RECURRENT ISCHEMIA IN THE CANINE HEART CAUSES RECURRENT BURSTS OF FREE-RADICAL PRODUCTION THAT HAVE A CUMULATIVE EFFECT ON CONTRACTILE FUNCTION - A PATHOPHYSIOLOGICAL BASIS FOR CHRONIC MYOCARDIAL STUNNING

Open-chest dogs (total number used, 117) underwent 10 5-min coronary o cclusions (O) interspersed with 10 min of reperfusion (R), When systol ic thickening fraction was measured 9 min after each R, the first O-R cycle was found to cause the largest decrement, with only a slight add itional loss during the next four cycles and no further loss during th e last five cycles (group IV), suggesting that the first few episodes of ischemia preconditioned the myocardium against the stunning induced by the last five episodes. However, different results were obtained w hen the total deficit of wall thickening during the final 4-h R interv al was measured. The total deficit was similar after one and three 5-m in O (groups V and VI, respectively), indicating that the first ischem ic episode did precondition against the next two episodes; however, it was similar to 2.5-fold greater after 10 O (group IV) than after 3, i ndicating that the first 3 episodes failed to precondition against the next 7. Thus, at some point between the 4th and 10th O, the precondit ioning effect was lost and recurrent ischemic episodes started to have a cumulative effect. Measurements of free radicals with cu-phenyl N-t ert-butyl nitrone (PEN) demonstrated a burst of free radical generatio n immediately after the Ist, 5th, and 10th R (group Vm). The total cum ulative release of PEN adducts during the initial 5 min of reflow was 58% less after the 5th R than after the Ist (P < 0.05) but did not dif fer significantly between the Ist and 10th R. When administered throug hout the 10 O-R cycles, the . OH scavenger mercaptopropionyl glycine s ignificantly enhanced the recovery of function (group I) and markedly suppressed the formation of free radicals (group VII). However, the be neficial effects of mercaptopropionyl glycine were completely, or larg ely, lost if the drug was discontinued after the first five (group II) or eight (group III) O-R cycles, respectively, implying that (a) the oxidative stress associated with the last five, or even two, cycles wa s sufficient to cause severe postischemic dysfunction, and (b) the cum ulative injury caused by repetitive ischemic episodes is mediated by r ecurrent oxidative stress. This study provides direct in vivo evidence that oxygen radicals play an important role in the pathogenesis of my ocardial stunning after repetitive ischemia, and implicates . OH as a primary culprit. Taken together, the data indicate that recurrent brie f ischemic episodes result in recurrent bouts of oxyradical-mediated i njury that have a cumulative effect on contractility, a situation that could lead to protracted or even chronic myocardial stunning.