Attenuation of postischaemic dysfunction by ischaemic preconditioning is not mediated by adenosine in the isolated rat heart

Objective: The aim was to test the hypothesis that adenosine mediates the cardioprotective effects of ischaemic preconditioning in the isolated rat heart. Methods: Transient exposure of the hearts to adenosine and the A₁ selective agonist, PIA, were tested for the ability to mimic the cardioprotective effects of ischaemic pre-conditioning in hearts that underwent 40 min normothermic ischaemia followed by 30 min reperfusion. Treated hearts were perfused with 10 or 50 μM adenosine or 10^-7 M R-phenylisopropyladenosine (PIA) for 5 min followed by a 5 min washout period. Preconditioned hearts underwent 5 min of ischaemia and 5 min of reflow prior to the 40 min ischaemic period. The ability of the adenosine receptor antagonist, BW A1433U, to inhibit the cardioprotective effects of ischaemic preconditioning was also tested. The effects of these treatments on metabolite levels and postischaemic haemodynamic function were assessed. Results: Adenosine (50 μM), but not PIA, resulted in enhanced accumulation of lactate after 40 min ischaemia: 122(SEM 8) v 96(5) nmol·mg^-1 protein in control hearts (p < 0.002). Adenosine and PIA treatments did not significantly affect myocardial acidosis during ischaemia. Postischaemic contractile function (as assessed by percent recovery of the heart rate× developed pressure) was lower in 50 μM, but not 10 μM, adenosine treated hearts [8.8(2.2)] and PIA treated hearts [11.9(2.5)] than in control hearts [20.4(3.6)] (p < 0.01). Ischaemic preconditioning (1) lowered glycogen levels prior to the 40 min ischaemic period [57(6) v 110(18) nmol glucosyl units·mg^-1 protein; p < 0.01]; (2) lowered lactate levels at the end of the 40 min ischaemic period [61(4) v 104(5) nmol·mg^-1 protein]; (3) preserved myocardial pH during ischaemia [6.69(0.07) v 6.40(0.07); p < 0.0l]; and (4) enhanced recovery of postischaemic contractile function [42.3(4.4)% v 19.7(6.0)%; p < 0.02]. BW A1433U did not prevent these effects of ischaemic preconditioning. Conclusions: The cardioprotective effects of ischaemic preconditioning are not mediated by adenosine released during the preconditioning period in the isolated rat heart. Also, transient treatment of the heart with A₁ adenosine receptor agonists can exacerbate postischaemic contractile dysfunction.Cardiovascular Research 1993;27:1522-1530.