Adenosine and preconditioning revisited

1. Myocardial tolerance against infarction is substantially increased by exposing myocytes to 3-10 min transient ischaemia, In this phenomenon, termed 'preconditioning', the adenosine receptor is one of the redundant triggers and the best characterized factor in the cardioprotective mechanism. 2. An increase in interstitial adenosine during preconditioning is thought to he derived primarily from hydrolysis of 5'-AMP in the myocyte by cytosolic 5'-nucleotidase, although a contribution of ectosolic 5'-nucleotidase remains controversial, Adenosine production during ischaemia is substantially suppressed in the preconditioned myocardium, probably due to a decrease in ATP utilization. 3. The adenosine receptor needs to be activated not only at the time of preconditioning ischaemia, but also during ischaemic insult for the preconditioning to be cardioprotective. However, the extent of cardioprotection afforded by preconditioning is primarily determined by the interstitial adenosine level achieved during preconditioning ischaemia, not by the level during sustained ischaemia. These data suggest that a post-receptor mechanism downstream of the adenosine receptor may be upregulated after preconditioning, 4. Studies in vitro suggest that the subtypes of adenosine receptor relevant to preconditioning against infarction are A(1) and A(3), the activation of which appears to provide additive protection. The functional interrelationship between these subtypes in vivo remains unknown. 5. An important step downstream of adenosine receptor activation is protein kinase C (PKC), which facilitates opening of ATP-sensitive potassium (K-ATP) channels, probably leading to enhancement of myocardial tolerance. However, activation of other protein kinases, such as tyrosine kinase, mag also be important in preconditioning, depending on the animal species and preconditioning protocols. The PKC isoform and location of K-ATP channels (i,e. sarcolemmal vs mitochondrial K-ATP) that induce anti-infarct tolerance in myocytes remain to be identified.