Adenosine and the Cardiovascular System

Allison B. Reiss; David Grossfeld; Lora J. Kasselman; Heather A. Renna; Nicholas A. Vernice; Wendy Drewes; Justin Konig; Steven E. Carsons; Joshua DeLeon


Am J Cardiovasc Drugs. 2019;19(5):449-464. 

In This Article

Synthesis and Metabolism

Adenosine is released in tissues at times of cellular stress such as hypoxia, ischemia and inflammation. With ischemic insult, when metabolic demands exceed oxygen supply, endogenous levels of adenosine increase rapidly.[31] Cell hypoxia is a potent stimulus for adenosine release. Adenosine is formed via dephosphorylation of adenosine triphosphate (ATP) both inside and outside the cell[32] (Figure 1). It can be formed intracellularly from ATP, adenosine diphosphate (ADP) or adenosine monophosphate (AMP) by activity of cytoplasmic 5′-nucleotidases or extracellularly from ATP or ADP by the sequential action of ecto-nucleoside triphosphate diphosphohydrolase (ecto-NTPDase-1 [CD39])—or possibly other NTDPases—that form AMP and ecto-5′-nucleotidase (CD73), which converts AMP to adenosine. Adenosine can also be generated from S-adenosylhomocysteine (SAH) via SAH hydrolase.[33] A biochemical mechanism responsible for significant adenosine production from cAMP is referred to as the cAMP–adenosine pathway.[34] This pathway involves the conversion of cAMP to AMP by an enzyme—phosphodiesterase (PDE) or exonuclease—followed by dephosphorylation of 5′-AMP by intra- and extracellular 5′-nucleotidases. Adenosine is able to travel across cell membranes to maintain equilibrium between intracellular and extracellular adenosine concentrations. Extracellular adenosine is rapidly taken into cells via both sodium-dependent and sodium-independent transporters for subsequent metabolism. Very rapid uptake of adenosine takes place via endothelial cells, erythrocytes, and adjacent tissues, where adenosine can move across the plasma membrane space and be utilized within the cell. Once adenosine is taken up by endothelium, it is phosphorylated by adenosine kinases to form AMP or degraded by adenosine deaminase (ADA) to inosine.[35] The physiological concentration of adenosine in human plasma is 0.1–1 μM.[36] The half-life of adenosine in human plasma is very short, ranging from 0.6 to 1.5 s.[37] The short halflife is attributed to the rapid elimination of adenosine from the extracellular space, which depends to a large extent on nucleoside transporters. Adenosine moves by means of these nucleoside transporters because it is hydrophilic and not permeable to cell membranes. The receptor-mediated effects of adenosine are terminated by uptake into cells by these transporters, categorized as equilibrative nucleoside transporters (ENTs) and concentrative nucleoside transporters (CNTs).[38,39] ENTs act via facilitative diffusion, are bidirectional, sodium-independent, have a large selectivity and exist in multiple cell types, while CNTs are nucleoside-sodium symporters that are seen in only certain types of cells and have a more limited specificity. The human ENT1 is an important transporter in the vasculature. ENT1 and ENT2 are found predominantly in the plasma membrane. Certain CNTs can interact with adenosine, and human CNT1 has a high affinity for adenosine, which acts as a competitive inhibitor for other permeants. This solidifies the phenomena that adenosine is involved in different interactions with various selective transporters, and inhibitors of nucleoside transporters would block uptake and metabolism of extracellular adenosine, augmenting the receptor-mediated physiological effects of adenosine.[40,41]

Figure 1.

Intracellular and extracellular biogenesis of adenosine. Adenosine is formed via dephosphorylation of ATP both inside and outside the cell. It can be formed intracellularly from ATP via adenylyl cyclase-mediated conversion of ATP to cAMP, which is then converted to AMP by phosphodiesterases. Subsequent activity of cytoplasmic 5′-nucleotidases converts AMP into adenosine, which can in turn be converted back to AMP through adenosine deaminase and adenosine kinase activity, with an inosine intermediate. A second intracellular pathway exists in which adenosine can be generated from SAH via SAH hydrolase. Extracellularly, ATP is converted to adenosine through the sequential action of ecto-NTP-Dase-1 (CD39) that forms AMP, and ecto-5′-nucleotidase (CD73) which converts AMP to adenosine. ADP adenosine diphosphate, AMP adenosine monophosphate, ATP adenosine triphosphate, cAMP cyclic AMP, ecto-NTP-Dase-1 ecto-nucleoside triphosphate diphosphohydrolase, GPCR G-protein-coupled receptor, SAH S-adenosylhomocysteine