Reversal of doxorubicin-induced vascular dysfunction by resveratrol in rat thoracic aorta: Is there a possible role of nitric oxide synthase inhibition?

Olukman, Murat; CAN, Cenk; ÇINAR, GÜLCİHAN MEHTAP; ORAL, Onur; Erol, Ayşe; Oktem, Gulperi

Reversal of doxorubicin-induced vascular dysfunction by resveratrol in rat thoracic aorta: Is there a possible role of nitric oxide synthase inhibition?

Murat OLUKMAN, (Ege Üniversitesi, Tıp Fakültesi, Farmakoloji ve Klinik Farmakoloji Anabilim Dalı, İzmir, Türkiye)

Cenk CAN, (Ege Üniversitesi, Tıp Fakültesi, Farmakoloji ve Klinik Farmakoloji Anabilim Dalı, İzmir, Türkiye)

Ayşe EROL, (Ege Üniversitesi, Tıp Fakültesi, Farmakoloji ve Klinik Farmakoloji Anabilim Dalı, İzmir, Türkiye)

Gülperi ÖKTEM, (Ege Üniversitesi, Tıp Fakültesi, Histoloji ve Embriyoloji Anabilim Dalı, İzmir, Türkiye)

Onur ORAL, (Konak Gültepe Aile Planlama Merkezi, İzmir, Türkiye)

GÜLCİHAN MEHTAP ÇINAR (Ege Üniversitesi, Tıp Fakültesi, Farmakoloji ve Klinik Farmakoloji Anabilim Dalı, İzmir, Türkiye)

Anadolu Kardiyoloji Dergisi

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Yıl: 2009 Cilt: 9 Sayı: 4 Sayfa Aralığı: 260 - 266 Metin Dili: Türkçe İndeks Tarihi: 29-07-2022

Reversal of doxorubicin-induced vascular dysfunction by resveratrol in rat thoracic aorta: Is there a possible role of nitric oxide synthase inhibition?

Öz:

Amaç: Doğal bir antioksidan olan resveratrolün doksorubisine bağlı kardiyotoksisiteye karşı koruduğu öne sürülmektedir. Nitrik oksit (NO) sentezindeki düzensizliklerin doksorubisine bağlı damar endotel disfonksiyonuna katkısı olduğu düşünülmekle birlikte, resveratrolün söz konusu parametreler üzerindeki etkileri henüz araştırılmamıştır. Deneysel, prospektif, kontrollü çalışmada resveratrol uygulamasının sıçan torasik aortunda doksorubisinin oluşturduğu endotel fonksiyon değişiklikleri üzerine etkileri ve bu etkilerin NO sentezi ile ilişkisi incelenmiştir. Yöntemler: Wistar sıçanları 5 gruba ayrıldı; doksorubisin (n=9), çözücü (dimetilsülfoksit) (n=8), resveratrol (n=8), doksorubisin+resveratrol (n=10), kontrol (n=9). Gruplardan izole edilen torasik aort preparatlarında kasılma ve endotel aracılı/aracısız gevşeme yanıtları ile değişik NO-sentaz (NOS) izoformlarının ekspresyon düzeyleri histopatolojik olarak değerlendirildi. Doz-yanıt eğrilerinin istatistiksel değerlendirmesinde tekrarlayan ölçümler için ANOVA, eğrilerin pD2 ve Emax (maksimum fenilefrin kontraksiyonu) değerleri için ise tek yönlü ANOVA yöntemlerinin ardından Bonferroni testi uygulandı. Bulgular: Doksorubisin uygulaması (20 mg/kg, i.p.), endotelli preparatlarda fenilefrinle indüklenen kontraktil yanıtların (p<0.001) yanı sıra, asetilkolin (ACh) (p=0.002), kalsiyum iyonofor (A23187) (p=0.002) ve sodyum nitroprusit (SNP) (p=0.007) ile elde edilen gevşeme yanıtlarında azalmaya neden oldu. İmmünohistokimyasal incelemelerde doksorubisin uygulamasından sonra endotelyal NOS (eNOS) ve indüklenebilir NOS (iNOS) ekspresyon düzeylerinin anlamlı olarak arttığı gözlendi (p<0.05). Sadece resveratrol (10 mg/kg/i.p.) uygulanan grupta eNOS ya da iNOS ekspresyonu değişmedi. Ancak doksorubisin+ resveratrol uygulanan grupta NOS enzim ekspresyon düzeyi doksorubisin grubuna göre azaldı (p<0.05). Resveratrol tek başına damar yanıtlarında belirgin değişiklikler oluşturmazken, birlikte uygulandığında doksorubisin tarafından azaltılan ACh (p=0.013) ve A23187 (p=0.038) yanıtlarında anlamlı artışlara neden oldu. Sonuç: Endotelyal ve indüklenebilir NOS izoformlarının ekspresyonunda artışa bağlı aşırı NO üretiminin resveratrol tarafından önlenmesi doksorubisin tedavisi ile ilişkili damar endotel fonksiyon bozukluğunun düzelmesine katkıda bulunabilir.

