LATE PRECONDITIONING AGAINST MYOCARDIAL STUNNING - AN ENDOGENOUS PROTECTIVE MECHANISM THAT CONFERS RESISTANCE TO POSTISCHEMIC DYSFUNCTION 24-H AFTER BRIEF ISCHEMIA IN CONSCIOUS PIGS

Conscious pigs underwent a sequence of 10 2-min coronary occlusions, e ach separated by 2 min of reperfusion, for three consecutive days (day s 1, 2, and 3 of stage I). The recovery of systolic wall thickening (W Th) after the 10th reperfusion was markedly improved on days 2 and 3 c ompared with day 1, indicating that the myocardium had become precondi tioned against ''stunning.'' 10 d after stage I, pigs underwent again a sequence of 10 2-min coronary occlusions for two consecutive days (d ays 1 and 2 of stage II). On day 1 of stage II, the recovery of WTh af ter the 10th reperfusion was similar to that noted on day 1 of stage I ; on day 2 of stage II, however, the recovery of WTh was again markedl y improved compared with day 1. Blockade of adenosine receptors with 8 -p-sulfophenyl theophylline failed to prevent the development of preco nditioning against stunning. Northern blot analysis demonstrated an in crease in heat stress protein (HSP) 70 mRNA 2 h after the precondition ing ischemia; at this same time point, immunohistochemical analysis re vealed a concentration of HSP70 in the nucleus and an overall increase in staining for HSP70. 24 h after the preconditioning ischemia, Weste rn dot blot analysis demonstrated an increase in HSP70. This study ind icates the existence of a new, previously unrecognized cardioprotectiv e phenomenon. The results demonstrate that a brief ischemic stress ind uces a powerful, long-lasting (at least 48 h) adaptive response that r enders the myocardium relatively resistant to stunning 24 h later (lat e preconditioning against stunning). This adaptive response disappears within 10 d after the last ischemic stress but can be reinduced by an other ischemic stress. Unlike early and late preconditioning against i nfarction, late preconditioning against stunning is not blocked by ade nosine receptor antagonists, and therefore appears to involve a mechan ism different from that of other forms of preconditioning currently kn own. The increase in myocardial HSP70 is compatible with, but does not prove, a role of HSPs in the pathogenesis of this phenomenon.