Cardioprotective effects of zofenopril, a new angiotensin-converting enzyme inhibitor, on doxorubicin-induced cardiotoxicity in the rat

We have studied the effect of zofenopril, a new angiotensin-converting enzy me inhibitor in preventing cardiac injury induced by chronic doxorubicin tr eatment in rats. Cardiac function was assessed by measuring changes in elec trocardiogram (ECG) tracings, haemodynamics and cardiac responses in vivo t o isoprenaline, 4 weeks after suspension of doxorubicin treatment, in vehic le-treated rats and in animals receiving zofenopril (15 mg/kg/os/day) alone , doxorubicin (1.5 mg/kg i.v. once a week for 5 weeks) or zofenopril + doxo rubicin treatment. Doxorubicin induced a significant lengthening of the Q a lphaT interval, which was completely prevented by zofenopril treatment. The cardiac positive inotropic effect induced by i.v. isoprenaline was selecti vely depressed by doxorubicin (no changes in chronotropic responses) and th is adverse effect of doxorubicin was also prevented in zofenopril + doxorub icin pretreated rats. Doxorubicin induced a significant increase in relativ e heart weight, which was likewise prevented in zofenopril + doxorubicin tr eated rats. In separate experiments, zofenopril did not interfere with the antitumor activity of doxorubicin (inhibition of tumor growth in nude mice xenografted with A2780 human tumor line). In conclusion, the oral administr ation of zofenopril is able to significantly ameliorate, up to 4 weeks afte r the end of doxorubicin administration, doxontbicin-induced cardiotoxicity without affecting the antitumor activity of this anthracycline. (C) 2001 E lsevier Science B.V. All rights reserved.