Consequences of eliminating adenosine A1 receptors in mice

Bertil B Fredholm, Linda Halldner, Catarina Johansson, Gunnar Schulte, Cecilia Lovdahl, Peter Thoren, Thomas V Dunwiddie, Susan A Masino, Wolfgang Poelchen, Lihong Diao, Peter Illes, Nancy R Zahniser, Guro Valen, Shinichi Tokuno, Hilchen Sommerschild, Lydia Gimenez-Llort, Alberto Fernandez-Teruel, Rosa M Escorihuela, Zsuzsanna Wiesenfeld-Hallin, Xiao-Jun XuAnna Hardemark, Eric Herlenius, Milos Pekny, Samuel Gebre-Medhin, Russell Deputy Brown, Anna Ollerstam, Erik Persson, Ole Skott, Bjorn Johansson

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The second coding exon of the adenosine A1 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 A1 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 A1 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.
Original languageEnglish
Pages (from-to)350 - 353
Number of pages4
JournalDrug Development Research
Issue number4
Publication statusPublished - 2003

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