Anahtar Kelime:

Konular: Kalp ve Kalp Damar Sistemi

Sıçan torasik aortunda doksorubisinin oluşturduğu fonksiyon bozukluğunun resveratrol uygulaması ile düzelmesi: Nitrik oksit sentaz inhibisyonunun olası rolü var mı?

Öz:

Objective: The natural antioxidant, resveratrol has been suggested to protect against doxorubicin-induced cardiotoxicity. Although derangements in nitric oxide (NO) synthesis contribute to vascular endothelial dysfunction caused by doxorubicin, the effects of resveratrol on these parameters have not been evaluated yet. We investigated the impact of resveratrol on doxorubicin-induced vascular dysfunction in rat thoracic aorta with regard to NO synthesis in an experimental, prospective, controlled study.Methods: Wistar rats were assigned to 5 groups; doxorubicin (n=9), vehicle (dimethylsulphoxide) (n=8), resveratrol (n=8), doxorubicin+resveratrol (n=10), controls (n=9). Contractile and relaxant responses were evaluated on the isolated thoracic aortas. The expressions of endothelial (eNOS) and inducible (iNOS) isoforms of NO-synthase were also examined histopathologically on the aortas. Statistical analysis was performed by ANOVA for repeated measures for the response curves and one-way ANOVA for the pD2 (-log EC50) and Emax (maximum phenylephrine contraction) values with subsequent Bonferroni test. Results: Doxorubicin (20 mg/kg, i.p), not only decreased the contractile responses to phenylephrine (p<0.001), but also attenuated the relaxant responses to acetylcholine (ACh) (p=0.002), calcium ionophore (A23187) (p=0.002) and sodium nitroprusside (SNP) (p=0.007). Immunohistochemistry revealed increased (p<0.05) eNOS and iNOS protein expressions after doxorubicin treatment. Coadministration of resveratrol (10 mg/kg/i.p.) reversed the increased expression of both NOS isoforms (p<0.05). Similarly, it prevented the doxorubicin-induced attenuation in ACh- (p=0.013) and A23187- (p=0.038) induced responses. In healthy rats the antioxidant did not cause significant changes. Conclusion: Prevention of excessive NO formation through eNOS and iNOS overexpression by resveratrol might contribute to the reversal of vascular endothelial dysfunction associated with doxorubicin treatment.

Anahtar Kelime:

