ACE inhibition and protection from doxorubicin-induced cardiotoxicity in the rat.

ABSTRACT

The angiotensin converting enzyme inhibitor zofenopril has been shown to possess cardioprotective effects toward myocardial damage induced by chronic doxorubicin treatment in the rat. In the present study we have investigated the relationship between cardioprotection exerted by 2 angiotensin converting enzyme inhibitors (zofenopril and lisinopril) and degree of inhibition of cardiac versus serum angiotensin converting enzyme. Both zofenopril and lisinopril produced a dose-dependent inhibition of serum and cardiac angiotensin converting enzyme in rats (0.1, 1 or 10 mg/kg/day in the diet for 1 week). However, zofenopril at 0.1 mg/kg/day showed a significantly (P < 0.05) greater inhibition of angiotensin converting enzyme in the myocardium than in the serum (delta about 20%). Using dose levels (0.1 mg/kg/day and 10 mg/kg/day) which inhibits partially (about 50%) or almost totally (about 80%) serum angiotensin converting enzyme, we evaluated the effects of zofenopril and lisinopril in preventing cardiac alterations (QalphaT prolongation) induced by chronic treatment with doxorubicin (1.5 mg/kg q7dx5 i.v.). Zofenopril, at a dose level (0.1 mg/kg/ day) that did not affect haemodynamics and only partially inhibits serum angiotensin converting enzyme activity, almost totally prevent the QalphaT lengthening induced by doxorubicin, whereas lisinopril was ineffective at this dose level. At the higher dose level (10 mg/kg/day), both angiotensin converting enzyme inhibitors totally prevented the electrocardiographic alteration induced by chronic doxorubicin administration. Cardioprotection exerted by zofenopril at a dose level that partially inhibits serum angiotensin converting enzyme without affecting haemodynamics, suggests that inhibition of cardiac angiotensin converting enzyme and additional cardioprotective mechanism(s) may have a role in its ability to prevent myocardial damages in the rat subjected to chronic anthracycline treatment.