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982 results on '"Fredholm, Bertil B."'

121. Genetic Abrogation of Adenosine A(3) Receptor Prevents Uninephrectomy and High Salt-Induced Hypertension

Author

Yang, Ting, Zollbrecht, Christa, Winerdal, Malin E., Zhuge, Zhengbing, Zhang, Xing-Mei, Terrando, Niccolo, Checa, Antonio, Sällström, Johan, Wheelock, Craig E., Winqvist, Ola, Harris, Robert A., Larsson, Erik, Persson, A. Erik G., Fredholm, Bertil B., Carlström, Mattias, Yang, Ting, Zollbrecht, Christa, Winerdal, Malin E., Zhuge, Zhengbing, Zhang, Xing-Mei, Terrando, Niccolo, Checa, Antonio, Sällström, Johan, Wheelock, Craig E., Winqvist, Ola, Harris, Robert A., Larsson, Erik, Persson, A. Erik G., Fredholm, Bertil B., and Carlström, Mattias

Abstract

Background - Early-life reduction in nephron number (uninephrectomy [UNX]) and chronic high salt (HS) intake increase the risk of hypertension and chronic kidney disease. Adenosine signaling via its different receptors has been implicated in modulating renal, cardiovascular, and metabolic functions as well as inflammatory processes; however, the specific role of the A(3) receptor in cardiovascular diseases is not clear. In this study, gene-modified mice were used to investigate the hypothesis that lack of A(3) signaling prevents the development of hypertension and attenuates renal and cardiovascular injuries following UNX in combination with HS (UNX-HS) in mice. Methods and Results - Wild-type (A(3)(+/+)) mice subjected to UNX-HS developed hypertension compared with controls (mean arterial pressure 106 +/- 3 versus 82 +/- 3 mm Hg; P<0.05) and displayed an impaired metabolic phenotype (eg, increased adiposity, reduced glucose tolerance, hyperinsulinemia). These changes were associated with both cardiac hypertrophy and fibrosis together with renal injuries and proteinuria. All of these pathological hallmarks were significantly attenuated in the A(3)(-/-) mice. Mechanistically, absence of A(3) receptors protected from UNX-HS-associated increase in renal NADPH oxidase activity and Nox2 expression. In addition, circulating cytokines including interleukins 1 beta, 6, 12, and 10 were increased in A(3)(+/+) following UNX-HS, but these cytokines were already elevated in naive A(3)(-/-) mice and did not change following UNX-HS. Conclusions - Reduction in nephron number combined with chronic HS intake is associated with oxidative stress, chronic inflammation, and development of hypertension in mice. Absence of adenosine A(3) receptor signaling was strongly protective in this novel mouse model of renal and cardiovascular disease.

Published
2016
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122. Hyperalgesia, anxiety, and decreased hypoxic neuroprotection in mice lacking the adenosine [A.sub.1] receptor

Author

Johansson, Bjorn, Halldner, Linda, Dunwiddie, Thomas V., Masino, Susan A., Poelchen, Wolfgang, Gimenez-Llort, Lydia, Escorihuela, Rosa M., Fernandez-Teruel, Alberto, Wiesenfeld-Hallin, Zsuzsanna, Xu, Xiao-Jun, Hardemark, Anna, Betsholtz, Christer, Herlenius, Eric, and Fredholm, Bertil B.

Subjects
Anxiety -- Physiological aspects, Hypoxia -- Physiological aspects, Mice -- Physiological aspects, Adenosine -- Physiological aspects, Caffeine -- Physiological aspects, Science and technology
Abstract

Caffeine is believed to act by blocking adenosine [A.sub.1] and [A.sub.2A] receptors ([A.sub.1]R, [A.sub.2A]R), indicating that some [A.sub.1] receptors are tonically activated. We generated mice with a targeted disruption of the second coding exon of the [A.sub.1]R ([A.sub.1][R.sup.-/-]). These animals bred and gained weight normally and had a normal heart rate, blood pressure, and body temperature. In most behavioral tests they were similar to [A.sub.1][R.sup.+/+] mice, but [A.sub.1][R.sup.-/-] mice showed signs of increased anxiety. Electrophysiological recordings from hippocampal slices revealed that both adenosine-mediated inhibition and theophylline-mediated augmentation of excitatory glutamatergic neurotransmission were abolished in [A.sub.1][R.sup.-/-] mice. In [A.sub.1][R.sup.+/-] mice the potency of adenosine was halved, as was the number of [A.sub.1]R. In [A.sub.1][R.sup.-/-] mice, the analgesic effect of intrathecal adenosine was lost, and thermal hyperalgesia was observed, but the analgesic effect of morphine was intact. The decrease in neuronal activity upon hypoxia was reduced both in hippocampal slices and in brainstem, and functional recovery after hypoxia was attenuated. Thus [A.sub.1]Rs do not play an essential role during development, and although they significantly influence synaptic activity, they play a nonessential role in normal physiology. However, under pathophysiological conditions, including noxious stimulation and oxygen deficiency, they are important.

