Role of Adenosine in Cardioprotection

Abstract

Adenosine may act as an endogenous cardioprotective substance in pathophysiological conditions of the heart, such as myocardial ischemia and heart failure. For example, when brief periods of ischemia precede sustained ischemia, infarct size is markedly limited, a phenomenon known as ischemic preconditioning. Because exogenous adenosine limits infarct size markedly, we tested whether endogenous adenosine is involved in the mediation of the infarct size-limiting effect of ischemic preconditioning. In the open-chest dog model, we found that ischemic preconditioning activates the enzyme responsible for adenosine release, i.e., ecto-5'-nucleotidase. Furthermore, the inhibitor of ecto-5'-nucleotidase blunted the infarct size-limiting effect of ischemic preconditioning, which establishes the cause-effect relationship between activation of ecto-5'-nucleotidase and the infarct size-limiting effect. We also found that activation of protein kinase C was responsible for this activation of ecto-5'-nucleotiase. On the other hand, we found that plasma adenosine levels were increased in patients with chronic heart failure. Ecto-5'-nucleotidase activity was increased in blood and myocardium in patients with chronic heart failure, which may be responsible for the increases in adenosine levels in plasma and the myocardium. Furthermore, we found that further elevation of plasma adenosine levels caused by either dipyridamole or dilazep improves the severity of chronic heart failure. Taken together, we propose potential mechanisms for cardioprotection attributable to adenosine in pathophysiological states in heart diseases. The establishment of adenosine therapy may throw light on the new paradigm for the treatment of either ischemic heart diseases or chronic heart failure.