Protective effect of PBN on ischemic-reperfused myocardium

Conflicting views exist in the literature on the cardioprotective effect of PBN. By far the most detailed investigation on this subject came from pioneering studies by Bolli and coworkers [104-110], These investigators reported a causal relationship between production of PBN adducts and the post-ischemic functional recovery of stunned myocardium afforded by PBN in canine models. However, another report on the lack of cardioprotection by PBN in a canine model has recently appeared [132]. Hearse and Tosaki [114,115] have previously shown that PBN inhibits the development of arrhythmias in a rat model however, the concentrations of PBN used in that study were too low to be acting as a radical scavenger. It is plausible that some hitherto unknown pharmacologic property of PBN could have been responsible for the observed antiarrhythmic effect. 

Several lipophilic hydroxyl-radical scavengers inhibited formation of PBN adducts [104-110], By virtue of its amphiphilic nature, PBN could trap radicals formed in both intra- and extracellular compartments. Consistent with this, several studies have reported only partial inhibition of PBN adducts in the presence of catalase, superoxide dismutase and water-soluble iron chelators [95]. 

Cova et al. [126] have recently investigated the intracellular distribution of PBN in rat myocardium. They found that a large fraction of PBN accumulates in the cytosolic compartment as compared to the nuclear and mitochondrial 

PBN failed to exert a cardioprotective role in our model of ischemia and reperfusion. There are a number of possibilities that may explain the absence of any protective effect. Firstly, PBN may not have gained access to the site where the hydroxyl radical is generated. Failure to deliver PBN to this locus of radical production would exclude any possible protective effect for this spin trap. Secondly, the kinetic reaction between a radical species and the spin trap is rather inefficient. Thus PBN may trap only a small fraction of the total amount of hydroxyl radical produced. Thirdly, in the aqueous environment of the myocardial cell the PBN/ OH adduct formed is unstable and spontaneously decomposes into benzaldehyde and the tert-butylhydroaminoxyl radical. These toxic breakdown products are more stable than the parent molecule and may diffuse from their site of production to other areas, resulting in an extension of tissue injury. Fourthly, we must acknowledge the possibility that the hydroxyl radical contributes only minimally to myocardial cell injury in this model. 

---