Role of adenosine in the heart and circulation

Adenosine (Ado), a metabolite of adenine nucleotides, is a ubiquitous biological compound found in every cell of the human body l. Since the classic work by Drury and Szent-GyGrgyi in 1929 2, in which the coronary vasodilator and antiarrhytbmic properties of this nucleoside were first described, and in which its role as a regulator of coronary blood flow was first proposed, it has become increasingly clear that Ado plays not only a biological role in cellular metabolism, but also an important physiological role in the cardiovascular system l-4. Interest in the subject was rekindled by Beme in 1963, who presented experimental evidence for the ‘Ado hypothesis’, which suggests that Ado is an endogenous dilator of coronary vessels and is released during reduced myocardial 0, supply or increased myocardial workload 5. Many of the cardiovascular actions of Ado are homeostatic and protective in nature, and the nucleoside has therefore been termed a ‘retaliatory metabolite’, equalizing local energy requirements with energy supply 6,7. It is only in the last decade that the clinical relevance of these actions has started to be recognized, greatly increasing interest in the therapeutic and diagnostic potential of Ado 4,8. The aim of this review is to put recent research and major advances in our understanding of the role of Ado in the heart and circulation into perspective, and to demonstrate the importance of Ado in cardiology today. Emphasis is placed on the therapeutic and diagnostic implications of the regulatory functions of Ado, and on exciting opportunities with novel agents that modulate the actions of this nucleoside. The development of the Ado hypothesis was intimately associated with an increased understanding of coronary hemodynamics. Early studies showed that arterial inflow to the heart is precisely regulated by the coronary vasculature over a wide range of cardiac activity, maintaining a nearly constant and high level of 0, extraction by the myocardium, and resulting in low coronary venous 0, saturation levels (20-30%) 9-l 11. Since this high level of 0, extraction is maintained even during basal, or resting, conditions, little reserve capacity exists for increasing 0, uptake when 0, demand is increased. Furthermore, the myocardium has a very limited capacity for anaerobic metabolism, and is largely dependent on oxidative metabolism. Substantial increases in cardiac activity cannot therefore be met by increased 0, extraction or anaerobic metabolism, hence prolonged alterations in 0, demand must be met by proportional changes in coronary blood flow [ll. In the myocardium, blood flow appears to be under the control of the nervous system (neurogenic control), of a myogenic mechanism, and of chemical substances originating from the myocytes (metabolic autoregulation). The relative importance of each mechanism varies in different tissues. Some evidence suggests that the decreased 0, tension that results from an inadequate coronary inflow has a direct effect on coronary vascular smooth muscle relaxation 1:2. However, a much larger body of evidence suggests that an indirect regulatory process is involved, in which hypoxia leads to metabolic alterations that modify the flux of vasoactive substances, which in turn act on