The Anti-infarct Effect of an Adenosine A1-Selective Agonist is Diminished After Prolonged Infusion as is the Cardioprotective Effect of Ischaemic Preconditioning in Rabbit Heart

Our aim was to determine whether adenosine A1 receptor-mediated protection could be maintained for a prolonged period of time by a continuous infusion of an A1-selective agonist. To produce myocardial infarction a branch of the left coronary artery of rabbit hearts was occluded for 30 min and reperfused for 3 h. Infarct size was determined with tetrazolium staining. Prior to the 30 min ischaemia, rabbits were subjected to one of the following six protocols: (1) 6 h i.v. saline infusion; (2) 6 h i.v. CCPA (0.043 mg/kg/h) infusion; (3) 72 h saline infusion; (4) 72 h CCPA infusion; (4) 72 h CCPA infusion; (5) 72 h CCPA infusion plus preconditioning with 5 min ischaemia followed by 10 min reperfusion; (6) 72 h saline infusion plus preconditioning. The 6 h CCPA infusion group had significantly smaller infarct sizes than the 6 h vehicle group, 16.2 ± 2.9% infarction of the ischaemic region v 39.5 ± 2.6%, P < 0.01. Infarction in the 72 h CCPA infusion group (37.7 ± 2.7%) was the same as in the 72 h vehicle group (35.2 ± 3.1%). Ischaemic preconditioning could not limit infarct size in 72 h CCPA animals (%infarction; 29.1 ± 4.6%) but did protect animals given vehicle for 72 h (8.4 ± 1.2%, P < 0.01). After 72 h infusion of CCPA, both the cardioprotective effect of adenosine A1-selective agonist and ischaemic preconditioning were attenuated. These findings indicate that: (1) the myocytes become desensitized to the protective effect of CCPA with prolonged exposure; and (2) ischaemic preconditioning is no longer protective when tachyphylaxis to CCPA occurs.