Spare Adenosine A2a Receptors Are Associated With Positive Exercise Stress Test In Coronary Artery Disease

During exercise, cardiac oxygen-consumption increases and the resulting low oxygen level in myocardium triggers coronary vasodilation. This response to hypoxia is controlled notably by the vasodilator adenosine and its A_2A receptor (A_2AR). According to the "spare receptor" pharmacological model, a strong A_2AR-mediated response can occur in the context of a large number of receptors remaining unoccupied, activation of only a weak fraction of A_2AR (evaluated using K_D) resulting in maximal cAMP production (evaluated using EC₅₀), and hence in maximal coronary vasodilation. In coronary artery disease (CAD), myocardial ischemia limits adaptation to exercise, which is commonly detected using the exercise stress test (EST). We hypothesized that spare A_2AR are present in CAD patients to correct ischemia. Seventeen patients with angiographically-documented CAD and 17 control subjects were studied. We addressed adenosine-plasma concentration and A_2AR-expression at the mononuclear cell-surface, which reflects cardiovascular expression. The presence of spare A_2AR was tested using an innovative pharmacological approach based on a homemade monoclonal antibody with agonist properties. EST was positive in 82% of patients, and in none of the controls. Adenosine plasma-concentration increased by 60% at peak exercise in patients only (p<0.01). Most patients (65%), and none of the controls, had spare A_2AR (identified when EC₅₀/K_D≤0.1) and a low A_2AR-expression (mean: -37% vs controls; p<0.01). All patients with spare A_2AR had a positive EST whereas the subjects without spare A_2AR had a negative EST (p<0.05). Spare A_2AR are therefore associated with positive EST in CAD patients and their detection may be used as a diagnostic marker.