Sites and mechanism of adenosine formation in the cardiovascular system

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This review summarizes recent developments on the mechanisms by which adenosine is formed in the cardiovascular system. The concept is developed that AMP is both a precursor of adenosine but also a product when rephosphorylated by adenosine kinase. The functional significance of this metabolic cycle is the amplification of changes in free cytosolic adenosine, which translates a minor decrease of cardiac energetics in a substantial rise in adenosine. Furthermore, the metabolism of adenosine is highly compartmentalized, and the vascular endothelium forms an important metabolic barrier, which significantly influences the dose-response curve for adenosine when this nucleoside is applied intervascularly. Inadequate supply of oxygen (critical Po 2 : 3 mm Hg) is the most important physiologic trigger for the formation of adenosine. In the range above the critical Po 2 , cardiomyocytes have the remarkable ability to down-regulate their oxygen consumption before metabolic signs of hypoxia occur. Therefore, a reduction in oxygen supply as such is not a sufficient cause for the formation of adenosine but the imbalance between ATP formation and consumption. Future studies must resolve which factors govern the in-vivo activity of adenosine kinase and 5'-nucleotidase and how this is linked to the known physiologic effects of adenosine. Furthermore, the molecular mechanisms by which ATP can permeate through cell membranes and gives rise to the extracellular formation of adenosine need to be resolved.