The mechanisms of the adverse effects of free fatty acids on the ischemic-reperfused myocardium are not fully understood. Long-chain fatty acids, including palmitate, uncouple oxidative phosphorylation and should therefore promote the formation of oxygen-derived free radicals, with consequent adverse effects. Conversely, the antianginal agent trimetazidine (TMZ), known to inhibit cardiac fatty acid oxidation, could hypothetically lessen the formation of reactive oxygen species (ROS) and thus improve reperfusion mechanical function. Isolated perfused rat hearts underwent 30 min of total global ischemia followed by 30 min of reperfusion. Hearts were perfused with glucose 5.5 mmol/l or palmitate 1.5 mmol/l with or without TMZ (100 micromol/l). Ascorbyl free radical (AFR) release during perfusion periods was measured by electron spin resonance as a marker of oxidative stress. Post-ischemic recovery in the palmitate group of heart was lower than in the glucose group with a marked rise in diastolic tension and reduction in left ventricular developed pressure (Glucose: 85 +/- 11 mmHg; Palmitate: 10 +/- 6 mmHg; p < 0.001). TMZ decreased diastolic tension in both glucose- and in palmitate-perfused hearts. Release of AFR within the first minute of reperfusion was greater in palmitate-perfused hearts and in hearts perfused with either substrate, this marker of oxidative stress was decreased by TMZ (expressed in arbitrary units/ml; respectively: 8.49 +/- 1.24 vs. 1.06 +/- 0.70 p < 0.05; 12.47 +/- 2.49 vs. 3.37 +/- 1.29 p < 0.05). Palmitate increased the formation of ROS and reperfusion contracture. TMZ, a potential inhibitor of palmitate-induced mitochondrial uncoupling, decreased the formation of free radicals and improved postischemic mechanical dysfunction. The novel conclusion is that adverse effects of fatty acids on ischemic-reperfusion injury may be mediated, at least in part, by oxygen-derived free radicals.

To evaluate the effects of alpha-lipoic acid (AL) in a model of doxorubicin (DOX)-induced cardiotoxicity, male Wistar rats were treated with DOX (1 mg/kg/d; 10 d) in combination or not with AL (50 mg/kg/d; 15 d). Plasma oxidative stress was determined by hydroperoxides (ROOH) and the ascorbyl radical/ascorbate ratio. One and two months later, the functional parameters of the hearts were determined in vivo by catheterization and cardiac oxidative stress was assessed by malonedialdehyde (MDA) and O₂*⁻ (dihydroethidium fluorescence) content in tissue. After two months, body weight was higher in the DOX-AL group than in DOX (+16%), but this was due to ascites. Histological liver alterations were observed in both the DOX and DOX-AL groups. Plasma ROOH concentrations decreased after 10 days of AL treatment, but were greater in both the DOX and DOX-AL groups. After two months, a decrease in the cardiac contractility index (-27% and -29%, respectively) and cardiac hypertrophy were observed in DOX and DOX-AL. These dysfunctions were associated with 1) a reduction in plasma ascorbate levels and an increase in the ascorbyl/ascorbate ratio and 2) an increase MDA and O₂*⁻ content in cardiac tissue. In conclusion, a cumulative dose of 10 mg/kg doxorubicin induced functional alterations in the heart associated with plasma and cardiac oxidative stress. The co-administration of the antioxidant compound AL had no beneficial effects in this situation.

We reported previously that glycerol is a substrate for energy production in cardiomyocytes. Increasing glycerol availability results in increased glycerol uptake and its involvement in complex lipid biosynthesis and energy production. This study evaluated the relationship between glycerol supply, energy demand, and intermediary metabolism leading to energy production. The work was performed on isolated rat heart perfused in the working mode. Glycerol concentrations modeled the fasting (0.33 mM) and fed (3.33 mM) states. Cardiac energy demand was modeled by increasing heart rate from 350 to 450 beats/min (bpm). Increasing glycerol supply increased glycerol uptake from 1.4 (350 bpm) to 3.8 (450 bpm) and from 9.7 (350 bpm) to 34.2 (450 bpm) micro mol glycerol/heart in 30 min at 0.33 and 3.33 mM glycerol, respectively. At low glycerol supply, increasing heart rate did not influence the complex lipid synthesis. Conversely, high glycerol concentration increased the complex lipid synthesis by 5- and 30-fold at 350 and 450 bpm, respectively. Increasing glycerol supply and heart rate significantly increased glycerol oxidation rate. Moreover, increasing glycerol supply did not affect glucose oxidation but increased palmitate uptake and significantly decreased its beta-oxidation. Physiological concentrations of glycerol contribute to the cardiac intermediary metabolism, both for energy production and glycerolipid synthesis. Increasing energy demand enhances the requirement and use of glycerol. Glycerol contributes to the regulation of cardiac metabolism and energy balance, mainly by decreasing the contribution of fatty acid oxidation, and may thus represent a new factor in cardiac protection through the reduction of oxygen demand.

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