATP), alpha,beta-methylene ATP, adenosine 5'-diphosphate (ADP) and adenosine. 2. Signs of overt nociception, i.e. hindpaw lifting and licking, were apparent in animals injected subplantar with the P2X receptor agonist, alpha,beta-methylene ATP. Nociceptive behaviours continued for 15 min following administration of alpha,beta-methylene ATP (200 nmol) and were dose-related (0-5 min hindpaw lifting times after injection of alpha,beta-methylene ATP 100 nmol and 1000 nmol were 89 +/- 26 s and 232 +/- 11 s, respectively). Subplantar ATP evoked a modest response only at the highest dose tested (1000 nmol; 0-5 min hindpaw lifting time 66 +/- 19 s) whilst ADP or adenosine (both 600 nmol) elicited negligible spontaneous nociceptive activity. 3. Morphine (3 mg kg-1, i.v.) abolished hindpaw licking behaviour induced by subplantar injection of either alpha,beta-methylene ATP (600 nmol) or bradykinin (1 nmol) and substantially reduced (88 +/- 5%) paw licking in formalin (0.5%, 0.1 ml) injected animals. In contrast, hindpaw lifting was only modestly inhibited (34 +/- 11%) in morphine-pretreated animals that had received subplantar bradykinin and was unaffected in rats in which the noxious stimulus was either subplantar alpha,beta-methylene ATP or formalin. Pretreatment of hindpaws with subplantar bupivacaine (1% w/v, 0.1 ml) abolished alpha,beta-methylene ATP-evoked nociceptive behaviours. 4. Hindpaw lifting and licking mediated by alpha,beta-methylene ATP (600 nmol, subplantar) were inhibited (72 +/- 15% and 95 +/- 5%, respectively) by 30 min local pretreatment with 600 nmol alpha,beta-methylene ATP. Subplantar alpha,beta-methylene ATP pretreatment did not inhibit behaviour stimulated by subsequent bradykinin (1 nmol) or formalin (0.5%, 0.1 ml) injection into the hindpaw. 5. Desensitization of small diameter sensory neurones with a single subplantar injection of capsaicin (100 micrograms) abolished all behaviours indicative of spontaneous nociceptive sensation in animals subsequently injected with alpha,beta-methylene ATP (600 nmol), bradykinin (1 nmol) or formalin (0.5%, 0.1 ml). 6. We conclude that activation of P2X receptors present on small diameter (capsaicin-sensitive) primary afferent neurones in the rat hindpaw mediates behaviour indicative of acute nociception. more...
- Published
- 1997
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6. 7-nitroindazole: an inhibitor of nitric oxide synthase.
- Author
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Moore PK and Bland-Ward PA
- Subjects
- Analgesics pharmacology, Animals, Aorta, Arginine metabolism, Carbachol pharmacology, Cattle, Cerebellum enzymology, Endothelium, Vascular enzymology, Female, Indazoles chemistry, Lung enzymology, Male, Mice, Molecular Structure, N-Methylaspartate pharmacology, NG-Nitroarginine Methyl Ester pharmacology, Neurons enzymology, Nitro Compounds pharmacology, Rabbits, Radioisotope Dilution Technique, Rats, Sensitivity and Specificity, Structure-Activity Relationship, Tritium, Enzyme Inhibitors pharmacology, Indazoles pharmacology, Isoenzymes antagonists & inhibitors, Nitric Oxide Synthase antagonists & inhibitors
- Published
- 1996
- Full Text
- View/download PDF
7. 7-Nitro indazole derivatives are potent inhibitors of brain, endothelium and inducible isoforms of nitric oxide synthase.
- Author
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Bland-Ward PA and Moore PK
- Subjects
- Amino Acid Oxidoreductases biosynthesis, Animals, Cattle, Endothelium, Vascular enzymology, Enzyme Induction drug effects, In Vitro Techniques, Nitric Oxide Synthase, Rats, Rats, Wistar, Amino Acid Oxidoreductases antagonists & inhibitors, Cerebellum enzymology, Indazoles pharmacology
- Abstract
The effect of 7-nitro indazole (7-NI) and a range of substituted indazole derivatives on nitric oxide synthase (NOS) enzyme activity in homogenates of rat cerebellum, bovine endothelial cells and lung from endotoxin-pretreated rats was investigated. 3-bromo 7-nitro indazole was either equipotent (IC50, 0.86 +/- 0.05 microM c.f. 0.78 +/- 0.2 microM, n = 6, P > 0.05) or approximately 4x (IC50, 0.17 +/- 0.01 microM c.f. 0.71 +/- 0.01 microM, n = 6, P < 0.05) or 20x (IC50, 0.29 +/- 0.01 microM c.f. 5.8 +/- 0.4 microM, n = 6, P < 0.05) more potent than 7-NI as an inhibitor of bovine endothelial, rat cerebellar and rat lung NOS enzyme activity respectively. 2,7-dinitro indazole also inhibited NOS in all three tissue sources with a potency similar to that of 7-NI. These results suggest that 3-bromo 7-NI and 2,7-dinitro indazole may prove to be useful additional tools with which to examine the biological properties of nitric oxide (NO). more...
