Potential of adenosine receptor agonists for the prevention and treatment of coronary artery disease and acute myocardial infarction

Abstract

Adenosine is an ubiquitously produced autocoid which mediates its effects via four receptor subtypes (A₁, A_2A, A_2B and A₃) which show a relatively widespread tissue distribution. Adenosine itself is upregulated in vascular tissue in response to hypoxia and induces vasodilation as a homeostatic response. The vasodilator effects of adenosine are exploited clinically, where it is used as a pharmacological vasodilator during stress testing. More recently, it has become clear that adenosine and adenosine agonists possess significant potential for cardioprotection. Thus, given prior to an ischaemic insult, adenosine and adenosine A₁ receptor agonists can reduce infarct size, reduce arrhythmia and improve post-ischaemic cardiac function. In addition, when given during myocardial ischaemia just prior to reperfusion, adenosine and adenosine A_2A receptor agonists can inhibit neutrophil adhesion, activation and infiltration into post-ischaemic myocardium, thereby inhibiting lethal reperfusion injury and further salvaging myocardial tissue. There is also some evidence that stimulation of adenosine A₃ receptors can protect myocardium. The realisation that adenosine analogues possess cardioprotective activity has stimulated research to identify subtype selective analogues with the optimal profile for use in acute myocardial infarction (MI) and cardiac surgery. Several compounds have reached the stage of early clinical development and hold significant promise as future therapies. In addition to direct cardioprotective effects, adenosine A₁ selective agonists may also indirectly benefit the heart via their metabolic effects. Thus, adenosine A₁ receptor stimulation results in a marked suppression of lipolysis in adipose tissue, which in turn leads to a reduction in the levels of circulating free fatty acids, triglycerides and very low density lipoproteins. Triglycerides are now accepted as an independent risk factor for mortality from coronary artery disease. Thus, the potential exists for the development of orally-active selective A₁ receptor agonists for the treatment of hypertriglyceridaemic patients to reduce the incidence of primary or secondary coronary events. Progress is being made in the design of such A₁ selective agonists.Therefore, the next decade should see advances in the therapeutic application of adenosine agonists in the porphylactic treatment of coronary artery disease and in acute MI.

• acute myocardial infarction
• adenosine agonist
• cardioprotection
• coronary artery disease
• triglycerides