Plasma nitric oxide levels used as an indicator of doxorubicin-induced cardiotoxicity in rats.
BACKGROUND
The clinical efficacy of doxorubicin is severely limited by its cardiotoxicity. The currently noninvasive techniques used to detect this complication lack sensitivity to identify its early stages. Nitric oxide (NO) is a free radical that has been implicated in the etiology of doxorubicin-induced cardiotoxicity. In the present study, we investigated whether plasmatic NO levels can be used as a noninvasive and reliable biomarker of doxorubicin-induced cardiotoxicity.


METHODS
Two groups of six spontaneously hypertensive rats (SHR) were used for the experiment. Group 1 received 1.5 mg/kg intraperitoneal (IP) doxorubicin weekly for up to 9 weeks. Group 2 (Control) received nine weekly IP injection of 0.5 cm3 saline. Plasmatic NO levels and cardiac ejection fraction (EF%) were determined. Ventricular biopsies were analyzed by light microscopy according with the Billinghan score.


RESULTS
Doxorubicin treatment significantly increased plasmatic NO concentration (35.30+/-5.63 microM versus 14.72+/-2.66 microM in control animals, n=6, P<0.05). In addition, doxorubicin decreased EF by 23% approximately (from 77.00+/-3.89 in controls, to 59.00+/-5.61 in doxorubicin-treated animals, n=6, P<0.05). The mean score of histological cardiac damage was 2.33+/-0.33 for doxorubicin-treated versus 0.08+/-0.08 for controls, n=6, P<0.001.


CONCLUSIONS
Our results revealed a correlation between plasmatic NO levels, systolic function and histopathological myocardial damage. Therefore, it is plausible to postulate that plasmatic NO levels could be used as a biomarker for myocardial damage in doxorubicin-treated SHR, and may be a potential tool for noninvasive evaluation of doxorubicin-induced toxicity in humans.
Guerra
Jhon
J
Department of Pediatrics, University of Puerto Rico-School of Medicine, San Juan, Puerto Rico. jhonguerra@wartech-pro.com
De Jesus
Ana
A
Santiago-Borrero
Pedro
P
Roman-Franco
Angel
A
Rodríguez
Edwin
E
Crespo
Maria J
MJ
D000818:Animals; D015415:Biomarkers / Q000097:blood; D004317:Doxorubicin / Q000633:toxicity*; D004452:Echocardiography; D006321:Heart / Q000187:drug effects* / Q000503:physiopathology; D008297:Male; D023421:Models, Animal; D009206:Myocardium / Q000473:pathology; D009569:Nitric Oxide / Q000097:blood*; D051381:Rats; D011918:Rats, Inbred SHR; D013599:Systole
D015415:Biomarkers; D009569:Nitric Oxide; D004317:Doxorubicin