- Published
- 1995
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8. Augmented antinociception following 7-nitro indazole and flurbiprofen in the conscious mouse.
- Author
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Gaffen Z, Bland-Ward PA, Pitcher A, Wallace P, and Moore PK
- Subjects
- Amino Acid Oxidoreductases metabolism, Animals, Blood Pressure drug effects, Drug Synergism, Edema prevention & control, Male, Mice, Nitric Oxide Synthase, Analgesics pharmacology, Flurbiprofen pharmacology, Indazoles pharmacology
- Abstract
Co-administration of the nitric oxide synthase inhibitor, 7-nitro indazole (1 mg/kg i.p.), with the cyclooxygenase inhibitor, flurbiprofen (5-75 mg/kg i.p.), resulted in significantly enhanced antinociceptive activity in mice (formalin-induced hindpaw licking assay) without affecting hindpaw inflammation. No antinociception was observed in animals pretreated with 7-nitro indazole (1 mg/kg i.p.) and flurbiprofen (100 micrograms subplantar). Flurbiprofen (50 mg/kg i.p.) pretreatment did not influence the inhibition of cerebellar or spinal cord nitric oxide synthase activity observed after 7-nitro indazole (1 or 25 mg/kg i.p.) administration and did not alter blood pressure in anaesthetised animals. Thus, flurbiprofen acts by a mechanism unrelated to a local anti-inflammatory effect in the hindpaw. Since nitric oxide synthase inhibitors are antinociceptive by an effect in the spinal cord (dorsal horn) this would appear to be a likely location for the nitric oxide synthase and cyclooxygenase enzymes targetted by 7-nitro indazole and flurbiprofen respectively. more...
- Published
- 1994
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9. Time course of inhibition of brain nitric oxide synthase by 7-nitro indazole.
- Author
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MacKenzie GM, Rose S, Bland-Ward PA, Moore PK, Jenner P, and Marsden CD
- Subjects
- Administration, Oral, Animals, Brain drug effects, In Vitro Techniques, Injections, Intraperitoneal, Male, Nitric Oxide Synthase, Rats, Rats, Wistar, Amino Acid Oxidoreductases antagonists & inhibitors, Brain enzymology, Indazoles pharmacokinetics, Indazoles pharmacology
- Abstract
7-Nitro indazole (7-NI) inhibits rat striatal, cerebellar, hippocampal, cerebral cortex and olfactory bulb nitric oxide synthase (NOS) in vitro with IC50 values of 0.68 +/- 0.01 microM, 0.64 +/- 0.03 microM, 1.53 +/- 0.05 microM, 0.93 +/- 0.04 microM and 1.05 +/- 0.02 microM respectively (n = 6). Intraperitoneal (i.p.) or oral administration of 7-NI (30 mg kg-1) to rats inhibited NOS enzyme activity measured ex vivo in all five brain regions (n = 5-6). NOS inhibition (maximal effect, 0.5 h post-injection) was transient with complete recovery at either 4 h (oral administration) or 24 h (i.p. administration). Repeated i.p. injection of 7-NI (30 mg kg-1, every 4 h for 20 h) inhibited NOS enzyme activity at 24 h by 51-61% in all brain regions. The relatively transient NOS inhibitory effect of 7-NI following parenteral administration should be taken into account when using this drug to evaluate the central effects of nitric oxide. more...
- Published
- 1994
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10. Effect of 7-nitro indazole on neurotransmission in the rat vas deferens: mechanisms unrelated to inhibition of nitric oxide synthase.
- Author
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Allawi HS, Wallace P, Pitcher A, Gaffen Z, Bland-Ward PA, and Moore PK
- Subjects
- Adenosine Triphosphate analogs & derivatives, Adenosine Triphosphate pharmacology, Amino Acid Oxidoreductases metabolism, Animals, Arginine analogs & derivatives, Arginine pharmacology, Electric Stimulation, In Vitro Techniques, Male, Muscle Contraction drug effects, Muscle, Smooth innervation, Muscle, Smooth physiology, NG-Nitroarginine Methyl Ester, Nitric Oxide Synthase, Norepinephrine pharmacology, Potassium Chloride pharmacology, Propranolol pharmacology, Rats, Rats, Wistar, Vas Deferens innervation, Vas Deferens physiology, Yohimbine pharmacology, Amino Acid Oxidoreductases antagonists & inhibitors, Indazoles pharmacology, Muscle, Smooth drug effects, Synaptic Transmission drug effects, Vas Deferens drug effects
- Abstract
