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 enzyme inhibitor in preventing cardiac injury induced by chronic doxorubicin treatment in rats. Cardiac function was assessed by measuring changes in electrocardiogram (ECG) tracings, haemodynamics and cardiac responses in vivo to isoprenaline, 4 weeks after suspension of doxorubicin treatment, in vehicle-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+doxorubicin treatment. Doxorubicin induced a significant lengthening of the QalphaT interval, which was completely prevented by zofenopril treatment. The cardiac positive inotropic effect induced by i.v. isoprenaline was selectively depressed by doxorubicin (no changes in chronotropic responses) and this adverse effect of doxorubicin was also prevented in zofenopril+doxorubicin pretreated rats. Doxorubicin induced a significant increase in relative heart weight, which was likewise prevented in zofenopril+doxorubicin treated 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 administration of zofenopril is able to significantly ameliorate, up to 4 weeks after the end of doxorubicin administration, doxorubicin-induced cardiotoxicity without affecting the antitumor activity of this anthracycline.
Sacco
G
G
Department of Pharmacology, Menarini Ricerche, Via Tito Speri 10, 00040 Pomezia, Rome, Italy. cgoso@menarini-ricerche.it
Bigioni
M
M
Evangelista
S
S
Goso
C
C
Manzini
S
S
Maggi
C A
CA
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000037:antagonists & inhibitors*; D001835:Body Weight / Q000187:drug effects / Q000502:physiology; D002216:Captopril / Q000031:analogs & derivatives* / Q000494:pharmacology* / Q000627:therapeutic use; D002316:Cardiotonic Agents / Q000494:pharmacology*; D004317:Doxorubicin / Q000009:adverse effects / Q000037:antagonists & inhibitors*; D004359:Drug Therapy, Combination; D004562:Electrocardiography / Q000187:drug effects*; D005260:Female; D006321:Heart / Q000187:drug effects / Q000503:physiopathology; D006439:Hemodynamics / Q000187:drug effects* / Q000502:physiology; D007545:Isoproterenol / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009929:Organ Size / Q000187:drug effects; D010051:Ovarian Neoplasms / Q000188:drug therapy; D051381:Rats; D017207:Rats, Sprague-Dawley; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
D000806:Angiotensin-Converting Enzyme Inhibitors; D000970:Antineoplastic Agents; D002316:Cardiotonic Agents; C044958:zofenopril; D004317:Doxorubicin; D002216:Captopril; D007545:Isoproterenol