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| 2. |
- Asplund Persson, Anna, 1966-, et al.
(författare)
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Cross-talk between adenosine and the oxatriazole derivative GEA 3175 in platelets
- 2005
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Ingår i: European Journal of Pharmacology. - : Elsevier BV. - 0014-2999 .- 1879-0712. ; 517:3, s. 149-157
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Tidskriftsartikel (refereegranskat)abstract
- We examined the interplay between adenosine and the nitric oxide (NO)-containing oxatriazole derivative GEA 3175 in human platelets. The importance of cyclic guanosine 3′5′-monophosphate (cGMP)-inhibited phosphodiesterases (PDEs) was elucidated by treating the platelets with adenosine combined with either GEA 3175 or the PDE3-inhibitor milrinone. The drug combinations provoked similar cyclic adenosine 3′5′-monophosphate (cAMP) responses. On the contrary, cGMP levels were increased only in GEA 3175-treated platelets. Both drug combinations reduced P-selectin exposure, platelet adhesion and fibrinogen-binding. However, adenosine together with GEA 3175 was more effective in inhibiting platelet aggregation and ATP release. Thrombin-induced rises in cytosolic Ca2+ were suppressed by the two drug combinations. Adenosine administered with GEA 3175 was, however, more effective in reducing Ca2+ influx.In conclusion, the interaction between adenosine and GEA 3175 involves cGMP-mediated inhibition of PDE3. The results also imply that inhibition of Ca2+ influx represent another cGMP-specific mechanism that enhances the effect of adenosine.
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| 3. |
- Asplund Persson, Anna, 1966-, et al.
(författare)
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Dual actions of dephostatin on the nitric oxide/cGMP-signalling pathway in porcine iliac arteries
- 2005
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Ingår i: European Journal of Pharmacology. - : Elsevier BV. - 0014-2999 .- 1879-0712. ; 521:1-3, s. 124-132
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Tidskriftsartikel (refereegranskat)abstract
- We examined the effects of the nitrosoamine dephostatin on the nitric oxide (NO)/cyclic guanosine 3′,5′-monophosphate (cGMP)-signalling in porcine iliac arteries. Dephostatin has been characterised as a tyrosine phosphatase inhibitor, but Western blot analyses showed that dephostatin did not augment tyrosine phosphorylation of arterial proteins. However, dephostatin relaxed pre-contracted arteries, and this effect was antagonised by the soluble guanylyl cyclase inhibitor 1H[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ). Furthermore, dephostatin increased the cGMP content and the serine phosphorylation of vasodilator-stimulated phosphoprotein. Dephostatin also inhibited the relaxation induced by acetylcholine and the NO-donor S-nitroso-N-acetyl-penicillamine (SNAP). In contrast, dephostatin did not affect the NO-dependent actions of 1,2,3,4-Oxatriazolium, 3-(3-chloro-2-metylphenyl)-5-[[(4methylphenyl)sulfonyl]amino]-hydroxide inner salt (GEA 3175). Measurement of NO revealed that dephostatin accelerated the consumption of NO. In conclusion, dephostatin exerts dual effects on the NO/cGMP-signalling pathway in iliac arteries. The drug actions included scavenging of NO, but also stimulation of cGMP production. These effects were not related to inhibition of tyrosine phosphatases.
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| 4. |
- Birzniece, Vita, et al.
(författare)
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GABA(A) receptor changes in acute allopregnanolone tolerance
- 2006
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Ingår i: European Journal of Pharmacology. - : Elsevier BV. - 0014-2999 .- 1879-0712. ; 535:1-3, s. 125-134
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Tidskriftsartikel (refereegranskat)abstract
- To study acute tolerance, rats were anesthetized with interrupted i.v. allopregnanolone infusions where the "silent second" in the electroencephalogram (EEG) was the target. Animals were killed either directly at the first silent second or at the silent second level after 30 or 90 min of anaesthesia. Acute tolerance was demonstrated at 90 min of anaesthesia as earlier shown. In situ hybridization showed a decreased expression of the gamma-aminobutyric acid(A) (GABA(A)) receptor subunit alpha4mRNA amount in the thalamus ventral-posteriomedial nucleus of the tolerant rats. A parallel change in the abundance of the alpha4 subunit was detected with immunohistochemistry. The increase in maintenance dose rate (MDR) was significantly negatively correlated with the alpha4mRNA in the thalamus ventral-posteriomedial nucleus, and positively correlated with alpha2mRNA in different hippocampal subregions. There was also a positive relationship between the alpha1mRNA amounts in the different hippocampal subregions, with significant differences between groups. These changes in GABA(A) receptor subunits mRNA expression and protein (alpha4) might be of importance for the development of acute tolerance to allopregnanolone.
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| 5. |
- Braun, Oscar, et al.
(författare)
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Primary and secondary capture of platelets onto inflamed femoral artery endothelium is dependent on P-selectin and PSGL-1.
