Figure 50-15 Schematic representation of the cellular mechanisms underlying late preconditioning (PC). A nonlethal cellular stress (e.g., reversible ischemia, heart stress, ventricular pacing, or exercise) causes release of chemical signals (nitric oxide [NO], reactive oxygen species [ROS], adenosine, and possibly opioid receptor agonists) that serve as triggers for the development of late PC. These substances activate a complex signal transduction cascade that includes protein kinase C (PKC; specifically, the epsilon isoform), protein tyrosine kinases (PTKs; specifically, Src and/or Lck), and probably other as-yet-unknown kinases. Similar activation of PKC and downstream kinases can be elicited pharmacologically by a wide variety of agents, including naturally occurring—and often noxious—substances (e.g., endotoxin, interleukin-1, tumor necrosis factor-α [TNF-α], TNF-β, leukemia inhibitor factor, or ROS), as well as clinically applicable drugs (NO donors, adenosine A₁ or A₃ receptor agonists, endotoxin derivatives, or δ₁ -opioid receptor agonists). Recruitment of PKC and distal kinases leads to activation of the nuclear factor NF-κB and almost certainly other transcription factors, and such activation results in increased transcription and synthesis of multiple cardioprotective proteins that serve as comediators of protection 2 to 4 days after the PC stimulus. Mediators of late PC identified thus far include inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), aldose reductase, and manganese-superoxide dismutase (MnSOD). Among the products of COX-2, prostaglandin E₂ (PGE₂ ) and prostacyclin (PGI₂ ) appear to be the most likely effectors of COX-2-dependent protection. Increased synthesis of heat shock proteins (HSPs) is unlikely to be a mechanism of late PC, although the role of post-translational modification of preexisting HSPs remains to be determined. In addition, the occurrence of cardioprotection on days 2 to 4 requires the activity of PTKs and possibly p38 mitogen-activated protein kinases (MAPKs), potentially because iNOS and other mediators need to undergo post-translational modulation to confer protection against ischemia. Opening of adenosine triphosphate-sensitive potassium (K_ATP ) channels is also essential for protection against infarction (but not against stunning). The exact interrelationships among iNOS, COX-2, aldose reductase, MnSOD, and K_ATP channels are unknown, although recent evidence suggests that COX-2 may be downstream of iNOS (i.e., COX-2 is activated by NO).