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ADENOSINE AND PRECONDITIONING REVISITED
Author(s) -
Miura Tetsuji,
Tsuchida Akihito
Publication year - 1999
Publication title -
clinical and experimental pharmacology and physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.752
H-Index - 103
eISSN - 1440-1681
pISSN - 0305-1870
DOI - 10.1046/j.1440-1681.1999.03003.x
Subject(s) - adenosine , cardioprotection , ischemic preconditioning , adenosine receptor , adenosine a3 receptor , adenosine a1 receptor , myocyte , ischemia , purinergic signalling , pharmacology , chemistry , receptor , medicine , agonist
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 be 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 up‐regulated 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, may 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.