1. The effect of the nitric oxide synthase (NOS) inhibitor, 7-nitro indazole (7-NI), on sympathetic and purinergic neurotransmission in the rat isolated vas deferens preparation has been studied. 2. 7-NI (50-200 microM) caused a dose- and frequency-dependent inhibition of the phasic (predominantly purinergic) contractile response of the rat vas deferens to electrical (field) stimulation (100 V, 0.5 ms). Greatest inhibition occurred at lower frequencies of stimulation (0.1-10 Hz). The sustained tonic contractile response (predominantly noradrenergic) was inhibited only at a high frequency of stimulation (60 Hz) and only at the highest concentration of 7-NI studies (200 microM). 3. 7-NI (100 microM) significantly reduced the contractile response of the vas deferens to exogenous ATP (20 microM-5 mM) and the stable P2X purinoceptor agonist, alpha, beta-methylene ATP (2.5 and 25.0 microM) but was without effect on contractions due to noradrenaline (0.1-50 microM) indicating a lack of antagonist effect on post-junctional alpha 1 adrenoceptors. 4. The effect of 7-NI (100 microM) on the phasic contractile response to field stimulation (0.1 and 2.0 Hz) was unaffected by preincubation of preparations with yohimbine (1.0 microM) or propranolol (0.01-10.0 microM) indicating the absence of involvement of alpha 2- or beta-adrenoceptors in this response. 5. 7-NI (50-600 microM) caused dose-related inhibition of contractions elicited by addition of a depolarizing concentration of KCl (64 mM). 6. The effect of 7-NI (100 microM) on the phasic contractile response to field stimulation (0.1 and 2.0 Hz) was unaffected by preincubation of preparations with L-arginine (1 mM). Neither L-arginine (1 mM) nor NC nitro L-arginine methyl ester (L-NAME, 100 LM) affected the response of the vas deferens to field stimulation at 0.1 or 2.0 Hz. Nitric oxide synthase (NOS) enzyme activity, measured as the conversion of[3H]-L-arginine to [3H]-citrulline, was not detectable in rat vas deferens homogenates.7. 7-Nr preferentially inhibits the purinergic component of the response of the rat vas deferens to field stimulation. The mechanism of action of 7-NI is not known but is not related to NOS inhibition. It seems likely that 7-NI combines an antagonist action at smooth muscle cell P2X-purinoceptors with the ability to inhibit the cellular influx of calcium ions. Although these hitherto unrecorded effects of 7-NI occur at relatively high concentrations, the effects described may contribute to the pharmacological effects of this NOS inhibitor. more...
- Published
- 1994
- Full Text
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11. Inhibition of rat cerebellar nitric oxide synthase by 7-nitro indazole and related substituted indazoles.
- Author
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Babbedge RC, Bland-Ward PA, Hart SL, and Moore PK
- Subjects
- Adrenal Glands drug effects, Adrenal Glands enzymology, Animals, Brain enzymology, Cattle, Cerebellum drug effects, In Vitro Techniques, Injections, Intraperitoneal, Kinetics, Male, Nitric Oxide Synthase, Rats, Rats, Sprague-Dawley, Spleen drug effects, Spleen enzymology, Stomach drug effects, Stomach enzymology, Structure-Activity Relationship, Amino Acid Oxidoreductases antagonists & inhibitors, Cerebellum enzymology, Indazoles pharmacology
- Abstract
1. 7-Nitro indazole (7-NI) produces potent inhibition of rat cerebellar nitric oxide synthase (NOS) with an IC50 of 0.9 +/- 0.1 microM (n = 6). NOS activity is dependent on the presence of both exogenous CaCl2 and NADPH. The inhibitory potency of 7-NI remained unaltered in the presence of different concentrations of either CaCl2 (0.75-7.5 mM) or NADPH (0.05-5.0 mM). 2. Kinetic (Lineweaver-Burke) analysis of the effect of 7-NI on rat cerebellar NOS revealed that inhibition was of a competitive nature with a Ki value of 5.6 microM. The Km of of cerebellar NOS with respect to L-arginine was 2.5 microM. 3. The following indazole derivatives (IC50 values shown in parentheses, all n = 6) caused concentration-related inhibition of rat cerebellar NOS in vitro: 6-nitro indazole (31.6 +/- 3.4 microM), 5-nitro indazole (47.3 +/- 2.3 microM), 3-chloro indazole (100.0 +/- 5.5 microM), 3-chloro 5-nitro indazole (158.4 +/- 2.1 microM) and indazole (177.8 +/- 2.1 microM). The IC50 values for 5-amino indazole, 6-amino indazole and 6-sulphanilimido indazole were in excess of 1 mM; 3-indazolinone was inactive. 4. 7-NI (10 mg kg-1) administered i.p. to rats produced 60 min thereafter a significant inhibition of NOS activity in cerebellum (31.1 +/- 3.2%, n = 6), cerebral cortex (38.2 +/- 5.6%, n = 6), hippocampus (37.0 +/- 2.8%, n = 6) and adrenal gland (23.7 +/- 3.0%, n = 6). NOS activity in olfactory bulb and stomach fundus were unchanged. 5. These results indicate that 7-NI is a potent and competitive inhibitor of rat brain NOS in vitro and also inhibits NOS in different brain regions and in the adrenal gland in vivo. Inhibition of NOS is a characteristic property of the indazole nucleus. Nitration of the indazole ring at positions 5, 6 and 7 results in a graded increase in inhibitory potency. Indazole-based inhibitors of NOS may prove useful tools with which to evaluate the biological roles of nitric oxide in the central nervous system. more...
- Published
- 1993
- Full Text
- View/download PDF
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