Numerous studies have indirectly suggested that
oxygen-derived
free radicals play an important pathogenetic role in the prolonged depression of contractile function observed in myocardium reperfused after reversible
ischemia (myocardial "stunning"). In order to provide direct evidence for the oxy-radical hypothesis of stunning, we administered the spin trap,
alpha-phenyl N-tert-butyl nitrone (PBN), to open-chest dogs undergoing a 15-min coronary artery occlusion followed by reperfusion. Plasma of local coronary venous blood was analyzed by electron paramagnetic resonance (EPR) spectroscopy. EPR signals characteristic of radical adducts of PBN appeared during
ischemia and increased dramatically in the first few minutes after reperfusion. After this initial burst, the production of adducts abated but did not cease, persisting up to 3 h after reflow. The production of PBN adducts after reperfusion was inversely related to collateral flow during
ischemia. PBN itself enhanced recovery of contractile function, indicating that the radicals trapped may play a pathogenetic role in
myocardial stunning.
Superoxide dismutase plus
catalase attenuated PBN adduct production and, at the same time, improved recovery of contractile function.
Antioxidant therapy given 1 min before reperfusion suppressed PBN adduct production and improved contractile recovery; however, the same
therapy given 1 min after reperfusion did not suppress early radical production and did not attenuate contractile dysfunction. After i.v. administration, the elimination half-life of PBN was estimated to be approximately 4-5 h. The results demonstrate that 1)
free radicals are produced in the
stunned myocardium in intact animals; 2) inhibition of
free radical production results in improved contractile recovery; and 3) the
free radicals important in causing dysfunction are produced in the first few minutes of reperfusion. Taken together, these studies provide cogent evidence supporting the oxy-radical hypothesis of stunning in open-chest dogs. It is now critical to determine whether these results can be reproduced in conscious animal preparations.