Activation of Adenosine A1 and A3 Receptors Protects Mitochondria during Hypoxia in Cardiomyocytes by Distinct Mechanisms

Abstract

Results of many investigations indicate that activation of adenosine (ADO) A1 and A3 receptors (A1Rs and A3Rs) elicits delayed protection against infarction, ischemia or hypoxia and that both A1R and A3R induce cardioprotection through opening of KATP channels. We suppose that opening of KATP channels may not be the only final mediator of cardioprotection. The protection of the mitochondrial respiratory chain and its impact on mitochondrial bioenergetics after ADO receptor activation may be achieved by different mechanisms. The contribution of mitochondrial and sarcolemmal KATP channels, the rate of mitochondrial ATP synthesis and redox state of mitochondria were compared in normoxic and hypoxic conditions on cultured newborn cardiomyocytes. Activation of both subtypes of ADO receptors induces certain decrease in energy supply and simultaneously promotes preservation of adequate amounts of ATP and maintenance of mitochondrial metabolism on a level sufficient for cell survival. It was found that neither diazoxide nor A1R agonist CCPA nor A3R agonist Cl-IB-MECA modified mitochondrial membrane potential in intact cells. Activation of adenosine A1 receptor slowed down the ΔΨ repolarization. Diazoxide also decreases the rate of energization capacity in living cardiomyocytes upon succinate oxidation. The A3R agonist Cl-IB-MECA did not affect mitochondrial bioenergetics in normoxic cardiomyocytes. It was shown that A3 adenosine receptor stimulation modulates the sarcoplasmic reticulum (SR) Ca2+ channel and may regulate Ca2+ overloading. In conclusion, our data establish that adenosine can mediate myocardial protection by acting on A1 and A3 adenosine receptors. However, the cascades of events involved in cardioprotection against hypoxia appear to be distinct for A1 and A3 receptor signaling.