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This Article Full Text Full Text (PDF) All Versions of this Article: 288/6/H2792    most recent 01157.2004v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (9) Citing Articles via Google Scholar Google Scholar Articles by Shneyvays, V. Articles by Shainberg, A. Search for Related Content PubMed PubMed Citation Articles by Shneyvays, V. Articles by Shainberg, A.

Role of adenosine A₁ and A₃ receptors in regulation of cardiomyocyte homeostasis after mitochondrial respiratory chain injury

¹Gonda (Goldschmied) Medical Diagnostic Research Center, Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan, Israel; and ²Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland

Submitted 17 November 2004 ; accepted in final form 24 January 2005

Activation of either the A₁ or the A₃ adenosine receptor (A₁R or A₃R, respectively) elicits delayed cardioprotection against infarction, ischemia, and hypoxia. Mitochondrial contribution to the progression of cardiomyocyte injury is well known; however, the protective effects of adenosine receptor activation in cardiac cells with a respiratory chain deficiency are poorly elucidated. The aim of our study was to further define the role of A₁R and A₃R activation on functional tolerance after inhibition of the terminal link of the mitochondrial respiratory chain with sodium azide, in a state of normoxia or hypoxia, compared with the effects of the mitochondrial ATP-sensitive K⁺ channel opener diazoxide. Treatment with 10 mM sodium azide for 2 h in normoxia caused a considerable decrease in the total ATP level; however, activation of adenosine receptors significantly attenuated this decrease. Diazoxide (100 µM) was less effective in protection. During treatment of cultured cardiomyocytes with hypoxia in the presence of 1 mM sodium azide, the A₁R agonist 2-chloro-N⁶-cyclopentyladenosine was ineffective, whereas the A₃R agonist 2-chloro-N⁶-iodobenzyl-5'-N-methylcarboxamidoadenosine (Cl-IB-MECA) attenuated the decrease in ATP level and prevented cell injury. Cl-IB-MECA delayed the dissipation in the mitochondrial membrane potential during hypoxia in cells impaired in the mitochondrial respiratory chain. In cells with elevated intracellular Ca²⁺ concentration after hypoxia and treatment with NaN₃ or after application of high doses of NaN₃, Cl-IB-MECA immediately decreased the elevated intracellular Ca²⁺ concentration toward the diastolic control level. The A₁R agonist was ineffective. This may be especially important for the development of effective pharmacological agents, because mitochondrial dysfunction is a leading factor in the pathophysiological cascade of heart disease.

Ca²⁺ transience; hypoxia; ATP-sensitive K⁺ channel; sodium azide; heart disease; ischemia

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