Sites and mechanism of adenosine formation in the cardiovascular system

This review summarizes recent developments on the mechanisms by which adeno sine is formed in the cardiovascular system. The concept is developed that AMP is both a precursor of adenosine but also a product when rephosphorylat ed by adenosine kinase. The functional significance of this metabolic cycle is the amplification of changes in free cytosolic adenosine, which transla tes a minor decrease of cardiac energetics in a substantial rise in adenosi ne. Furthermore, the metabolism of adenosine is highly compartmentalized, a nd the vascular endothelium forms an important metabolic barrier, which sig nificantly influences the dose-response curve for adenosine when this nucle oside 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 re markable 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 be tween ATP formation and consumption. Future studies must resolve which fact ors govern the in-vivo activity of adenosine kinase and 5'-nucleotidase and how this is linked to the known physiologic effects of adenosine. Furtherm ore, the molecular mechanisms by which ATP can permeate through cell membra nes and gives rise to the extracellular formation of adenosine need to be r esolved. Drug Dev. Res. 45:288-294, 1998. (C) 1998 Wiley-Liss, Inc.