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

Xian Liang Tang, Harparkash Kaur, Jian Zhong Sun, Yumin Qiu, Seong Wook Park, Margo Schleman, Barry Halliwell, Roberto Bolli

Research output: Contribution to journalArticlepeer-review

Abstract

We have previously shown in dogs that the hydrophilic α-tocopherol analog, MDL 74,405, attenuates postischemic myocardial dysfunction ("stunning") and generation of free radicals as assessed with the spin trap α-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.

Original languageEnglish (US)
Pages (from-to)940-948
Number of pages9
JournalAmerican heart journal
Volume130
Issue number5
DOIs
StatePublished - Nov 1995

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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