| 1. |
- Asplund Persson, Anna K, et al.
(author)
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Characterisation of GEA 3175 on human platelets : comparison with S-nitroso-N-acetyl-D,L-penicillamine
- 2004
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In: European Journal of Pharmacology. - : Elsevier BV. - 0014-2999 .- 1879-0712. ; 496:1-3, s. 1-9
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Journal article (peer-reviewed)abstract
- By comparing the effect of two nitric oxide (NO)-containing compounds, we found that S-nitroso-N-acetyl-d,l-penicillamine (SNAP), but not GEA 3175 (1,2,3,4-Oxatriazolium,3-(3-chloro-2-metylphenyl)-5-[[(4-methylphenyl)sulfonyl]amino]-, hydroxide inner salt), released NO. Despite this, both drugs elevated cyclic guanosine 3′,5′-monophosphate (cGMP) levels in human platelets. However, SNAP was more effective after short exposure times (5 and 20 s). The compounds also inhibited thrombin-induced rises in cytosolic Ca2+. Time studies revealed that the action of SNAP rapidly declined by increasing the length of incubation (from 5 s to 30 min). This desensibilisation phenomenon mainly involved the release of Ca2+ from intracellular stores. In comparison, GEA 3175-induced inhibition of cytosolic Ca2+ signalling was much more long-lasting. The soluble guanylyl cyclase (sGC) inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) reversed the effect of GEA 3175 on cytosolic Ca2+. Consequently, this inhibition depends solely on the increase in cGMP. In summary, differences between GEA 3175 and SNAP were observed in NO releasing, cGMP elevating and Ca2+ suppressive properties.
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| 2. |
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| 3. |
- Edvinsson, Lars, et al.
(author)
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Effect of the CGRP receptor antagonist BIBN4096BS in human cerebral, coronary and omental arteries and in SK-N-MC cells.
- 2002
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In: European Journal of Pharmacology. - 1879-0712. ; 434:1-2, s. 49-53
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Journal article (peer-reviewed)abstract
- Several lines of evidence suggest that a calcitonin-gene related peptide (CGRP) receptor antagonist may serve as a novel abortive migraine treatment. Here we present data on a human cell line and isolated human vessels for such an antagonist, BIBN4096BS. On SK-N-MC membranes, radiolabelled CGRP was displaced by both CGRP-(8-37) and BIBN4096BS, yielding pK(i) values of 8.5 and 11.4, respectively. Functional studies with SK-N-MC cells demonstrated that CGRP-induced cAMP production was antagonised by both CGRP-(8-37) and BIBN4096BS with pA(2) values of 7.8 and 11.2, respectively. Isolated human cerebral, coronary, and omental arteries were studied with a sensitive myograph technique. CGRP induced a concentration-dependent relaxation that was antagonized by both CGRP-(8-37) and BIBN4096BS in a competitive manner. CGRP was a weaker agonist on coronary arteries as compared to intracranial arteries; however, BIBN4096BS was an equally effective antagonist. In human omental arteries, CGRP did not induce relaxation. BIBN4096 had a pA(2) value of 10.1 in cerebral and 10.4 in coronary arteries. The results of clinical trials with BIBN4096BS for acute migraine attacks are awaited with great interest.
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| 4. |
- Eghbali, M, et al.
(author)
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Effects of propofol on GABA(A) channel conductance in rat-cultured hippocampal neurons
- 2003
-
In: European Journal of Pharmacology. - 1879-0712. ; 468:2, s. 75-82
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Journal article (peer-reviewed)abstract
- Channels were activated, in ripped-off patches from rat-cultured hippocampal neurons, by propofol alone, propofol plus 0.5 muM GABA (gamma-aminobutyric acid) or GABA alone. The propofol-activated currents were chloride-selective, showed outward-rectification and were enhanced by 1 muM diazepam. The maximum propofol-activated channel conductance increased with propofol concentration from less than 15 pS (10 muM) to about 60 pS (500 muM) but decreased to 40 pS in 1 mM propofol. Fitting the data from 10 to 500 muM propofol with a Hill-type equation gave a maximum conductance of 64 pS, an EC50 value of 32 muM and a Hill coefficient of 1.1. Addition of 0.5 muM GABA shifted the propofol EC50 value to 10 muM and increased the maximum channel conductance to about 100 pS. The Hill coefficient was 0.8. The maximum channel conductance did not increase further when 1 muM diazepam was added together with a saturating propofol concentration and GABA. The results are compared to effects other drugs have on GABA(A) channels conductance. (C) 2003 Elsevier Science B.V All rights reserved.
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| 5. |
- Eghbali, Mansoureh, et al.