Konular: Kalp ve Kalp Damar Sistemi

Belge Türü: Makale Makale Türü: Araştırma Makalesi Erişim Türü: Erişime Açık

1. Lefrak EA, Pitha J, Rosenheim S, Gotlieb JA. A clinicopathologic analysis of adriamycin cardiotoxicity. Cancer 1973; 32: 302-14.
2. Bristow MR, Thompson PD, Martin RP, Mason JW, Billingham ME, Harrison DC. Early anthracycline cardiotoxicity. Am J Med 1978; 65: 823-32.
3. Murata T, Yamawaki H, Hori M, Ozaki H, Karaki H. Chronic vascular toxicity of doxorubicin in an organ-cultured artery. Br J Pharmacol 2001; 132: 1365-73.
4. Wu S, Ko Y, Teng MS, Ko YL, Hsu LA, Hsueh C, et al. Adriamycin-induced cardiomyocyte and endothelial cell apoptosis: in vitro and in vivo studies. J Mol Cell Cardiol 2002; 34: 1595-607.
5. Wolf MB, Baynes JW. The anti-cancer drug, doxorubicin, causes oxidant stress-induced endothelial dysfunction. Biochim Biophys Acta 2006; 1760: 267-71.
6. Vasquez-Vivar J, Martasek P, Hogg N, Masters BS, Pritchard KA Jr, Kalyanaraman B. Endothelial nitric oxide synthase-dependent superoxide generation from adriamycin. Biochemistry 1997; 36: 11293-7.
7. Duquaine D, Hirsch GA, Chakrabarti A, Han Z, Kehrer C, Brook R, et al. Rapid-onset endothelial dysfunction with adriamycin: evidence for a dysfunctional nitric oxide synthase. Vasc Med 2003; 8: 101-7.
8. Kalivendi WSV, Kotamraju S, Zhaao H, Joseph J, Kalyanaraman B. Doxorubicin-induced Apoptosis Is Associated with Increased Transcription of Endothelial Nitric-oxide Synthase. J Biol Chem 2001; 276: 47266-77.
9. Soleas GJ, Diamandis E, Goldberg DM. Resveratrol: a molecule whose time has come? And gone? Clin Biochem 1997; 30: 91-113.
10. Fremont L. Biological effects of resveratrol. Life Sci 2000; 66: 663-73.
11. Ray PS, Maulik G, Cordis GA, Bertelli AAE, Bertelli A, Das DK. The red wine antioxidant resveratrol protects isolated rat hearts from ischemia reperfusion injury. Free Radic Biol Med 1999; 27: 160-9.
12. Hattori R, Otani H, Maulik N, Das DK. Pharmacological preconditioning with resveratrol: a role of nitric oxide. Am J Physiol Heart Circ Physiol 2002; 282: H1988-95.
13. Rezk YA, Balulad SS, Keller RS, Bennett JA. Use of Resveratrol to improve the effectiveness of cisplatin and doxorubicin: Study in human gynecologic cancer cell lines and in rodent heart. Am J Obstet Gynecol 2006; 194: e23-e26.
14. Yu BB, Han XZ, Lou HX. Oligomers of resveratrol and ferulic acid prepared by peroxidase-catalysed oxidation and their protective effects on cardiac injury. J Agric Food Chem 2007; 55: 7753-7.
15. Nwankola RN, West WL. Inhibition of alpha-tocopherol and calcium calmodulin-stimulated phosphodiesterase activity in vitro by anthracyclines. Clin Exp Pharmacol Physiol 1988; 15: 805-14.
16. Moncada S, Palmer RMJ, Higgs EAA. Nitric oxide: physiology, pathophysiology and pharmacology. Pharmacol Rev 1991; 43: 109-42.
17. Egleme C, Godfraind T, Miller RC. Enhanced responsiveness of rat isolated aorta to clonidine after removal of endothelial cells. Br J Pharmacol 1984; 81: 16-21.
18. Tsai S-H, Lin-Shiau S-Y, Lin J-K. Suppression of nitric oxide synthase and the down-regulation of the activation of NFκB in macrophages by resveratrol. Br J Pharmacol 1999; 126: 673-80.
19. Bi XL, Yang JY, Dong YX, Wang JM, Cui YH, Ikeshima T, et al. Resveratrol inhibits nitric oxide and TNF-α production by lipopolysaccharide-activated microglia. Int Immunopharmacol 2005; 5: 185-93.
20. Hsieh TC, Juan G, Darzynkiewicz Z, Wu JM. Resveratrol increases nitric oxide synthase, induces accumulation of p53 and P21 WAF1/CIP1, and suppresses cultured bovine pulmonary artery endothelial cell proliferation by pertubing progression through S and G2. Cancer Res 1999; 59: 2596-601.
21. Wallerath T, Deckert G, Ternes T, Anderson H, Li H, Witte K, et al. Resveratrol, a polyphenolic phytoalexin present in red wine, enhances expression and activity of endothelial nitric oxide synthase. Circulation 2002; 106: 1652-8.
22. Rush JWE, Quadrilatero J, Levy AS, Ford RJ. Chronic resveratrol enhances endothelium-dependent relaxation but does not alter eNOS levels of aorta of spontaneously hypertensive rats. Exp Biol Med 2007; 232: 814-22.
23. Neilan TG, Blake SL, Ichinose F, Raher MJ, Buys ES, Jassal DS, et al. Disruption of nitric oxide synthase 3 protects against the cardiac injury, dysfunction, and mortality induced by doxorubicin. Circulation 2007; 116: 506-14.
24. Pacher P, Liaudet L. Bai P, Mabley JG, Kaminski PM, Virág Li et al. Potent metalloporphyrin peroxynitrite decomposition catalyst protect against the development of doxorubicin-induced cardiac dysfunction. Circulation 2003; 107: 896-904.
25. Liu B, Li H, Qu H, Sun B. Nitric oxide synthase expressions in ADR-induced cardiomyopathy in rats. J Biochem Mol Biol 2006; 6: 759-65.

