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Background: Our purpose was to determine the effects of amifostine, a cytoprotective agent, on doxorubicin tolerance and cardiotoxicity in rats., Materials and Methods: Male Wistar rats were treated every other day with an intraperitoneal injection of amifostine or saline 30 minutes before intraperitoneal injection of doxorubicin or saline. Weight change was recorded, and contractile function was evaluated after 11 injections by means of the isolated heart., Results: Weight evolution and cardiac function were significantly improved by 7 and 20 mg/kg amifostine (p < 0.001) but not by 50 mg/kg. The final weight were: controls 349 +/- 16 g; doxorubicin alone 258 +/- 54 g; with amifostine: 7 mg/kg 314 + 28 g; 20 mg/kg 312 +/- 32 g; 50 mg/kg 250 +/- 34 g. Left ventricular developed pressure were: controls 137 +/- 15 mmHg; doxorubicin alone 119 +/- 20 mmHg; with amifostine: 7 mg/kg 140 +/- 20 mmHg; 20 mg/kg 137 +/- 25 mmHg; 50 mg/kg 124 +/- 20 mmHg., Conclusion: Seven and 20 mg/kg amifostine protected rats from the toxicity of doxorubicin at the cumulative dose of 18 mg/kg during a 12-day treatment, with regard to weight loss and heart contraction.

The electrophysiological effects of gallium chloride (Ga ) and its activity on arrhythmias induced by digitalis were investigated in guinea pig papillary muscle. KCl microelectrodes were used to record transmembrane electrical activity from Purkinje cells from the papillary muscle of guinea pig hearts during superfusion and electrical stimulation in vitro at 37 degrees C. Myocardial contractility was continuously monitored. Ga was superfused alone in cumulative concentrations(4.5 . 10(-5) to 3.6 . 10(-4) M). Arrhythmias were induced by a superfusion of Digitoxin (7.5 . 10 (-7) M). A superfusion of Ga (4.5 . 10(-5), 9 . 10(-5), 1.8 . 10(-4) M and 3.6 . 10(-4) M) was started 20 min later and maintained for 70 min. Ga alone produced a dose dependent reduction of action potential duration and contractility. Ga potentiated the decrease in the amplitude and duration of the action potential induced by Digitoxin. The incidence of arrhythmias was immediately reduced by two concentrations of Ga (4.5 . 10(-5) and 9 . 10(-5) M) in the digitalized papillary muscles. It is concluded that Ga inhibits calcium movements and has negative inotropic and antidysrhythmic effects.

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.

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.