(author)
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Effects of propofol on GABAA channel conductance in rat-cultured hippocampal neurons.
- 2003
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In: European Journal of Pharmacology. - 0014-2999 .- 1879-0712. ; 468:2, s. 75-82
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Journal article (peer-reviewed)abstract
- Channels were activated, in ripped-off patches from rat-cultured hippocampal neurons, by propofol alone, propofol plus 0.5 microM GABA (gamma-aminobutyric acid) or GABA alone. The propofol-activated currents were chloride-selective, showed outward-rectification and were enhanced by 1 microM diazepam. The maximum propofol-activated channel conductance increased with propofol concentration from less than 15 pS (10 microM) to about 60 pS (500 microM) but decreased to 40 pS in 1 mM propofol. Fitting the data from 10 to 500 microM propofol with a Hill-type equation gave a maximum conductance of 64 pS, an EC50 value of 32 microM and a Hill coefficient of 1.1. Addition of 0.5 microM GABA shifted the propofol EC50 value to 10 microM and increased the maximum channel conductance to about 100 pS. The Hill coefficient was 0.8. The maximum channel conductance did not increase further when 1 microM diazepam was added together with a saturating propofol concentration and GABA. The results are compared to effects other drugs have on GABAA channels conductance.
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| 6. |
- Elmi, Adrian, et al.
(author)
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Modulation of islet ATP content by inhibition or stimulation of the Na(+)/K(+) pump
- 2001
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In: European Journal of Pharmacology. - : Elsevier. - 0014-2999 .- 1879-0712. ; 426:1-2, s. 139-143
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Journal article (peer-reviewed)abstract
- High (30 mM) K(+), known to cause beta-cell membrane depolarisation, significantly decreased the islet total ATP content, supporting the view that beta-cell membrane depolarisation can activate the ATP-consuming Na(+)/K(+) pump. Ouabain (1 mM) did not change the islet ATP content after 5-15 min of incubation in the absence or presence of 3 mM glucose but reduced it after 30 min, and in the presence of 20 mM glucose, the reduction by ouabain occurred already after 15 min. Incubation of islets with ouabain for 60 min decreased the islet ATP content in the presence of 3, 10 or 20 mM glucose or 30 mM K(+). Also, the islet glucose oxidation rate was decreased by ouabain. When K(+) deficiency was used to inhibit the Na(+)/K(+) pump, no change in ATP content was observed irrespective of glucose concentration, although K(+) deficiency caused a slight inhibition of the glucose oxidation rate. Diazoxide reduced the islet glucose oxidation rate and increased the islet ATP content in the presence of 20 mM glucose. There may exist a feedback mechanism decreasing the flow of glucose metabolism in response to reduced ATP consumption by the Na(+)/K(+) pump.
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| 7. |
- Hoy, M, et al.
(author)
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Imidazoline NNC77-0074 stimulates insulin secretion and inhibits glucagon release by control of Ca2+-dependent exocytosis in pancreatic alpha- and beta-cells
- 2003
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In: European Journal of Pharmacology. - 1879-0712. ; 466:1-2, s. 213-221
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Journal article (peer-reviewed)abstract
- We have investigated the effects of the novel imidazoline compound (+)-2-(2-(4,5-dihydro-1H-imidazol-2-yl)-thiopene-2-yl-ethyl)pyridine (NNC77-0074) on stimulus-secretion coupling in isolated pancreatic alpha- and beta-cells. NNC77-0074 stimulated glucose-dependent insulin secretion in intact mouse pancreatic islets. No effect was observed at less than or equal to 2.5 mM glucose and maximal stimulation occurred at 10-15 mM glucose. NNC77-0074 produced a concentration-dependent stimulation of insulin secretion. Half-maximal (EC50) stimulation was observed at 24 muM and at maximally stimulatory concentrations insulin release was doubled. The stimulatory action of NNC77-0074 on insulin secretion was not associated with membrane depolarisation or a change in the activity of ATP-sensitive K+ channels. Using capacitance measurements, we found that NNC77-0074 stimulated depolarisation-induced exocytosis 2.6-fold without affecting the whole-cell Ca2+ current when applied via the extracellular medium. The concentration dependence of the stimulatory action was determined by intracellular application of NNC77-0074 through the recording pipette. NNC77-0074 stimulated exocytosis half-maximal at 44 nM and at maximally stimulatory concentrations the rate of exocytosis was increased twofold. NNC77-0074 stimulated depolarised-induced insulin secretion from islets exposed to diazoxide and high external KCl (EC50 = 0.45 muM). The stimulatory action of NNC77-0074 was dependent on protein kinase C activity. NNC77-0074 potently inhibited glucagon secretion from rat islets (EC50 = I I nM). This was not associated with a change in spontaneous electrical activity and ATP-sensitive K channel activity but resulted from a reduction of the rate of Ca2+-dependent exocytosis in single rat alpha-cells (EC50=9 nM). Inhibition of exocytosis by NNC77-0074 was pertussis toxin-sensitive and mediated by activation of the protein phosphatase calcineurin. In rat somatotrophs, PC12 cells and mouse cortical neurons NNC77-0074 did not stimulate Ca2+-evoked exocytosis, whereas the other imidazoline compounds phentolamine and efaroxan produced 2.5-fold stimulation of exocytosis. Our data suggest that the imidazoline compound NNC77-0074 constitutes a novel class of antidiabetic compounds that stimulates glucose-dependent insulin release while inhibiting glucagon secretion. These actions are exclusively exerted by modulation of exocytosis of the insulin- and glucagon-containing granules. (C) 2003 Elsevier Science B.V. All rights reserved.
