Adenosine and cardioprotection during ischaemia and reperfusion – an overview

Abstract

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.

Cardiac purinergic signalling in health and disease

“…Studies focusing on the attenuation of myocardial ischaemia by targeting A2BR have been reviewed recently [561]. Previous reviews discussed the role of adenosine in pre-conditioning and ischaemia-reperfusion injury [65, [562][563][564][565][566][567][568][569][570].…”

Pathophysiology and Therapeutic Potential of Purinergic Signaling

“…ATP was shown to inhibit atrioventricular conduction rather than the firing rate of sinoatrial nodes in patients with ischemic heart disease; injection of ATP is used only when a transient cardiac standstill is needed, such as for endovascular grafting surgery (Watanabe et al, 2002). Treatment of myocardial ischemia and reperfusion by ATP-MgCl 2 is still recommended (Katircioglu et al, 2000), but many reports suggest that adenosine (a breakdown product of ATP) also mediates this effect (Liang and Jacobson, 1999;Broadley, 2000;Sommerschild and Kirkeboen, 2000;Thompson et al, 2002).…”

Acute exercise increases the ventricular arrhythmia threshold via the intrinsic adenosine receptor system in conscious hypertensive rats

“…The half-life of adenosine in blood is very short (0.6 -1.5 s) (29). Thus endogenous adenosine acts locally at the site where it is produced (44). These facts support a cardiac A 1 receptor and coronary artery A 2A receptor effect because endogenous cardiac adenosine would not be expected to mediate peripheral vasodilatation.…”

“…Because adenosine reduces calcium currents, it can thereby be antiarrhythmic by inhibiting delayed afterdepolarizations elicited by sympathetic stimulation. Adenosine also antagonizes the response to adrenergic stimulation (30,44). For example, adenosine acts presynaptically to inhibit the release of norepinephrine (38).…”

“…During normoxia in the myocardium, adenosine is released in small amounts at a constant basal rate (44) and is present at low levels due to its rapid removal by three pathways. An imbalance between myocardial oxygen supply and demand results in the net breakdown of ATP, and adenosine release can increase up to 50-fold (31).…”