Abstract 1426: Beta-adrenergic (BPC) Preconditioning Depends on both Beta-1 and Beta-2 Adrenergic Receptor Activation and Utilizes Endogenous Adenosine via the A3 Receptor and the PI3-K/PKB Signal Transduction Pathway
Intermittent pharmacological stimulation of the beta-adrenergic receptor can elicit cardiac protection against ischemia (beta-adrenergic preconditioning) (BPC). The mechanism of BPC remains unclear. The role of beta-1 and beta-2 adrenergic receptors (AR) has not been elucidated - both receptor subtypes have been implicated to the exclusion of the other. The respective roles of endogenous adenosine production (which could be due to demand ischemia) and the survival kinases PI3-K/PKB have not been studied in BPC. The aim was to determine the involvement of the beta-1 and beta-2 AR, endogenous adenosine production and adenosine A1 and A3 receptors as well as the PI3-K/PKB signal transduction pathway in the mechanism of BPC.
Methods: Isolated perfused rat hearts were subjected to 35 min regional ischemia and reperfusion. Hearts were preconditioned with 5 min isoproterenol (Iso) 10−7 M in the presence and absence of the selective beta-1 AR blocker CGP 20712A (300 nM), the beta-2 receptor blocker ICI 118551 (50nM), adenosine A1 and A3 blockers DPCPX (1μM) and MRS-1191 (1μM) respectively, as well as the PI3-K blocker wortmannin (100 nM). Infarct size (IS) was determined using TTC staining. Minimum group size n=6. Data were analyzed with ANOVA and Bonferroni post-hoc analysis.
Results: IS of BPC hearts was significantly smaller compared to non-preconditioned (NPC) hearts. CGP 20712A, ICI 118551, MRS-1191 and wortmannin abolished BPC completely, while DPCPX had no effect on protection. (* p<0.001 for BPC vs NPC, NPC+DPCPX, NPC+MRS, NPC+ wortmannin, BPC+MRS, BPC+ wortmannin, BPC+CGP, BPC+ICI).
Conclusion: The mechanism of BPC depends on activation of both beta-1 and beta2 AR. Protection is mediated by production of endogenous adenosine through its action on the adenosine A3 receptor and utilizes the PI3-K/PKB signal transduction pathway.