A comparison between ischemic preconditioning and anti-adrenergic interventions: cAMP, energy metabolism and functional recovery

The postulate that ischemic preconditioning caused an attenuation in ischemia induced increases in tissue cAMP, and that this may pertain to the mechanism of ischemic preconditioning, was investigated in the isolated rat heart. A significant reduction in tissue cAMP in preconditioned hearts was observed for all time periods of global ischemia studied. The significance of this observation was evaluated by comparing the effect of antiadrenergic interventions on energy metabolism and post-ischemic functional recovery of both non-preconditioned and preconditioned hearts. The isolated perfused rat heart was used as experimental model. Six groups were studied: Non-preconditioned rat hearts: i) untreated controls (Non-PC), ii) reserpinised (Non-PC Res), iii) propranolol treated (10−7M) (Non-PC Prop); Preconditioned rat hearts: iv) preconditioned controls (PC), v) reserpinised (PC Res) and vi) propranolol (10−7M) treated (PC Prop). After 25 min global ischemia the concentration of cAMP was increased by 79.6% in the Non-PC group. This increase was attenuated in all of the treated groups, although in varying degrees. Energy utilization in these hearts also differed markedly between the groups. Functional recovery was however similar in all Non-PC and PC treated groups and significantly superior to that of Non-PC control hearts. Prior reserpinisation mimicked the protective effect of preconditioning on energy metabolism and functional recovery. To determine the significance of attenuation of the increase in cAMP in the protection conferred by preconditioning, hearts were pretreated with forskolin (10−6M). This caused an accumulation of tissue cAMP in preconditioned hearts to similar absolute values as seen in untreated non-preconditioned hearts during 25 min global ischemia. However, the percentage increase in forskolin-pretreated preconditioned hearts during sustained, ischemia was only 50% vs. 71% in non-preconditioned hearts treated with forskolin, confirming an attenuated β-response induced by preconditioning. Forskolin treatment of preconditioned hearts did not abolish the protective effect. The findings suggest that the protection against ischemic damage conferred by preconditioning is associated with an attenuated β-adrenergic response. However, whether the changes in cAMP occurring during sustained global ischemia is the cause or consequence of the elicited protection, remains to be established.