Effect of aging on cardiac contractility in a rat model of chronic daunorubicin cardiotoxicity.
Because the risk of chronic anthracycline cardiotoxicity increases with age, the effect of chronic daunorubicin was compared in young (6-9 mo) and senescent (24-26 mo) Fischer 344 rats in cumulative doses of 12 or 18 mg/kg. Senescent rats treated using 18 mg/kg of daunorubicin did not survive because of daunorubicin toxicity. Rats were euthanized 1 wk after the last dose of daunorubicin and ex vivo studies of isometric cardiac contractile function were done in left ventricular trabeculae carneae. In senescent rats given 12 mg/kg of daunorubicin, it caused significant impairment of contractility (dS/dt at 15 cpm; p = 0.001) that was not observed in either young adult group. In addition, the effect of 12 mg/kg of daunorubicin on contractility in senescent rats was significantly reduced compared to that in young rats administered 12 mg/kg of daunorubicin (p < 0.001), although the effect was similar to that in young rats given 18 mg/kg of daunorubicin. In rats receiving 12 mg/kg of daunorubicin, there was an age-dependent effect of daunorubicin on rate-related contractility and on Ca2+-induced contractility. Daunorubicinol, but not daunorubicin, concentrations were increased in the senescent rat heart tissue. This suggests that chronic daunorubicin cardiotoxicity increases with age, at least partly resulting from sarcoplasmic reticulum dysfunction caused by increased anthracycline exposure.
Cusack
Barry J
BJ
Clinical Pharmacology and Gerontology Research Unit, Veterans Affairs Medical Center, Boise, ID 83702, USA. barry.cusack@med.va.gov
Young
Stephen P
SP
Gabliel
Hervé
H
Olson
Richard D
RD
D000375:Aging / Q000097:blood / Q000502:physiology*; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000009:adverse effects / Q000494:pharmacology*; D015220:Calcium Channels / Q000187:drug effects; D002784:Cholesterol / Q000097:blood; D002908:Chronic Disease; D003404:Creatinine / Q000097:blood; D003630:Daunorubicin / Q000009:adverse effects / Q000494:pharmacology*; D003864:Depression, Chemical; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006331:Heart Diseases / Q000139:chemically induced; D006352:Heart Ventricles / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008955:Models, Cardiovascular; D009200:Myocardial Contraction / Q000187:drug effects*; D009206:Myocardium / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D012519:Sarcoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D013997:Time Factors; D014280:Triglycerides / Q000097:blood; D016277:Ventricular Function, Left / Q000187:drug effects
D000903:Antibiotics, Antineoplastic; D015220:Calcium Channels; D014280:Triglycerides; D002784:Cholesterol; D003404:Creatinine; D003630:Daunorubicin