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 pathogenetic role in postischemic ventricular dysfunction (myocardial ''stunning''). This concept, however, is predicated exclusively on results obtained in anesthetized open-chest preparations, which are subject to the confounding influence of many unphysiological conditions and in which both myocardial stunning and free radical generation are greatly exaggerated. The lack of supporting evidence in more physiological animal models represents a major limitation of the .OH hypothesis of stunning. Furthermore, concern has been raised that myocardial stunning may be a period of ''rest'' necessary for full recovery, so that attenuation of the early phase of stunning by antioxidant therapy may have subsequent detrimental effects on the resting function and/or on the return of myocardial contractile reserve. To address these issues, in phase 1 of this study conscious unsedated dogs undergoing a 15-minute coronary 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 significantly 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 in the first 6 hours was not followed by any deterioration of resting wall thickening at 24 or 48 hours. Furthermore, in dogs treated with MPG or DF, the increase in wall thickening elicited by maximal inotropic stimulation (isoproterenol or dopamine) was similar before stunning and shortly after resting wall thickening had normalized (24 or 48 hours after reflow); thus, despite the fact that most of the early postischemic dysfunction had been eliminated by antioxidant therapy, there was no subsequent impairment of either resting function or contractile reserve. In phase 2, production of free radicals (measured with the spin trap alpha-phenyl N-tert-butyl nitrone) was markedly (>80%) inhibited 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 of postischemic dysfunction and the concomitant production of free radicals 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 independent of the exaggerated free radical production caused by open-chest preparations and provide direct evidence that .OH plays an important role in the pathogenesis of myocardial stunning under physiological conditions. Furthermore, our results indicate that myocardial stunning is not a teleologically useful phenomenon and that it can be safely prevented without fear of detrimental effects.