Ischemic Preconditioning: Bioenergetic and Metabolic Changes and the Role of Endogenous Adenosine

Abstract

The role of adenosine in ischemic preconditioning in different species remains controversial. Ischemic preconditioning was examined in perfused rat and rabbit hearts. In rat and rabbit hearts subjected to 30 min global normothermic ischemia followed by 30 min of reperfusion, left ventricular developed pressure (LVDP) recovered to 36±8% and 44±7% of pre-ischemia, respectively. Pre-treatment with transient (6 min) global ischemia improved recovery of LVDP (75±7% and 82±9% pre-ischemia, respectively), and improved recovery of coronary flow and end-diastolic pressure. Effects of preconditioning were unrelated to cytosolic [ATP], but were associated with reduced ischemic acidosis, and improved post-ischemic recovery of [Mg 2+], [P i], and ΔG ATP. In addition to ischemia, transient episodes of hypoxia (5% O 2), norepinephrine stimulation (0.1 μ m) or metabolic inhibition (5 m mcyanide minus glycolytic substrate) all improved recovery from prolonged ischemia. Microdialysis revealed that 6 min of ischemic preconditioning increased dialysate [adenosine] from 0.25 to 6.81±0.87 μ min rat hearts, and from 0.33 to 1.98±0.41 μ min rabbit hearts. Extracellular [adenosine] was also enhanced during the transient periods of hypoxia, norepinephrine stimulation and metabolic inhibition shown to be protective. Pre-treatment with 0.5 μ mN 6-cyclohexyladenosine mimicked preconditioning, and 50 μ m8-( ρ-sulfophenyl) theophylline attenuated ischemic preconditioning in rat and rabbit hearts. 8-( ρ-sulfophenyl)theophylline also abolished effects of preconditioning on ischemic acidosis, and post-ischemic [Mg 2+], [P i] and ΔG ATP. The data demonstrate that (i) preconditioning is triggered by transient periods of energy imbalance; (ii) endogenous adenosine is of primary importance in mediating the cardioprotection following a single transient ischemic stimulus in rat and rabbit hearts; and (iii) post-receptor mechanisms of this adenosine-mediated preconditioning appear to involve reduced ischemic acidosis and enhanced recovery of [P i], [Mg 2+] and ΔG ATP.