Type-5 phosphodiesterase inhibition in prevention of doxorubicin cardiomyopathy

2005 2005

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Abstract (summary)

Prior studies have demonstrated the effect of diazoxide in protecting against apoptosis via mitochondrial KATP channel opening in vitro. The current investigations are designed to determine if sildenafil, a phosphodiesterase-5 inhibitor and known mitochondrial K ATP channel opener, would protect against chronic doxorubicin cardiomyopathy both in vivo and in vitro.

Male ICR mice were randomized to 1 of 4 treatments: saline, sildenafil (0.7 mg/kg IP), doxorubicin (5 mg/kg IP), and sildenafil (0.7 mg/kg IP)+doxorubicin. Apoptosis was determined using the terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling and in situ oligo ligation methods. Desmin distribution was determined via immunofluorescence. Bcl-2 was analyzed by Western blot. Left ventricular function was measured in Langendorff mode. Electrocardiographical analysis measured changes indicative of doxorubicin cardiotoxicity (ST-prolongation). In vitro studies using adult ventricular cardiomyocytes were exposed to doxorubicin (1 μM), sildenafil (1 μM) with or without N G-nitro-L-arginine methyl ester (L-NAME; 100 μM)), or 5-hydroxydecanoate (5-HD; 100 μM)) 1 hour before doxorubicin and incubated for 18 hours.

Doxorubicin-treated mice demonstrated increased apoptosis and desmin disruption, which was attenuated in the sildenafil+doxorubicin group. Bcl-2 decreased in the doxorubicin group but was maintained at basal levels in the sildenafil+doxorubicin group. Left ventricular developed pressure and rate pressure product were significantly depressed in the doxorubicin group but attenuated in the sildenafil+doxorubicin group. ST-interval significantly increased in the doxorubicin group over 8 weeks. In the sildenafil+doxorubicin group, ST-interval remained unchanged from baseline. Doxorubicin significantly increased apoptosis, caspase-3 activation, and disruption of mitochondrial membrane potential in vitro. In contrast, sildenafil significantly protected against doxorubicin cardiotoxicity; however, protection was abolished by both L-NAME and 5-HD. Cell viability studies using spectrophotometer and flow cytometric techniques demonstrated that sildenafil did not affect the antitumor efficacy of doxorubicin in PC-3 cells in vitro. In fact, flow cytometry data indicate that sildenafil, when combined with doxorubicin, was synergistic in the antineoplastic action of doxorubicin.

Prophylactic treatment with sildenafil prevented apoptosis and left ventricular dysfunction in a chronic model of doxorubicin-induced cardiomyopathy. Moreover, these studies provide relevant clinical data on the safety and efficacy of sildenafil, leading the way for clinical trials in humans receiving doxorubicin chemotherapy.

Indexing (details)

Molecular biology;
0992: Oncology
0564: Surgery
0307: Molecular biology
0571: Pathology
0419: Pharmacology
Identifier / keyword
Health and environmental sciences; Biological sciences; Apoptosis; Cardiomyopathy; Doxorubicin; Phosphodiesterase
Type-5 phosphodiesterase inhibition in prevention of doxorubicin cardiomyopathy
Fisher, Patrick William
Number of pages
Publication year
Degree date
School code
DAI-B 66/03, Dissertation Abstracts International
Place of publication
Ann Arbor
Country of publication
United States
0542020033, 9780542020032
Kukreja, Rakesh C.
Virginia Commonwealth University
University location
United States -- Virginia
Source type
Dissertations & Theses
Document type
Dissertation/thesis number
ProQuest document ID
Database copyright ProQuest LLC; ProQuest does not claim copyright in the individual underlying works.
Document URL
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