Early and delayed preconditioning: differential mechanisms and additive protection.

The purposes of this study were to determine whether 1) 24-h endotoxin (ETX) pretreatment induces delayed ("second window") myocardial protection against ischemia-reperfusion (I/R), 2) acute adenosine (Ado) or phenylephrine (PE) pretreatment confers similar protection, 3) the mechanisms of Ado- and PE-induced early protection remain intact after endotoxemia, 4) Ado- and PE-induced protection may combine with ETX-induced delayed protection to optimize cardiac protection, and 5) these strategies of early and/or delayed myocardial protection require de novo protein synthesis. Rats (n = 6-8/group) were treated with ETX (0.5 mg/kg i.p.) or vehicle, with or without prior inhibition of protein synthesis. Twenty-four hours later, the hearts were isolated, perfused, and acutely pretreated with Ado or PE before I/R (20-min ischemia and 40-min reperfusion). Developed pressure, coronary flow, compliance (end-diastolic pressure), and reperfusion creatine kinase leak were measured. Results indicated that 1) Ado, PE, and ETX independently induced myocardial functional protection; 2) either Ado or PE acutely enhanced ETX induced protection; and 3) cycloheximide abolished delayed, but not acute, protection. We conclude that early and delayed forms of protection 1) may be combined to optimize protection and 2) differentially rely on de novo protein synthesis.