Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2014 Mar;31(1):68-74.
doi: 10.4274/Tjh.2013.0013. Epub 2014 Mar 5.

The role of nitric oxide in Doxorubicin-induced cardiotoxicity: experimental study

Ayşenur Bahadır  1 , Nilgün Kurucu  2 , Mine Kadıoğlu  3 , Engin Yenilme  4
Affiliations

The role of nitric oxide in Doxorubicin-induced cardiotoxicity: experimental study

Ayşenur Bahadır et al. Turk J Haematol. 2014 Mar.

Abstract
in English, Turkish

Objective: We evaluated the myocardial damage in rats treated with doxorubicin (DOX) alone and in combination with nitric oxide synthase (NOS) inhibitors.

Materials and methods: Twenty-four male Sprague Dawley rats (12 weeks old, weighing 262±18 g) were randomly assigned into 4 groups (n=6). Group I was the control group. In Group II, rats were treated with intraperitoneal (ip) injections of 3 mg/kg DOX once a week for 5 weeks. In Group III, rats received weekly ip injections of 30 mg/kg L-NAME (nonspecific NOS inhibitor) 30 min before DOX injections for 5 weeks. In Group IV, rats received weekly ip injections of 3 mg/kg L-NIL (inducible NOS inhibitor) 30 min before DOX injections for 5 weeks. Rats were weighed 2 times a week. At the end of 6 weeks, hearts were excised and then fixed for light and electron microscopy evaluation and tissue lipid peroxidation (malondialdehyde). Blood samples were also obtained for measuring plasma lipid peroxidation.

Results: Weight loss was observed in Group II, Group III, and Group IV. Weight loss was statistically significant in the DOX group. Findings of myocardial damage were significantly higher in animals treated with DOX only than in the control group. Histopathological findings of cardiotoxicity in rats treated with DOX in combination with L-NAME and L-NIL were not significantly different compared with the control group. The level of plasma malondialdehyde in the DOX group (9.3±3.4 µmol/L) was higher than those of all other groups.

Conclusion: Our results showed that DOX cardiotoxicity was significantly decreased when DOX was given with NO synthase inhibitors.

Amaç: Bu çalışmada sıçanlarda doksorubisinin (DOX) tek başına ve nitrik oksit sentaz (NOS) inhibitörleri ile birlikte kullanımının kalp kası üzerinde yarattığı hasar araştırıldı.Gereç ve Yöntemler: Çalışmada 12 haftalık 24 adet erkek “Sprague Dawley” sıçanı (ortalama ağırlık 262±18 gr) rastgele dört gruba (n=6) dağıtıldı. Grup I kontrol grubu olarak ayırıldı. Grup II’ye haftada bir kez intraperitoneal (ip) 3 mg/kg, beş hafta DOX uygulandı. Grup III’e DOX enjeksiyonundan 30 dakika önce ip 30 mg/kg L-NAME (nonselektif NOS inhibitörü) 5 hafta uygulandı. Grup IV’e DOX enjeksiyonundan 30 dakika önce ip 3 mg/kg L-NIL (indüklenebilir NOS inhibitörü) 5 hafta uygulandı. Çalışma süresince sıçanlar haftada iki kez tartıldı. Altıncı haftada kalbin sol ventrikülünden alınan parçalardan elektron ve ışık mikroskobik inceleme ve lipit peroksidasyonu tayini (malondialdehid) yapıldı. Plazma lipit peroksidasyonunun belirlenmesi amacı ile sıçanlardan kan alındı.Bulgular: Grup II, Grup III ve Grup IV’te kilo kaybı gözlendi. DOX uygulanan grupta istatistiksel olarak anlamlı kilo kaybı saptandı. Miyokard hasarı bulguları tek başına DOX alan hayvanlarda kontrol grubuna oranla daha yüksek oranda izlendi. DOX’le beraber L-NAME ve L-NIL verilen sıçanlarda kardiyotoksitenin histopatolojik bulguları kontrol grubundan farklı değildi. Plazma malondialdehid düzeyi DOX grubunda (9,3± 3,4), diğer tüm gruplara göre daha yüksek olarak ölçüldü. Sonuç: Bizim çalışmamızda DOX’la beraber NOS inhibitörleri uygulandığında DOX’a bağlı kardiyak toksisite bulgularında anlamlı azalma olduğu gösterilmiştir.

Keywords: Doxorubicin; Nitric oxide synthase inhibitors; nitric oxide.

PubMed Disclaimer

Figures

Figure 1
Figure 1. Group I=control; normal histopathological morphology, no findings of myocardial toxicity.
Figure 2
Figure 2. Group II =DOX; arrow shows the myocyte edema, ‘a’ shows mitochondrial injury, and ‘b’ shows sarcoplasmic reticulum edema. There is also loss of myofibrils.
Figure 3
Figure 3. Group III=DOX + L-NAME; there is less mitochondrial injury.
Figure 4
Figure 4. Group IV=DOX + L-NIL; less myocyte edema is observed.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Minotti G, Menna P, Salvatorelli E, Cairo G, Gianni L. Anthracyclines: molecular advances and pharmacologic developments in antitumor activity and cardiotoxicity. Pharmocol Rev. 2004;56:185–229. - PubMed
    1. Paulides M, Kremers A, Stöhr W, Bielack S, Jürgens H, Treuner J, Beck JD. Prospective longitudinal evaluation of doxorubicin-induced cardiomyopathy in sarcoma patients: a report of the late effects surveillance system (LESS) Pediatr Blood Cancer. 2006;46:489–495. - PubMed
    1. Kremer LC, Dalen EC, van, Offringa M, Ottenkamp J, Voûte PA. Anthracycline-induced clinical heart failure in a cohort of 607 children: long-term follow-up study. J Clin Oncol. 2001;19:191–196. - PubMed
    1. Doroshow JH. Effect of anthracycline antibiotics on oxygen radical formation in rat heart. Cancer Res. 1983;43:460–472. - PubMed
    1. Keizer HG, Pinedo HM, Schuurhuis GJ, Joenje H. Doxorubicin (adriamycin): a critical review of free radical-dependent mechanisms of cytotoxicity. Pharmacol Ther. 1990;47:219–231. - PubMed

LinkOut - more resources