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| 8. |
- Jansen-Olesen, I, et al.
(author)
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In-depth characterization of CGRP receptors in human intracranial arteries
- 2003
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In: European Journal of Pharmacology. - : Elsevier BV. - 1879-0712 .- 0014-2999. ; 481:2-3, s. 207-216
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Journal article (peer-reviewed)abstract
- The purpose of the present study was to characterize the effects of human (h) alpha- and beta-calcitonin gene-related peptide (CGRP) on intracranial arteries from man and to investigate the presence of mRNA for the calcitonin receptor like receptor (CRLR) and the receptor activity modifying proteins (RAMPs) 1, 2 and 3, in cerebral and middle meningeal arteries with and without endothelium, in microvessels and in the endothelial cells isolated from the human basilar artery. Reverse transcriptase-polymerase chain reaction (RT-PCR) revealed the presence of CRLR, RAMP 1, RAMP 2 and RAMP 3 in cerebral and middle meningeal arteries with and without endothelium as well as in microvessels and in the endothelial cells. Human and rat a- and p-CGRP, amylin, adrenomedullin and [acetamidomethyl-Cys(2,7)]human CGRP induced strong concentration-dependent relaxation of human cerebral and middle meningeal arteries. Removal of the endothelium neither changed the maximum relaxant response nor the pIC(50) values for alpha- and beta-CGRP as compared to the responses in arteries with an intact endothelium. Human alpha-CGRP-(8-37) caused a shift of halpha- and hbeta-CGRP-induced relaxations in cerebral and middle meningeal arteries. Calculation of pK(B) values revealed that halpha-CGRP-(8-37) could not significantly discriminate between relaxations induced by halpha-CGRP (pK(B) around 6.8) and hbeta-CGRP (pK(B) around 5.4). There was no significant difference in pK(B) value of halpha-CGRP-(8-37) on hbeta-CGRP-induced relaxation of human cerebral and middle meningeal arteries with and without endothelium. In conclusion, our molecular and pharmacological data support the existence of a single type of CGRP(1) receptors in the human intracranial circulation. (C) 2003 Elsevier B.V. All rights reserved.
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| 9. |
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| 10. |
- Jonsson, M., et al.
(author)
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Neuromuscular blocking agents block carotid body neuronal nicotinic acetylcholine receptors
- 2004
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In: European Journal of Pharmacology. - : Elsevier BV. - 0014-2999 .- 1879-0712. ; 497:2, s. 173-180
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Journal article (peer-reviewed)abstract
- Neuromuscular blocking agents predominantly block muscle type nicotinic acetylcholine receptors as opposed to the neuronal type. However, there is growing evidence that neuromuscular blocking agents have affinity to some neuronal nicotinic acetylcholine receptors. The carotid body chemoreceptor as the essential oxygen-sensing cell, relies on cholinergic signalling. Atracurium and vecuronium impair carotid body chemoreceptor activity during hypoxia. Here, we characterize atracurium and vecuronium as antagonists at nicotinic receptors of the carotid body chemoreceptor. Isolated rabbit carotid body preparations with carotid sinus nerve were used, and chemoreceptor activities were recorded. There was a concentration-dependent reduction in the chemoreceptor responses to nicotine, with an IC50 to 50 µg nicotine of 3.64 and 1.64 µM and to 500 µg nicotine of 27.00 µM and 7.29 µM for atracurium and vecuronium, respectively. It is concluded that atracurium and vecuronium depress nicotine-induced chemoreceptor responses of the carotid body in a dose-dependent fashion. © 2004 Elsevier B.V. All rights reserved.
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