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- Fredholm, BB, et al.
(author)
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Consequences of eliminating adenosine A(1) receptors in mice
- 2003
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In: Drug Development Research (Proceedings of the Seventh International Symposium on Adenosine and Adenine Nucleotides - Part 1). - : Wiley. - 1098-2299 .- 0272-4391. ; 58, s. 350-
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Conference paper (peer-reviewed)abstract
- The second coding exon of the adenosine A, receptor gene was eliminated by homologous recombination. The phenotype of mice (mixed C57B6/129OlaHsd background) was studied, using siblings from matings of heterozygous mice. Among the offspring the ratio between+/+, +/-and -/-animals was 1:2:1. Over the first half-year-at least-growth and viability were the same in all genotypes. Binding of A(1) ligands was eliminated in-/-mice and halved in+/-mice. Blood pressure was increased in-/-mice and this was paralleled by an increase in plasma renin. Heart rate was unaffected, as was contractility. Furthermore, the response of the perfused heart to ischemia was similar in+/+and -/-hearts. However, remote preconditioning was eliminated in-/-mouse hearts. Tubuloglomerular feedback in the kidney was also lost in-/-mice. The analgesic response to a non-selective adenosing receptor agonist was lost in-/-mice, which also showed hyperalgesia in the tail-flick test. There was a slight hypoactivity in-/-mice, but responses to caffeine were essentially normal. The inhibition of excitatory neurotransmission in hippocampus by adenosine was lost in-/-mice and reduced in+/-mice. Responses to ATP were affected similarly. Hypoxic depression of synaptic transmission was essentially eliminated in hippocampus and hypoxic decrease in spinal respiratory neuron firing was markedly reduced. These results show that adenosine A, receptors play a physiologically important role in the kidney, spinal cord, and hippocampus and that they are critically important in the adaptive responses to hypoxia. (C) 2003 Wiley-Liss, Inc.
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| 2. |
- Ghanem, E, et al.
(author)
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Luminal adenosine stimulates chloride secretion through A1 receptor in mouse jejunum
- 2005
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In: American journal of physiology. Gastrointestinal and liver physiology. - : American Physiological Society. - 0193-1857 .- 1522-1547. ; 288:5, s. G972-G977
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Journal article (peer-reviewed)abstract
- Adenosine is known to stimulate chloride secretion by mouse jejunum. Whereas the receptor on the basolateral side is believed to be A2B, the receptor involved in the luminal effect of adenosine has not been identified. We found that jejuna expressed mRNA for all adenosine receptor subtypes. In this study, we investigated the stimulation of chloride secretion by adenosine in jejuna derived from mice lacking the adenosine receptors of A1(A1R) and A2A(A2AR) or control littermates. The jejunal epithelium was mounted in a Ussing chamber, and a new method on the basis of impedance analysis was used to calculate the short-circuit current ( Isc) values. Chloride secretion was assessed by the Iscafter inhibition of the sodium-glucose cotransporter by adding phloridzin to the apical bathing solution. The effect of apical adenosine on chloride secretion was lost in jejuna from mice lacking the A1R. There was no difference in the response to basolaterally applied adenosine or to apical forskolin. Furthermore, in jejuna from control mice, the effect of apical adenosine was also abolished in the presence of 8-cyclopentyl-1,3-dipropylxanthine, a specific A1R antagonist. Responses to adenosine were identical in jejuna from control and A2AR knockout mice. This study demonstrates that A1R (and not A2AR) mediates the enhancement of chloride secretion induced by luminal adenosine in mice jejunum.
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| 10. |
- Lovdahl, C, et al.
(author)
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The synthetic metalloproteinase inhibitor batimastat suppresses injury-induced phosphorylation of MAP kinase ERK1/ERK2 and phenotypic modification of arterial smooth muscle cells in vitro
- 2000
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In: Journal of vascular research. - : S. Karger AG. - 1018-1172 .- 1423-0135. ; 37:5, s. 345-354
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Journal article (peer-reviewed)abstract
- Smooth muscle cell (SMC) migration and proliferation are important events in the formation of intimal lesions associated with atherosclerosis and restenosis following balloon angioplasty. The extracellular matrix has important functions in modulating SMC structure and function, but less is known about the role of the matrix metalloproteinases (MMPs) and their endogenous tissue inhibitors. The present study investigates the effects of the synthetic MMP inhibitor batimastat (BB94) on vascular SMCs. As experimental model, rat aortic smooth muscle cells in primary and secondary cultures were employed. Electron microscopy was used to investigate the effects of BB94 on the overall phenotypic properties of the cells. Induction of DNA synthesis and migration was studied by thymidine autoradiography and counting of cells moving into an injured zone. Gelatin zymography was used for the detection of BB94-mediated inhibition of injury-induced MMP activity. Phosphorylation of the mitogen-activated protein kinases ERK1/ERK2, two potential mediators of the injury-induced activation of the cells, was measured by Western blotting. The results show that BB94 restrained the phenotypic modulation of vascular SMCs in primary cultures and suppressed injury-induced DNA synthesis and migration. Moreover, the upregulation of ERK1/ERK2 phosphorylation in injured secondary cultures and in cells treated with bFGF was markedly reduced by BB94, whereas TIMP-2 lacked a clear effect. Our data suggest that BB94 inhibits injury-induced activation of vascular SMCs by acting on MMPs as well as other targets.
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