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Effect of the hydrophilic alpha-tocopherol analog MDL 74,405 on detection of hydroxyl radicals in stunned myocardium in dogs.

Abstract
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 (PBN). However, we could not discern whether this drug acts on primary radicals (such as hydroxyl radical [.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 coronary artery occlusion and 3 hours of reperfusion received an intravenous infusion of either saline solution (control group, n = 7) or MDL 74,405 (n = 6) starting 30 minutes before coronary occlusion and ending 60 minutes after reflow at a dose of 0.3 mg/kg/hr. Formation of .OH was estimated 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 blood were measured with high-performance liquid chromatography. In the control group a dramatic increase in the myocardial release of o-, m-, and p-tyr was observed immediately after reperfusion; the release of tyrosines peaked at 1 minute of reflow and continued up to 10 minutes after reperfusion. MDL 74,405 abolished the release of o-tyr throughout the first 10 minutes of reperfusion but had a less pronounced effect on the production of m- and p-tyr. These results demonstrate that MDL 74,405 is effective in inhibiting .OH-initiated reactions in the postischemic stunned myocardium in the dog, suggesting that the anti-.OH action of MDL 74,405 is an important mechanism of action of this antioxidant.
AuthorsX L Tang, H Kaur, J Z Sun, Y Qiu, S W Park, M Schleman, B Halliwell, R Bolli
JournalAmerican heart journal (Am Heart J) Vol. 130 Issue 5 Pg. 940-8 (Nov 1995) ISSN: 0002-8703 [Print] United States
PMID7484754 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)
Chemical References
  • Antioxidants
  • Free Radical Scavengers
  • MDL 73404
  • Vitamin E
  • Tyrosine
  • Phenylalanine
Topics
  • Animals
  • Antioxidants (pharmacology, therapeutic use)
  • Coronary Circulation (drug effects)
  • Dogs
  • Female
  • Free Radical Scavengers (pharmacology, therapeutic use)
  • Heart (drug effects)
  • Hemodynamics
  • Hydroxylation
  • Male
  • Myocardial Stunning (drug therapy, physiopathology)
  • Myocardium (metabolism)
  • Phenylalanine (blood)
  • Tyrosine (metabolism)
  • Vitamin E (analogs & derivatives, pharmacology, therapeutic use)

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