Increased iron content in rat myocardium after 5-fluorouracil chronic administration.

The isovolumic perfused rat heart model according to Langendorff has been used in order to characterize the changes occurring in the heart following 5-Fluorouracil (5-FU) administration. Preliminary published data pointed out that perfusion of isolated heart with 1 mg/l 5-FU failed to show any differences in contractility and oxygen consumption in comparison with the control group. However, when Wistar rats received 5-FU once a day (50 mg/kg, I.P.) for five consecutive days a consistent increase in oxygen consumption throughout the 80 min of perfusion associated with a decrease in the fractional extraction of oxygen and a lowered + dP/dt max were observed, without any drug added during the in vitro perfusion. Further investigation has been performed for a better understanding of the results observed after 5-FU pretreatment. Magnesium, potassium, calcium, copper and iron contents in the myocardium (at 0 min of perfusion) were measured by flame atomic absorption spectrophotometry. Iron levels were 20% higher in the 5-FU pretreated group than in the control group, whereas as no differences were observed for the other elemental concentrations. Both initial glycogen and ATP contents were respectively 42% and 29% higher in the pretreated than in the control group and alpha-hydroxybutyrate dehydrogenase release was lower after 40 min of perfusion in the pretreated group. However, 5-FU pretreatment increased net tissue water gain after 80 min of perfusion. Increases in mean oxygen partial pressure in the myocardium and in oxygen consumption associated with increased iron level might be candidates responsible for 5-FU induced cardiotoxicity through an increased in oxygen derived free radicals. Sympathetic over-stimulation or calcium overload do not appear to be involved in 5-FU induced cardiotoxicity.

Acute effects of gallium chloride on ventricular function and metabolism of the Langendorff perfused rat heart.

The effects of two concentrations of GaCl3 (1.79 microM and 7.17 microM) were studied on isolated perfused paced rat hearts. All hearts were submitted to an equilibration period of 20 minutes under normal conditions of oxygenation (95% O2, 5% CO2) and with 11 mM glucose in Krebs-Henseleit buffer. At the end of the perfusion (80 min) tissue Ga contents were 98.0 +/- 13.8 and 200.2 +/- 28.5 nM/g of wet weight for the lower and the higher Ga concentrations respectively. Left ventricular developed pressure (LVdp) as well as +LVdp/dt and -LVdp/dt were similar in control and Ga-treated groups during the 60 minutes following the equilibration period. At the same time mean coronary flow and oxygen consumption were lower (p < 0.05) in hearts perfused with 7.17 microM Ga than in the control group. Lactate production did not differ in the control and Ga-treated groups. Mean creatine kinase release was lower (p < 0.05) in the 7.17 microM Ga-treated group than in the 1.79 microM Ga-treated and control groups. Intratissular malondialdehyde as well as glycogen and ATP concentrations did not differ in all groups at the end of the experiment. Gallium chloride partially prevented the unavoidable oedema resulting from using saline Krebs-Henseleit solution. In conclusion, acute GaCl3 administration improves the functionality of the Langendorff-heart model.