Beneficial effects of MDL 74,405, a cardioselective water soluble tocopherol analogue, on the recovery of function of stunned myocardium in intact dogs

Abstract

Postischaemic myocardial dysfunction ("stunning") is caused in part by the generation of reactive oxygen species resulting in oxidant stress. The aim of this study was to test the hypothesis that the systemic administration of MDL 74,405, a hydrophilic cardioselective alpha tocopherol analogue, is beneficial in attenuating myocardial stunning. Open chest dogs undergoing a 15 min coronary artery occlusion and 4 h of reperfusion received an intravenous infusion of either saline (controls, n = 9) or MDL 74,405 (n = 8) at a dose of 0.3 mg.kg-1 x h-1 starting 30 min before coronary occlusion and ending 60 min after reflow. Regional myocardial function (assessed as systolic wall thickening) was similar in control and treated groups at baseline and during ischaemia. Following reperfusion, however, the dogs treated with MDL 74,405 had significant improvement in the recovery of function, which was evident 2 h after restoration of flow and was sustained throughout the rest of the reperfusion phase. Analysis of covariance showed that the differences in wall thickening after reperfusion 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 haemodynamic variables. Measurements of MDL 74,405 showed that the myocardial content of the antioxidant at 4 h of reperfusion was approximately 30 times greater than the plasma concentration at 1 h of reperfusion, suggesting preferential cardiac accumulation of this drug. This study shows (1) that systemic administration of the alpha tocopherol analogue MDL 74,405 in the setting of myocardial ischaemia and reperfusion does not result in adverse cardiovascular effects, at least in the first few hours after injection; (2) that the drug accumulates in myocardial tissue at concentrations much higher than in the plasma; (3) that intravenous infusion of MDL 74,405 produces an attenuation of myocardial stunning comparable to that previously observed with intracoronary administration of other antioxidants; and (4) that this beneficial effect is independent of non-specific actions on haemodynamic variables or coronary flow. The results suggest that the systemic administration of hydrophilic, cardioselective alpha tocopherol analogues represents an effective therapeutic approach to the alleviation of postischaemic dysfunction.