APA	Olukman M, CAN C, Erol A, Oktem G, ORAL O, ÇINAR G (2009). Reversal of doxorubicin-induced vascular dysfunction by resveratrol in rat thoracic aorta: Is there a possible role of nitric oxide synthase inhibition?. , 260 - 266.
Chicago	Olukman Murat,CAN Cenk,Erol Ayşe,Oktem Gulperi,ORAL Onur,ÇINAR GÜLCİHAN MEHTAP Reversal of doxorubicin-induced vascular dysfunction by resveratrol in rat thoracic aorta: Is there a possible role of nitric oxide synthase inhibition?. (2009): 260 - 266.
MLA	Olukman Murat,CAN Cenk,Erol Ayşe,Oktem Gulperi,ORAL Onur,ÇINAR GÜLCİHAN MEHTAP Reversal of doxorubicin-induced vascular dysfunction by resveratrol in rat thoracic aorta: Is there a possible role of nitric oxide synthase inhibition?. , 2009, ss.260 - 266.
AMA	Olukman M,CAN C,Erol A,Oktem G,ORAL O,ÇINAR G Reversal of doxorubicin-induced vascular dysfunction by resveratrol in rat thoracic aorta: Is there a possible role of nitric oxide synthase inhibition?. . 2009; 260 - 266.
Vancouver	Olukman M,CAN C,Erol A,Oktem G,ORAL O,ÇINAR G Reversal of doxorubicin-induced vascular dysfunction by resveratrol in rat thoracic aorta: Is there a possible role of nitric oxide synthase inhibition?. . 2009; 260 - 266.
IEEE	Olukman M,CAN C,Erol A,Oktem G,ORAL O,ÇINAR G "Reversal of doxorubicin-induced vascular dysfunction by resveratrol in rat thoracic aorta: Is there a possible role of nitric oxide synthase inhibition?." , ss.260 - 266, 2009.
ISNAD	Olukman, Murat vd. "Reversal of doxorubicin-induced vascular dysfunction by resveratrol in rat thoracic aorta: Is there a possible role of nitric oxide synthase inhibition?". (2009), 260-266.

APA	Olukman M, CAN C, Erol A, Oktem G, ORAL O, ÇINAR G (2009). Reversal of doxorubicin-induced vascular dysfunction by resveratrol in rat thoracic aorta: Is there a possible role of nitric oxide synthase inhibition?. Anadolu Kardiyoloji Dergisi, 9(4), 260 - 266.
Chicago	Olukman Murat,CAN Cenk,Erol Ayşe,Oktem Gulperi,ORAL Onur,ÇINAR GÜLCİHAN MEHTAP Reversal of doxorubicin-induced vascular dysfunction by resveratrol in rat thoracic aorta: Is there a possible role of nitric oxide synthase inhibition?. Anadolu Kardiyoloji Dergisi 9, no.4 (2009): 260 - 266.
MLA	Olukman Murat,CAN Cenk,Erol Ayşe,Oktem Gulperi,ORAL Onur,ÇINAR GÜLCİHAN MEHTAP Reversal of doxorubicin-induced vascular dysfunction by resveratrol in rat thoracic aorta: Is there a possible role of nitric oxide synthase inhibition?. Anadolu Kardiyoloji Dergisi, vol.9, no.4, 2009, ss.260 - 266.
AMA	Olukman M,CAN C,Erol A,Oktem G,ORAL O,ÇINAR G Reversal of doxorubicin-induced vascular dysfunction by resveratrol in rat thoracic aorta: Is there a possible role of nitric oxide synthase inhibition?. Anadolu Kardiyoloji Dergisi. 2009; 9(4): 260 - 266.
Vancouver	Olukman M,CAN C,Erol A,Oktem G,ORAL O,ÇINAR G Reversal of doxorubicin-induced vascular dysfunction by resveratrol in rat thoracic aorta: Is there a possible role of nitric oxide synthase inhibition?. Anadolu Kardiyoloji Dergisi. 2009; 9(4): 260 - 266.
IEEE	Olukman M,CAN C,Erol A,Oktem G,ORAL O,ÇINAR G "Reversal of doxorubicin-induced vascular dysfunction by resveratrol in rat thoracic aorta: Is there a possible role of nitric oxide synthase inhibition?." Anadolu Kardiyoloji Dergisi, 9, ss.260 - 266, 2009.
ISNAD	Olukman, Murat vd. "Reversal of doxorubicin-induced vascular dysfunction by resveratrol in rat thoracic aorta: Is there a possible role of nitric oxide synthase inhibition?". Anadolu Kardiyoloji Dergisi 9/4 (2009), 260-266.