Effects of amifostine on perfused isolated rat heart and on acute doxorubicin-induced cardiotoxicity

Purpose: To determine the effects of amifostine on an isolated perfused rat-heart model and its protective activity With regard to cardiotoxic doxorubicin perfusion. Methods: Langendorff constant-pressure isolated rat-heart preparations were used to analyze the effects of the drugs during a 40-min period of perfusion after a 20-min stabilization interval. The first study was conducted with amifostine alone (controls and 10(-6), 10(-5), and 10(-4) M amifostine; n = 6 in each group). The second study was conducted with amifostine and doxorubicin (controls, 2.5 x 10(-5) M doxorubicin, 2.5 x 10(-5) M doxorubicin and 10(-5) M amifostine, and 2.5 x 10(-5) n doxorubicin and 10(-4) M amifostine, n = 4 in each group). Results: Amifostine had no significant effect on hemodynamic parameters at 10(-6), 10(-5), and 10(-4) M concentrations. However, amifostine increased the coronary flow expressed as a percentage +/- SEM of the baseline flow as follows: 82 +/- 4% for controls, 95 +/- 6% for 10(-6) M amifostine, (P = 0.13), 111 +/- 4% for 10(-5) M amifostine (P < 0.01), and 104 +/- 3% for 10(-6) M amifostine (P < 0.01). When we commenced an amifostine perfusion 20 min in advance of and then during a 40-min perfusion with doxorubicin, at a cardiotoxic concentration of 2.5 x 10(-5) M the left ventricular pressures (LVDP, expressed as percentages +/- SEM of the baseline LVDP before doxorubicin) were 55 +/- 3% for the doxorubicin controls, 68 +/- 2% for duxorubicin with 10(-5) M amifostine (P = 0.05), and 80 +/- 3% for doxorubicin with 10(-4) M amifostine (P < 0.01). Whether this protective effect might be related to the known free-radical-scavenging activity of amifostine remains to be determined. Conclusion: On a Langendorff-type model of rat heart, 10(-5) and 10(-4) M amifostine alone induced a coronary dilation and, when associated with a cardiotoxic concentration of 2.5 x 10(-5) M doxorubicin, 10(-5) and 10(-4) M amifostine displayed a cardioprotective effect.