Biological and mechanical stressors such as
ischemia, hypoxia, cellular
ATP depletion, Ca2+ overload,
free radicals, pressure and volume overload,
catecholamines,
cytokines, and
renin-
angiotensin may independently cause reversible and/or irreversible cardiac dysfunction. As a defense against these forms of stress, several endogenous self-protective mechanisms are exerted to avoid cellular injury.
Adenosine, a degradative substance of
ATP, may act as an endogenous cardioprotective substance in pathophysiological conditions of the heart, such as
myocardial ischemia and chronic
heart failure. For example, when brief periods of
myocardial ischemia precede sustained
ischemia,
infarct size is markedly limited, a phenomenon known as ischemic preconditioning. We found that ischemic preconditioning activates the
enzyme responsible for
adenosine release, ie,
ecto-5'-nucleotidase. Furthermore, the inhibitor of
ecto-5'-nucleotidase reduced 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
protein kinase C is responsible for the activation of
ecto-5'-nucleotidase.
Protein kinase C phosphorylated the
serine and
threonine residues of
ecto-5'-nucleotidase. Therefore, we suggest that
adenosine produced via
ecto-5'-nucleotidase gives cardioprotection against
ischemia and
reperfusion injury. Also, we found that plasma
adenosine levels are increased in patients with chronic
heart failure.
Ecto-5'-nucleotidase activity increased in the blood and the myocardium in patients with chronic
heart failure, which may explain the increases in
adenosine levels in the plasma and the myocardium. In addition, we found that further elevation of plasma
adenosine levels due to either
dipyridamole or
dilazep reduces the severity of chronic
heart failure. Thus, we suggest that endogenous
adenosine is also beneficial in chronic
heart failure. We propose potential mechanisms for cardioprotection attributable to
adenosine in pathophysiological states in
heart diseases. The establishment of
adenosine therapy may be useful for the treatment of either
ischemic heart diseases or chronic
heart failure.