Published
2001

123. Genetic Abrogation of Adenosine A 3 Receptor Prevents Uninephrectomy and High Salt–Induced Hypertension

Author

Yang, Ting, primary, Zollbrecht, Christa, additional, Winerdal, Malin E., additional, Zhuge, Zhengbing, additional, Zhang, Xing‐Mei, additional, Terrando, Niccolo, additional, Checa, Antonio, additional, Sällström, Johan, additional, Wheelock, Craig E., additional, Winqvist, Ola, additional, Harris, Robert A., additional, Larsson, Erik, additional, Persson, A. Erik G., additional, Fredholm, Bertil B., additional, and Carlström, Mattias, additional

Published
2016
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124. In adenosine A(2B) knockouts acute treatment with inorganic nitrate improves glucose disposal, oxidative stress, and AMPK signaling in the liver

Author

Peleli, Maria, Hezel, Michael, Zollbrecht, Christa, Persson, Erik, Lundberg, Jon O., Weitzberg, Eddie, Fredholm, Bertil B., Carlstrom, Mattias, Peleli, Maria, Hezel, Michael, Zollbrecht, Christa, Persson, Erik, Lundberg, Jon O., Weitzberg, Eddie, Fredholm, Bertil B., and Carlstrom, Mattias

Abstract

Rationale: Accumulating studies suggest that nitric oxide (NO) deficiency and oxidative stress are central pathological mechanisms in type 2 diabetes (T2D). Recent findings demonstrate therapeutic effects by boosting the nitrate-nitrite-NO pathway, which is an alternative pathway for NO formation. This study aimed at investigating the acute effects of inorganic nitrate on glucose and insulin signaling in adenosine A2B receptor knockout mice (A(2B)(-/-), a genetic mouse model of impaired metabolic regulation. Methods: Acute effects of nitrate treatment were investigated in aged wild-type (WT) and A(2B)(-/-) mice. One hour after injection with nitrate (0.1 mmol/kg, i.p.) or placebo, metabolic regulation was evaluated by intraperitoneal glucose and insulin tolerance tests. NADPH oxidase-mediated superoxide production and AMPK phosphorylation were measured in livers obtained from non-treated or glucose-treated mice, with or without prior nitrate injection. Plasma was used to determine insulin resistance (HOMA-IR) and NO signaling. Results: A(2B)(-/-) displayed increased body weight, reduced glucose clearance, and attenuated overall insulin responses compared with age-matched WT mice. Nitrate treatment increased circulating levels of nitrate, nitrite and cGMP in the A(2B)(-/-), and improved glucose clearance. In WT mice, however, nitrate treatment did not influence glucose clearance. HOMA-IR increased following glucose injection in the A(2B)(-/-), but remained at basal levels in mice pretreated with nitrate. NADPH oxidase activity in livers from A(2B)(-/-), but not WT mice, was reduced by nitrate treatment. Livers from A(2B)(-/-) displayed reduced AMPK phosphorylation compared with WT mice, and this was increased by nitrate treatment. Finally, injection with the anti-diabetic agent metformin induced similar therapeutic effects in the A(2B)(-/-) as observed with nitrate. Conclusion: The A(2B)(-/-) mouse is a genetic mouse model of metabolic syndrome. Acute treatment with

Published
2015
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137. Adenosine A1 Receptors (A1R) Regulate Bone Resorption II Adenosine A1R Blockade or Deletion Increases Bone Density and Prevents Ovariectomy-Induced Bone Loss

Author

Kara, Firas M., Doty, Stephen B., Boskey, Adele, Goldring, Steven, Zaidi, Mone, Fredholm, Bertil B., and Cronstein, Bruce N.

Subjects
Mice, Knockout, Osteoblasts, Receptor, Adenosine A1, Ovariectomy, Osteoclasts, X-Ray Microtomography, Adenosine A1 Receptor Antagonists, Article, Mice, Inbred C57BL, Disease Models, Animal, Mice, Microscopy, Electron, Phenotype, Bone Density, Animals, Female, Bone Resorption
Abstract

