Adenosine and cardioprotection during ischaemia and reperfusion--an overview

Adenosine is a local hormone, with numerous tissue-specific biological functions. In the myocardium, adenosine is released in small amounts at constant basal rate during normoxia. During ischaemia the production of adenosine increases several fold due to breakdown of adenosine triphosphate (ATP). Increased production of adenosine causes coronary vasodilatation. Thus, adenosine couples myocardial metabolism and flow during ischaemia and is called a homeostatic or "retaliatory metabolite". Furthermore, adenosine has electrophysiological effects in supraventricular tissue, causing a decrease in heart rate. In 1985 it was discovered that adenosine also exerts cardioprotective effects directly on cardiomyocytes. The aim of this review is to give an overview of the role of adenosine as a directly cytoprotective agent during myocardial ischaemia and reperfusion. We will focus on its effects on the myocytes, elicited by stimulation of adenosine receptors in sarcolemma, which triggers intracellular signalling systems. We will also address the new aspect that adenosine can influence regulation of gene expression. There is evidence that the myocardium is capable of endogenous adaptation in response to ischaemia, namely "hibernation" and early and late phases of "preconditioning". Endogenous substances produced during ischaemia probably trigger these responses. We will discuss the role of adenosine in these different settings. Adenosine can be given exogenously through intravasal routes; however, this review will also focus on the effects of endogenously produced adenosine. We will discuss pharmacological ways to increase endogenous levels of adenosine, and the effects of such interventions during ischaemia and reperfusion. Finally, we will review results from studies in humans together with relevant experimental studies, and indicate potential therapeutic implications of adenosine.