- 2008
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Ingår i: European Journal of Pharmacology. - : Elsevier BV. - 1879-0712 .- 0014-2999. ; 592, s. 128-132
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Tidskriftsartikel (refereegranskat)abstract
- Platelets constitute a key role in vascular injuries, however, the detailed mechanisms behind platelet-endothelial cell and platelet-leukocyte interactions in the femoral artery are not yet fully elucidated. We used intravital fluorescence microscopy of the femoral artery in C57BL/6 mice to study primary and secondary capture of platelets onto endothelial cells as well as onto adherent platelets and leukocytes in vivo. By use of monoclonal antibodies, the role of P-selectin and P-selectin glycoprotein ligand 1 (PSGL-1) in these adhesive interactions in mice exposed to endotoxin was determined. Intravenous injection of endotoxin significantly increased gene expression of P-selectin as well as platelet tethering, rolling and adhesion in the femoral artery. Pretreatment with the anti-PSGL-1 antibody decreased platelet tethering by 85%, platelet rolling by 88% and platelet adhesion by 96%. Immunoneutralization of P-selectin reduced platelet tethering by 91%, platelet rolling by 98%, and platelet adhesion by 97%. In addition, inhibition of P-selectin and PSGL-1 completely abolished secondary capture of platelets onto adherent platelets and leukocytes. Our data show that P-selectin and PSGL-1 mediate early interactions between platelets and other cells, including endothelial cells and leukocytes, in inflamed arteries. These novel results suggest that interference with P-selectin and PSGL-1 may be a useful target in strategies aiming to protect the vascular wall during arterial inflammation.
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| 6. |
- Bäckström, Torbjörn, et al.
(författare)
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Isoallopregnanolone; an antagonist to the anaesthetic effect of allopregnanolone in male rats
- 2005
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Ingår i: European Journal of Pharmacology. - Amsterdam : North-Holland. - 0014-2999 .- 1879-0712. ; 512:1, s. 15-21
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Tidskriftsartikel (refereegranskat)abstract
- The interaction of isoallopregnanolone (3β-OH-5α-pregnan-20-one) on allopregnanolone (3α-OH-5α-pregnan-20-one) induced anaesthesia was studied in male rats using burst suppression of 1 s (“silent second”) with an electroencephalographic-threshold method. The i.v. administration of isoallopregnanolone was varied in relation to induction of “silent second”. Pre-treatment with isoallopregnanolone (12.5–50 mg/kg iv) 2 min prior to the threshold test gave an increase in the threshold dose of allopregnanolone(ANOVA df(3;36), F=13.61, P<0.001), which was dose dependent (r=0.73, b [slope]=0.08, df=38, P<0.001). After isoallopregnanolone pre-treatment, but not in the controls, anaesthesia time was positively related to the dose of allopregnanolone (r=0.52, b=1.72, df=28,P<0.01). Anaesthesia times were not influenced by a corresponding administration of isoallopregnanolone immediately after induction of “silent second”. When allopregnanolone and isoallopregnanolone were infused together at molar ratios of 1:1, 1:1.23, 1:1.43, a linear increase of the threshold doses of allopregnanolone was seen in relation to the dose of isoallopregnanolone (r=0.86, b=0.40, df=8,P<0.01). Thus isoallopregnanolone can antagonise the anaesthetic action of allopregnanolone.
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| 7. |
- Delbro, Dick, et al.
(författare)
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Is acetylcholine an autocrine/paracrine growth factor via the nicotinic α-receptor subtype in the human colon cancer cell line HT-29?
- 2009
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Ingår i: European Journal of Pharmacology. - : Elsevier BV. - 0014-2999 .- 1879-0712. ; 609:1-3, s. 27-33
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Tidskriftsartikel (refereegranskat)abstract
- We used immunochemistry to demonstrate expression of acetylcholine's nicotinic 7-receptor subtype inhuman colon cancer cell line HT-29. Moreover, RT-PCR and immunochemistry showed that cholineacetyltransferase and acetylcholine esterase, the enzymes responsible for acetylcholine synthesis anddegradation, respectively, localise in HT-29 cells. Bromoacetylcholine bromide, an inhibitor of cholineacetyltransferase, significantly attenuated basal cell growth. Our findings suggest that acetylcholine mightserve as an autocrine/paracrineor speculatively, even intracrinesignalling molecule in cell line HT-29, thuscontributing to carcinogenesis/cancer progression
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| 9. |
- Eskesen, K, et al.
(författare)
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Upregulation of endothelin ETB receptor-mediated vasoconstriction in rat coronary artery after organ culture
- 2006
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Ingår i: European Journal of Pharmacology. - : Elsevier BV. - 1879-0712 .- 0014-2999. ; 539:3, s. 192-194
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Tidskriftsartikel (refereegranskat)abstract
- The aim of this study was to examine if endothelin ETB receptor-mediated contraction occurred in isolated segments of rat coronary arteries during organ culture. Presence of contractile endothelin ETB receptors was studied by measuring the change in isometric tension in rings of left anterior descending coronary arteries isolated from hearts of rats as response to application of the selective endothelin ETB receptor agonist, Sarafotoxin 6c and endothelin-1. In segments cultured 1 day in serum free Dulbecco's Modified Eagle's Medium, Sarafotoxin 6c induced a concentration dependent contraction with pEC(50) value of 10.4 +/- 0.21 and a maximal response of 3.9 +/- 0.25 mN/mm (n = 15). The maximal contraction was significantly larger than the responses measured in fresh tissue, where the mean value of the maximal contractions was 0.22 +/- 0.03 mN/mm (n = 17). The increased contraction to Sarafotoxin 6c, after culturing could be eliminated with addition of the transcriptional blocker, actinomycin D, to the culture medium or be significantly attenuated by application of the translational inhibitor, cycloheximide. The vasoconstrictor effect of endothelin-1 or to depolarisation by high K+-solution was not modified after 1 day in culture medium. The experiments indicate that organ culture of rat coronary arteries upregulate endothelin ETB receptor-mediated contraction by inducing synthesis of new protein. (c) 2006 Elsevier B.V. All rights reserved.
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