Origin, metabolism and function of extracellular adenine nucleotides in the blood

In previous views the role of adenine nucleotides was thought to be confined to the intracellular space of the cell. However, research of the last decades has revealed that nucleotides also occur in the extracellular space. This survey deals with the sources, metabolism and the role in blood of the extracellular adenine mononucleotides ATP, ADP, AMP and the dinucleotides diadenosine tetraphosphate (Ap4A) and diadenosine triphosphate (Ap3A). The latter two are novel compounds, which have recently been discovered in human platelets. The mononucleotides originate from damaged tissues, from red blood cells during haemolysis, from activated platelets, the working muscle and from the nervous system, whereas the dinucleotides are exclusively released from stimulated platelets. Both the adenine mono- and the dinucleotides act as signal molecules on blood cells as well as on cells of the vascular wall, thereby modulating physiological processes such as platelet aggregation, histamine release from mast cells, regulation of vascular tone and white cell functions. In order to limit the signal effects of extracellular nucleotides, blood cells, plasma and the interior of the vessel walls are provided with nucleotide splitting enzymes: ATP, ADP and AMP are mainly degraded by ectoenzymes present on blood cells, endothelial and on smooth muscle cells, whereas dinucleotides are primarily metabolized by plasma enzymes. This review closes with the presentation of the clinical utility of Ap3A and Ap4A as tools for the diagnosis of platelet storage pool defects.