Adenosine, adenosine receptors and myocardial protection: An updated overview

Adenosine (Ado) accumulates in tissues under metabolic stress. On myocardia l cells, the nucleoside interacts with various receptor subtypes (A(1), A(3 ), and probably A(2A) and A(2B)) that are coupled, via G proteins, to multi ple effectors, including enzymes, channels, transporters and cytoskeletal c omponents. Studies using Ado receptor agonists and antagonists, as well as animals overexpressing the A, receptor indicate that Ado exerts anti-ischem ic action. Ado released during preconditioning (PC) by short periods of isc hemia followed by reperfusion induces cardioprotection to a subsequent sust ained ischemia. This protective action is mediated by A(1) and A(3) recepto r subtypes and involves the activation and translocation of PKC to sarcolem mal and to mitochondrial membranes. PKC activation leads to an increased op ening of ATP-sensitive K+ (K-ATP) channels. Recent studies implicate mitoch ondrial rather than sarcolemmal K,,p channels in the protective action of P C. Other effectors possibly contributing to cardioprotection by Ado or PC, and which seem particularly involved in the delayed (second window of) prot ection, include MAP kinases, heat shock proteins and NOS. Because of its an ti-ischemic effects, Ado has been tested as a protective agent in clinical interventions such as PTCA, CABG and tissue preservation, and was found in most cases to enhance the post-ischemic recovery of function. The mechanism s underlying the role of Ado and of mitochondrial function in PC are not co mpletely clear, and uncertainties remain concerning the role played by newl y identified potential effectors such as free radicals, the sarcoplasmic re ticulum, etc. In addition, more studies are needed to clarify the signallin g mechanisms by which A, receptor activation or overexpression may promote apoptosis and cellular injury, as reported by a few recent studies. (C) 200 1 Elsevier Science B.V. All rights reserved.