TY - JOUR
T1 - Inhibitory effect of a hydrophilic αtocopherol analogue, MDL 74, 405, on generation of free radicals in stunned myocardium in dogs
AU - Tang, Xian Liang
AU - Mccay, Paul B.
AU - Sun, Jian Zhong
AU - Hartley, Craig J.
AU - Schleman, Margo
AU - Bolli, Roberto
N1 - Funding Information:
This study was supported in part by grants from NIH (HL-43151 and SCOR HL-42267) and the Marion Merrell Dow Inc.
PY - 1995
Y1 - 1995
N2 - A previous study has demonstrated that the hydrophilic (αtocopherol analogue, MDL 74, 405, attenuates postischemic myocardial dysfunction ("stunning" in dogs. The present study was undertaken to determine directly whether the salutary effect of this drug on myocardial stunning results from inhibition of the generation of oxygen-derived free radicals. Open-chest dogs undergoing a 15-min coronary artery occlusion and 3 h of reperfusion received an intravenous infusion of either saline (controls, n = 7) or MDL 74, 405 (n = 6) starting 30 min before coronary occlusion and ending 60 min after reflow at a dose of 0.3 mg/kg/h. To measure free radical production, all dogs received an intravenous infusion of the spin trap αphenyl N-tert-butyl nitrone (PBN) and local coronary venous plasma was analyzed by electron paramagnetic resonance (EPR). In control dogs, the myocardial production of PBN adducts exhibited an initial burst immediately after the onset of reflow and remained elevated until 10 min after reperfusion. Dogs treated with MDL 74, 405 demonstrated a marked decrease in PBN adduct production. This effect of MDL 74, 405 could not be attributed to nonspecific factors such as differences in ischemic zone size, collateral flow, arterial pressure, heart rate, coronary flow or other hemodynamic variables. These results demonstrate that the hydrophilic vitamin E analogue, MDL 74, 405, inhibits free radical generation after myocardial ischemia-reperfusion in vivo. This finding provides direct evidence that the salutary effects of MDL 74, 405 on myocardial stunning are due to attenuation of oxidative stress.
AB - A previous study has demonstrated that the hydrophilic (αtocopherol analogue, MDL 74, 405, attenuates postischemic myocardial dysfunction ("stunning" in dogs. The present study was undertaken to determine directly whether the salutary effect of this drug on myocardial stunning results from inhibition of the generation of oxygen-derived free radicals. Open-chest dogs undergoing a 15-min coronary artery occlusion and 3 h of reperfusion received an intravenous infusion of either saline (controls, n = 7) or MDL 74, 405 (n = 6) starting 30 min before coronary occlusion and ending 60 min after reflow at a dose of 0.3 mg/kg/h. To measure free radical production, all dogs received an intravenous infusion of the spin trap αphenyl N-tert-butyl nitrone (PBN) and local coronary venous plasma was analyzed by electron paramagnetic resonance (EPR). In control dogs, the myocardial production of PBN adducts exhibited an initial burst immediately after the onset of reflow and remained elevated until 10 min after reperfusion. Dogs treated with MDL 74, 405 demonstrated a marked decrease in PBN adduct production. This effect of MDL 74, 405 could not be attributed to nonspecific factors such as differences in ischemic zone size, collateral flow, arterial pressure, heart rate, coronary flow or other hemodynamic variables. These results demonstrate that the hydrophilic vitamin E analogue, MDL 74, 405, inhibits free radical generation after myocardial ischemia-reperfusion in vivo. This finding provides direct evidence that the salutary effects of MDL 74, 405 on myocardial stunning are due to attenuation of oxidative stress.
KW - Free radical generation
KW - Hydrophilic αtocopherol analogue
KW - Myocardial stunning
KW - Open-chest dogs
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U2 - 10.3109/10715769509145641
DO - 10.3109/10715769509145641
M3 - Article
C2 - 7633559
AN - SCOPUS:0029004444
SN - 1071-5762
VL - 22
SP - 293
EP - 302
JO - Free Radical Research
JF - Free Radical Research
IS - 4
ER -