Protective effect of ICRF-187 on doxorubicin-induced cardiac and renal toxicity in spontaneously hypertensive (SHR) and normotensive (WKY) rats.
Loss of body weight, cardiomyopathy, and nephropathy were the main toxic manifestations found when male spontaneously hypertensive rats (SHR) and genetically related Wistar-Kyoto (WKY) rats were given 1 mg/kg doxorubicin iv once a week for 12 weeks. Each of these alterations was more severe in SHR. The most profound effects on body weight were observed from the 7th to the 12th week of dosing. During this period the body weight of SHR declined to preinjection control levels. Weight loss also occurred in WKY given doxorubicin, but was not as profound. Pretreatment with 25 mg/kg ICRF-187 ip attenuated the doxorubicin-induced loss in body weight in both types of animals. The frequency and severity of cardiac and renal lesions were graded on a score of 0 to 4. Alterations were found in hearts of all SHR and four of five WKY given doxorubicin alone. Cytoplasmic vacuolization and myofibrillar loss were more severe in SHR (average score, 2.6) than in WKY (average score, 1.0). At the end of the study mean arterial pressure was also decreased in SHR which had received doxorubicin alone. Pretreatment with ICRF-187 significantly attenuated the severity of the lesions in both SHR (average score, 1.0) and WKY (average score, 0); mean arterial pressure was higher in SHR treated with ICRF-187 and doxorubicin than in saline-treated SHR. Renal alterations, including glomerular vacuolization and tubular dilatation, were found in both strains of rats (average scores, 4.0 in SHR and 3.0 in WKY). ICRF-187 also reduced the severity of renal lesions (average scores, 2.0 in SHR and 1.0 in WKY). Thus, although ICRF-187 significantly alters myocardial, renal, and body weight effects of doxorubicin in both strains of rats, these toxic effects are more severe in SHR than in WKY. SHR provide an useful animal model for the critical examination of agents with potential protective activity against doxorubicin-induced toxicity.
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D004317:Doxorubicin / Q000633:toxicity*; D004347:Drug Interactions; D006331:Heart Diseases / Q000139:chemically induced* / Q000473:pathology / Q000517:prevention & control; D006339:Heart Rate / Q000187:drug effects; D007674:Kidney Diseases / Q000139:chemically induced* / Q000473:pathology / Q000517:prevention & control; D008297:Male; D010879:Piperazines / Q000494:pharmacology*; D051381:Rats; D011918:Rats, Inbred SHR; D011919:Rats, Inbred Strains; D011929:Razoxane / Q000494:pharmacology*; D013045:Species Specificity
D010879:Piperazines; D011929:Razoxane; D004317:Doxorubicin