BENEFICIAL-EFFECTS OF MDL-74,405, A CARDIOSELECTIVE WATER-SOLUBLE ALPHA-TOCOPHEROL ANALOG, ON THE RECOVERY OF FUNCTION OF STUNNED MYOCARDIUM IN INTACT DOGS

Objective: Postischaemic myocardial dysfunction (''stunning'') is caus ed in part by the generation of reactive oxygen species resulting in o xidant stress. The aim of this study was to test the hypothesis that t he systemic administration of MDL 74,405, a hydrophilic cardioselectiv e alpha tocopherol analogue, is beneficial in attenuating myocardial s tunning. Methods: Open chest dogs undergoing a 15 min coronary artery occlusion and 4 h of reperfusion received an intravenous infusion of e ither saline (controls, n = 9) or MDL 74,405 (n = 8) at a dose of 0.3 mg.kg(-1).h(-1) starting 30 min before coronary occlusion and ending 6 0 min after reflow. Results: Regional myocardial function (assessed as systolic wall thickening) was similar in control and treated groups a t baseline and during ischaemia. Following reperfusion, however, the d ogs treated with MDL 74,405 had significant improvement in the recover y of function, which was evident 2 h after restoration of flow and was sustained throughout the rest of the reperfusion phase. Analysis of c ovariance showed that the differences in wall thickening after reperfu sion between the two groups were independent of collateral flow during occlusion. Furthermore, the enhanced recovery effected by MDL 74,405 could not be attributed to non-specific factors such as coronary flow after reperfusion, arterial pressure, heart rate, or other haemodynami c variables. Measurements of MDL 74,405 showed that the myocardial con tent of the antioxidant at 4 h of reperfusion was approximately 30 tim es greater than the plasma concentration at 1 h of reperfusion, sugges ting preferential cardiac accumulation of this drug. Conclusions: This study shows (1) that systemic administration of the alpha tocopherol analogue MDL 74,405 in the setting of myocardial ischaemia and reperfu sion does not result in adverse cardiovascular effects, at least in th e first few hours after injection; (2) that the drug accumulates in my ocardial tissue at concentrations much higher than in the plasma; (3) that intravenous infusion of MDL 74,405 produces an attenuation of myo cardial stunning comparable to that previously observed with intracoro nary administration of other antioxidants; and (4) that this beneficia l effect is independent of non-specific actions on haemodynamic variab les or coronary flow. The results suggest that the systemic administra tion of hydrophilic, cardioselective alpha tocopherol analogues repres ents an effective therapeutic approach to the alleviation of postischa emic dysfunction.