EFFECT OF THE HYDROPHILIC ALPHA-TOCOPHEROL ANALOG MDL-74,405 ON DETECTION OF HYDROXYL RADICALS IN STUNNED MYOCARDIUM IN DOGS

We have previously shown in dogs that the hydrophilic alpha-tocopherol analog, MDL 74,405, attenuates postischemic myocardial dysfunction (' 'stunning'') and generation of free radicals as assessed with the spin trap alpha-phenyl N-tert-butyl nitrone (PEN), However, we could not d iscern whether this drug acts on primary radicals (such as hydroxyl ra dical [. OH]) or on secondary radicals. The goal of this study was to directly determine whether the beneficial effects of MDL 74,405 result from actions against . OH. Open-chest dogs undergoing a 15-minute cor onary artery occlusion and 3 hours of reperfusion received an intraven ous infusion of either saline solution (control group, n=7)or MDL 74,4 05 (n=6) starting 30 minutes before coronary occlusion and ending 60 m inutes after reflow at a dose of 0.3 mg/kg/hr. Formation of . OH was e stimated by the technique of aromatic hydroxylation of phenylalanine. Phenylalanine was infused intravenously, and the plasma concentrations of the hydroxylated products ortho-, meta-, and para-tyrosines (o-, m -, and p-tyr) in the coronary venous effluent and in the arterial bloo d were measured with high-performance liquid chromatography. In the co ntrol group a dramatic increase in the myocardial release of o-, m-, a nd p-tyr was observed immediately after reperfusion; the release of ty rosines peaked at 1 minute of reflow and continued up to 10 minutes af ter reperfusion. MDL 74,405 abolished the release of o-tyr throughout the first 10 minutes of reperfusion but had a less pronounced effect o n the production of m- and p-tyr. These results demonstrate that MDL 7 4,405 is effective in inhibiting OH-initiated reactions in the postisc hemic stunned myocardium in the dog, suggesting that the anti-. OH act ion of MDL 74,405 is an important mechanism of action of this antioxid ant.