Abstract 245: AZD6140 Inhibits Adenosine Uptake Into Erythrocytes and Enhances Coronary Blood Flow After Local Ischemia or Intracoronary Adenosine Infusion
Background. Adenosine is one of the mediators of the reactive hyperemia response to temporary coronary artery occlusion. AZD6140, a reversible oral P2Y12 receptor antagonist, in a routine selectivity screen was shown to inhibit adenosine uptake by isolated human erythrocytes. We investigated the physiological consequences of adenosine uptake inhibition by AZD6140 in an anesthetized dog model of coronary blood flow regulation.
Methods. [3H]adenosine uptake was measured in purified human erythrocytes (n=5) in the presence of the adenosine metabolism inhibitor EHNA [erythro-9-(2-hydroxy-3-nonyl)adenine]. Coronary blood flow was measured in an open-chest dog model in which left anterior descending coronary artery (LAD) flow was continuously monitored over a 4-hr period before and during reactive hyperemia (3 episodes induced by 1-min LAD occlusion, or by direct LAD adenosine infusion [15 and 30 μg/kg/min]). AZD6140 was systemically administered sequentially at 30 and 100 μg/kg/min IV (n=4 – 6), with saline as a control (n=6).
Results. AZD6140 dose-dependently inhibited adenosine uptake by erythrocytes with a pIC50 of 7.0±0.1 (mean±SEM). In saline-treated animals, reproducible hyperemia responses and intracoronary adenosine-induced flow responses were obtained. Administration of AZD6140 dose-dependently augmented the hyperemic response to temporary occlusion or direct intracoronary adenosine infusion (Table⇓). Simultaneous blood flow in the circumflex artery was unaffected.
Conclusions. Our data show that AZD6140 potently inhibits adenosine uptake by erythrocytes, which causes a potentiation of both reactive hyperemia and adenosine-induced coronary flow increases in an in vivo dog model. These data suggest that treatment of ACS patients with AZD6140 may have additional benefits beyond inhibition of platelet aggregation by enhancing coronary blood flow.