The Role of β-adrenergic Receptors in the Cardioprotective Effects of Beta-Preconditioning (βPC)

Aim To determine the mechanism whereby transient stimulation of the â-adrenergic receptor subtypes (â-AR) elicit cardioprotection against subsequent ischaemia. Methods Isolated rat hearts were subjected to 35 min regional ischaemia (RI) and reperfusion and infarct size (IS) determined. Hearts were preconditioned with 5 min isoproterenol (â1/â2-AR agonist), denopamine (â1-AR agonist), formoterol hemifumarate (â2-AR agonist) or BRL37344 (â3-AR agonist) and 5 min reperfusion. The roles of the â-ARs, NO, PKA, and PI3-K were explored by using selective antagonists/blockers. Pertussis toxin was administered i.p., 48 h prior to experimentation. Results IS of hearts preconditioned with either isoproterenol, denopamine or formoterol (% of area at risk: 23.6± 1.26; 24.52±0.89; 20.74±0.85 respectively) were significantly smaller than that of non-preconditioned hearts (41.7±1.65) and associated with improvement in postischaemic mechanical performance. The â3-AR agonist BRL37344 could not reduce IS. The â1- and â2-AR blockers CGP-20712A and ICI-118551 abolished the reduction in IS and improvement in mechanical recovery during reperfusion induced by isoproterenol preconditioning, while the â3-AR blocker SR59230A was without effect. Both Rp-8-CPT-cAMPs and wortmannin significantly increased IS when administered before and during â1/â2-AR preconditioning and reduced mechanical recovery. PTX pretreatment had no significant effect on the reduction in IS induced by â1/â2-AR or â2-AR preconditioning, but reduced mechanical recovery in â2- AR preconditioning. Similarly the NOS inhibitors L-NAME and LNNA had no effect on IS in â1/â2-AR preconditioning, but depressed mechanical recovery. Conclusion Protection afforded by â-ARs stimulation, depends on activation of both â1-AR and â2-ARs but not â3-AR. With functional recovery as endpoint, results suggest involvement of NO in â1/â2-AR preconditioning and the Gi protein in â2-AR preconditioning. Both PKA and PI3-K activation were essential for â1/â2-AR cardioprotection.