Role of adenosine receptor activation in myocardial infarct size limitation by ischaemic preconditioning.

Abstract

The aims were to examine the role of adenosine receptors in the mechanism of preconditioning in a chronic rabbit model of myocardial infarction; to assess whether the preconditioning effect is blocked by an adenosine receptor antagonist, 8-phenyltheophylline; and to determine whether an adenosine A1 receptor agonist, R(-)N6-2-phenylisopropyl adenosine (R-PIA), mimics infarct size limitation by preconditioning. Myocardial infarction was induced in male rabbits by occlusion of the left coronary artery for 30 min, which was followed by 72 h reperfusion. Before the 30 min ischaemia, rabbits were subjected to one of the following six protocols: (1) untreated control; (2) intravenous injection of 8-phenyltheophylline; (3) preconditioning with 5 min ischaemia; (4) pretreatment with 8-phenyltheophylline plus preconditioning; (5) intravenous injection of R-PIA; or (6) R-PIA plus atrial pacing (240.min-1). Infarct size and area at risk were determined by histology and fluorescent particles, respectively. Preconditioning significantly limited infarct size, normalised as a percent of area at risk (%IS/AR), to 19.2 (SEM 2.3)% v control value of 46.5(2.8)%. 8-Phenyltheophylline alone did not modify the %IS/AR, but its injection before preconditioning attenuated the preconditioning effect such that IS/AR = 34.4(2.5)%. While R-PIA did not achieve statistically significant myocardial salvage, R-PIA plus atrial pacing limited infarct size to 33.7(3.0)% (p<0.05 v control). The R-PIA group had severe hypotension and their infarct sizes were inversely correlated with diastolic blood pressure at reperfusion. There was no such correlation in the R-PIA plus pacing group in which bradycardia and hypotension induced by R-PIA were attenuated by atrial pacing. The infarct size limiting effect of preconditioning was attenuated by 8-phenyltheophylline, and pretreatment with R-PIA was able to limit myocardial infarct size when severe hypotension was avoided by atrial pacing. These findings suggest that adenosine receptor activation plays a crucial role in the mechanism of preconditioning.