title: Reversal of doxorubicin-induced vascular dysfunction by resveratrol in rat thoracic aorta: Is there a possible role of nitric oxide synthase inhibition?
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors: Department of Pharmacology and Clinical Pharmacology, Faculty of Medicine, Ege University, Izmir, Turkiye.
authors: Murat
authors: M
authors: Olukman
authors: Cenk
authors: C
authors: Can
authors: Ayşe
authors: A
authors: Erol
authors: Gülperi
authors: G
authors: Oktem
authors: Onur
authors: O
authors: Oral
authors: Mehtap Gülcihan
authors: MG
authors: Cinar
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000633:toxicity; D000975:Antioxidants / Q000494:pharmacology*; D001013:Aorta, Thoracic / Q000187:drug effects* / Q000201:enzymology / Q000502:physiology; D004317:Doxorubicin / Q000633:toxicity; D004336:Drug Antagonism; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000201:enzymology / Q000502:physiology; D007150:Immunohistochemistry; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D052250:Nitric Oxide Synthase Type III / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D011446:Prospective Studies; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D000077185:Resveratrol; D013267:Stilbenes / Q000494:pharmacology*
chemical_list: D000903:Antibiotics, Antineoplastic; D000975:Antioxidants; D017382:Reactive Oxygen Species; D013267:Stilbenes; D009569:Nitric Oxide; D004317:Doxorubicin; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D000077185:Resveratrol