Ischemic preconditioning and the beta-adrenergic signal transduction pathway

Background-Previous studies from our laboratory showed cyclic increases in tissue cAMP during a multiple-cycle preconditioning (PC) protocol, followed by attenuated cAMP accumulation during sustained ischemia. The aim of this study was to determine whether ischemia-induced activation of the beta-adr energic signaling pathway could act as a trigger in eliciting protection. Methods and Results-Isolated perfused rat hearts were preconditioned by 3X5 minutes of global ischemia, interspersed by 5 minutes of reperfusion. beta -Adrenergic responsivity was assessed by measurement of tissue cAMP generat ion after beta-adrenergic agonist administration at the end of the PC proto col, Tissue cAMP, adenylyl cyclase, and protein kinase A (PKA) activities a nd beta-adrenergic receptor characteristics were assessed at different time s. The role of cAMP generation in eliciting PC was studied by investigation of functional recovery during reperfusion after 25 minutes of global ische mia after(1) cAMP increases in the trigger period were prevented with the b eta-adrenergic blocker alprenolol 7.5x10(-5) mol/L and (2) increases in cAM P were elicited by administration of forskolin 10(-7) and 10(-6) mol/L or i soproterenol 10(-8), 10(-7), and 10(-6) mol/L. Intermittent ischemia result ed in reduced beta-adrenergic responsivity at the end of the protocol, alth ough B-max and K-d values of the beta-adrenergic receptor population and ad enylyl cyclase and PKA activities were increased, Abolishment of cyclic inc reases in cAMP before sustained ischemia attenuated myocardial protection a gainst ischemia, whereas agonists elicited protection. No clear correlation between protection and beta-adrenergic desensitization was observed. Conclusions-Ischemia-induced activation of the beta-adrenergic signaling pa thway during preconditioning should also be considered a trigger in eliciti ng preconditioning.