Figure 3.

Schematic illustrating the multiple trigger hypothesis of classical preconditioning advanced by Goto et al. (1995). The hypothesis proposes that the preconditioning response is only elicited when a critical threshold of intracellular kinase activity is exceeded. All of the endogenous mediators known to act as triggers of the preconditioning response can independently activate the intracellular signal cascade but they act in concert to trigger the preconditioning response. When a single preconditioning cycle is used (1×PC), blockade of adenosine receptors with 8-sulphophenyltheophylin (SPT), blockade of bradykinin B2 receptors with icatibant, blockade of opioid receptors with (−)-naloxone or scavenging of free radicals with mercaptoprionylglycine (MPG) will be sufficient to reduce the intensity of the intracellular signal below the critical threshold. When multiple preconditioning cycles are used (e.g. 3×PC), relatively more of the endogenous triggers are released. Under these conditions, antagonism of any single trigger may still result in sufficient kinase activation to exceed the threshold which elicits protection.