Accelerated osteoclastic bone resorption plays a central role in the pathogenesis of osteoporosis and other bone diseases. Because identifying the molecular pathways that regulate osteoclast activity provides a key to understanding the causes of these diseases and developing new treatments, we studied the effect of adenosine A(1) receptor blockade or deletion on bone density.The bone mineral density (BMD) in adenosine A(1) receptor-knockout (A(1)R-knockout) mice was analyzed by dual x-ray absorptiometry (DXA) scanning, and the trabecular and cortical bone volume was determined by microfocal computed tomography (micro-CT). The mice were ovariectomized or sham-operated, and 5 weeks after surgery, when osteopenia had developed, several parameters were analyzed by DXA scanning and micro-CT. A histologic examination of bones obtained from A(1)R-knockout and wild-type mice was carried out. Visualization of osteoblast function (bone formation) after tetracycline double-labeling was performed by fluorescence microscopy.Micro-CT analysis of bones from A(1)R-knockout mice showed significantly increased bone volume. Electron microscopy of bones from A(1)R-knockout mice showed the absence of ruffled borders of osteoclasts and osteoclast bone resorption. Immunohistologic analysis demonstrated that although osteoclasts were present in the A(1)R-knockout mice, they were smaller and often not associated with bone. No morphologic changes in osteoblasts were observed, and bone-labeling studies revealed no change in the bone formation rates in A(1)R-knockout mice.These results suggest that the adenosine A(1) receptor may be a useful target in treating diseases characterized by excessive bone turnover, such as osteoporosis and prosthetic joint loosening.

Published
2010

142. Contributors

Author

Ashwell, Margaret, primary, Belfrage, Per, additional, Berlan, Michel, additional, Björntorp, Per, additional, Cannon, Barbara, additional, Clegg, Roger A., additional, Cryer, Anthony, additional, Faust, Irving M., additional, Fredholm, Bertil B., additional, Hausman, Gary J., additional, Himms-Hagen, Jean, additional, Hiragun, Akiyoshi, additional, Kasser, Tom R., additional, Kral, John G., additional, Lafontan, Max, additional, Martin, Roy J., additional, Nedergaard, Jan, additional, Ramsay, Tim G., additional, Saggerson, E. David, additional, Sjöström, Lars, additional, Slavin, Bernard G., additional, Van, Robin L.R., additional, Vernon, Richard G., additional, and York, David A., additional

Published
1985
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149. Binding of the prototypical adenosine A2A receptor agonist CGS 21680 to the cerebral cortex of adenosine A1 and A2A receptor knockout mice

Author

Lopes, Luisa V., Halldner, Linda, Rebola, Nelson, Johansson, Björn, Ledent, Catherine, Chen, Jian Fan, Fredholm, Bertil B, Cunha, Rodrigo A., and Repositório da Universidade de Lisboa

Subjects
Adenosine, Adenosine A2 Receptor Agonists, Receptor, Adenosine A2A, A1 receptors, Blotting, Western, Adenosine A1 Receptor Antagonists, Tritium, Binding, Competitive, Basal Ganglia, Striatum, Mice, CGS 21680, Phenethylamines, Animals, Cerebral Cortex, Mice, Knockout, Receptor, Adenosine A1, SCH 58261, Triazoles, Pyrimidines, Xanthines, Papers, Models, Animal, A2A receptors, Cortex, Autoradiography, Electrophoresis, Polyacrylamide Gel
Abstract

© 2004 Nature Publishing Group. All rights reserved, 1. 2-p-(2-carboxyethylphenethylamino-5'-ethylcarboxamidoadenosine) (CGS 21680) is considered the reference compound to study adenosine A(2A) receptors. However, CGS 21680 binding in the cerebral cortex, where adenosine A(1) receptors are predominant, displays a mixed A(2A)/A(1) receptor pharmacology. We now use adenosine A(1) and A(2A) receptor knockout mice to investigate the characteristics of cortical [(3)H]CGS 21680 binding. 2. [(3)H]CGS 21680 binding to the cerebral cortex was strongly reduced in adenosine A(1) receptor knockout mice, but only slightly reduced in A(2A) receptor knockout mice compared with the corresponding wild-type littermates. 3. Another selective A(2A) receptor ligand, [(3)H]-5-amino-7-(2-phenylethyl)-2-(2-furyl)-pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine ([(3)H]SCH 58261), displayed a saturable binding to mouse cortical membranes, albeit with a binding density 20 times lower than that of striatal membranes, and this [(3)H]SCH58261 binding was abolished in both striatal and cortical membranes of A(2A) receptor knockout mice and unchanged in A(1) receptor knockout mice. 4. The presence of A(2A) receptors in cortical neurons was further confirmed by Western blot in mouse cortical nerve terminal membranes. 5. It is concluded that, although A(2A) receptors are present in the cerebral cortex, the purportedly selective A(2A) receptor agonist [(3)H]CGS 21680 binds in the cerebral cortex to an entity that requires the presence of adenosine A(1) receptors. Thus, CGS 21680 should be used with care in all preparations where adenosine A(1) receptors out-number A(2A) receptors.

Published
2004

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