Formation and release of purine catabolites during hypoperfusion, anoxia, and ischemia

Abstract

To answer some of the as yet unresolved questions about the formation, metabolism, and release of purine catabolites in hypoxic myocardium, we compared their release from isolated rabbit hearts during hypoperfusion, anoxia, and after ischemia, with and without nucleoside-transport inhibition. Results provide evidence to suggest the following. Besides the supply-to-demand ratio for O2, other factors may affect the formation of adenosine. The myocyte is the major source of purine catabolites. Adenosine is not produced within the myocyte. Once in the interstitium, adenosine is (largely) taken up in the endothelial cells, where it is catabolized to inosine and hypoxanthine and released that way into the lumen. Some of the adenosine can reach the lumen unchanged through clefts. Nucleoside transport inhibition prevents the escape through the endothelial cells and thus the formation and release of inosine and hypoxanthine. As a consequence, more adenosine will accumulate in the interstitium and more will reach the lumen through the clefts. The pathway, as proposed, explains the long known paradox of increased extracellular levels of adenosine after inhibition of nucleoside transport.

Cutting Edge: Hypoxia-Inducible Factor 1α and Its Activation-Inducible Short Isoform I.1 Negatively Regulate Functions of CD4+ and CD8+ T Lymphocytes

“…Another possibility is that the short isoform of HIF-1␣ may inhibit NF-B activity (e.g., by binding and retaining NF-B from nuclear translocation, or by up-regulation of expression of I B), and thereby inhibit proinflammatory transcription. We suggest that HIF-1-mediated anti-inflammatory pathway in T cells is complementary to tissue-protecting immunosuppressive signaling by extracellular adenosine (2,14,15,28,29), which is accumulated in hypoxic conditions (30,31).…”

An Angiogenic Switch in Macrophages Involving Synergy between Toll-Like Receptors 2, 4, 7, and 9 and Adenosine A2A Receptors

“…74 Adenosine accumulates to high levels (up to 100 mol/L) extracellularly in ischemic situations, when blood flow to tissues is compromised, with intracellular breakdown of ATP resulting in the formation and release of adenosine. [15][16][17] To determine the effects of adenosine on macrophage expression of VEGF and TNF␣, macrophages were incubated with adenosine in the presence of EHNA, a potent inhibitor of adenosine deaminase, to prevent the breakdown of adenosine to inosine. Under these conditions, strong synergy with E. coli LPS to induce VEGF expression and suppress TNF␣ expression was observed.…”

Ligand-Activation of the Adenosine A2a Receptors Inhibits IL-12 Production by Human Monocytes

“…During ischemia or hypoxia, local ADO concentrations increase to the micromolar range (11), whereas the secretion of TNF-␣ has been implicated in the pathogenesis of ischemia-reperfusion injury (32). Recent evidence indicates that ADO attenuates reperfusion injury following ischemia partly through inhibition of TNF-␣ production (33,34).…”

“…Postganglionic sympathetic nerve terminals also release ATP that is rapidly degraded to ADO, which induces vasodilatation mediated by A2 receptors (10). Local extracellular ADO levels increase dramatically during ischemia and hypoxia, possibly providing cytoprotection and increased blood flow to ischemic tissues (11). Inflammation and tissue injury represent pathologic states that are also associated with enhanced extracelluar ADO concentrations.…”