Role of adenosine A1 and A3 receptors in regulation of cardiomyocyte homeostasis after mitochondrial respiratory chain injury.
Activation of either the A(1) or the A(3) adenosine receptor (A(1)R or A(3)R, 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 A(1)R and A(3)R 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 muM) was less effective in protection. During treatment of cultured cardiomyocytes with hypoxia in the presence of 1 mM sodium azide, the A(1)R agonist 2-chloro-N(6)-cyclopentyladenosine was ineffective, whereas the A(3)R agonist 2-chloro-N(6)-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 Ca(2+) concentration after hypoxia and treatment with NaN(3) or after application of high doses of NaN(3), Cl-IB-MECA immediately decreased the elevated intracellular Ca(2+) concentration toward the diastolic control level. The A(1)R 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.
Shneyvays
Vladimir
V
Faculty of Life Sciences, Bar-Ilan Univ., Ramat Gan 52900, Israel.
Leshem
Dorit
D
Zinman
Tova
T
Mamedova
Liaman K
LK
Jacobson
Kenneth A
KA
Shainberg
Asher
A
D058907:Adenosine A1 Receptor Agonists; D058909:Adenosine A3 Receptor Agonists; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000502:physiology; D015687:Cell Hypoxia; D002478:Cells, Cultured; D003981:Diazoxide / Q000494:pharmacology; D006321:Heart / Q000502:physiology*; D006706:Homeostasis; D008929:Mitochondria, Heart / Q000473:pathology / Q000502:physiology*; D032342:Muscle Cells / Q000166:cytology / Q000502:physiology*; D015221:Potassium Channels / Q000502:physiology; D051381:Rats; D043682:Receptor, Adenosine A1 / Q000502:physiology*; D043684:Receptor, Adenosine A3 / Q000502:physiology*; D019810:Sodium Azide / Q000494:pharmacology
D058907:Adenosine A1 Receptor Agonists; D058909:Adenosine A3 Receptor Agonists; D015221:Potassium Channels; D043682:Receptor, Adenosine A1; D043684:Receptor, Adenosine A3; D000255:Adenosine Triphosphate; D019810:Sodium Azide; D003981:Diazoxide; D002118:Calcium