DIRECT EVIDENCE THAT THE HYDROXYL RADICAL PLAYS A PATHOGENETIC ROLE IN MYOCARDIAL STUNNING IN THE CONSCIOUS DOG AND DEMONSTRATION THAT STUNNING CAN BE MARKEDLY ATTENUATED WITHOUT SUBSEQUENT ADVERSE-EFFECTS

Recent studies suggest that the hydroxyl radical (.OH) plays a pathoge netic role in postischemic ventricular dysfunction (myocardial ''stunn ing''). This concept, however, is predicated exclusively on results ob tained in anesthetized open-chest preparations, which are subject to t he confounding influence of many unphysiological conditions and in whi ch both myocardial stunning and free radical generation are greatly ex aggerated. The lack of supporting evidence in more physiological anima l models represents a major limitation of the .OH hypothesis of stunni ng. Furthermore, concern has been raised that myocardial stunning may be a period of ''rest'' necessary for full recovery, so that attenuati on of the early phase of stunning by antioxidant therapy may have subs equent detrimental effects on the resting function and/or on the retur n of myocardial contractile reserve. To address these issues, in phase 1 of this study conscious unsedated dogs undergoing a 15-minute coron ary artery occlusion received an intravenous infusion of normal saline (n = 22), of the .OH scavenger N-2-mercaptopropionyl glycine (MPG, n = 17), or of the iron chelator desferrioxamine (DF, n = 14). Compared with control dogs, the dogs treated with MPG or DF exhibited significa ntly greater postischemic wall thickening throughout the first 6 hours of reperfusion; the total deficit of wall thickening during this time interval was reduced 50% by MPG and 50% by DF. The magnitude of this beneficial effect was a function of the severity of ischemia, so that the dogs with the lowest collateral flows had the greatest improvement of wall thickening. The accelerated recovery produced by MPG and DF i n the first 6 hours was not followed by any deterioration of resting w all thickening at 24 or 48 hours. Furthermore, in dogs treated with MP G or DF, the increase in wall thickening elicited by maximal inotropic stimulation (isoproterenol or dopamine) was similar before stunning a nd shortly after resting wall thickening had normalized (24 or 48 hour s after reflow); thus, despite the fact that most of the early postisc hemic dysfunction had been eliminated by antioxidant therapy, there wa s no subsequent impairment of either resting function or contractile r eserve. In phase 2, production of free radicals (measured with the spi n trap alpha-phenyl N-tert-butyl nitrone) was markedly (>80%) inhibite d by the same doses of MPG and DF that attenuated stunning in phase 1. This study demonstrates that in the conscious dog both the severity o f postischemic dysfunction and the concomitant production of free radi cals are attenuated markedly, and to a similar degree, by antioxidants that scavenge .OH (MPG) or prevent its generation (DF). These results indicate that the beneficial effects of ''anti-.OH'' therapy are inde pendent of the exaggerated free radical production caused by open-ches t preparations and provide direct evidence that .OH plays an important role in the pathogenesis of myocardial stunning under physiological c onditions. Furthermore, our results indicate that myocardial stunning is not a teleologically useful phenomenon and that it can be safely pr evented without fear of detrimental effects.