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.