Assessment of vascular effects of tamoxifen and its metabolites on the rat perfused hindquarter vascular bed

Marcelo F. Montenegro, Lisandra R. Pessa, Valéria A. Gomes, Zeruesenay Desta, David A. Flockhart, Jose E. Tanus-Santos

Research output: Contribution to journalArticle

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Abstract

Tamoxifen has been suggested to produce beneficial cardiovascular effects, although the mechanisms for these effects are not fully known. Moreover, although tamoxifen metabolites may exhibit 30-100 times higher potency than the parent drug, no previous study has compared the effects produced by tamoxifen and its metabolites on vascular function. Here, we assessed the vascular responses to acetylcholine and sodium nitroprusside on perfused hindquarter vascular bed of rats treated with tamoxifen or its main metabolites (N-desmethyl-tamoxifen, 4-hydroxy-tamoxifen, and endoxifen) for 2 weeks. Plasma and whole-blood thiobarbituric acid reactive substances (TBARS) concentrations were determined using a fluorometric method. Plasma nitrite and NOx (nitrite + nitrate) concentrations were determined using an ozone-based chemiluminescence assay and Griess reaction, respectively. Treatment with tamoxifen reduced the responses to acetylcholine (pD2 = 2.2 ± 0.06 and 1.9 ± 0.05 after vehicle and tamoxifen, respectively; P < 0.05), while its metabolites improved these responses (pD2 = 2.5 ± 0.04 after N-desmethyl-tamoxifen, 2.5 ± 0.03 after 4-hydroxy-tamoxifen, and 2.6 ± 0.08 after endoxifen; P < 0.01). Tamoxifen and its metabolites showed no effect on endothelial-independent responses to sodium nitroprusside (P > 0.05). While tamoxifen treatment resulted in significantly higher plasma and whole blood lipid peroxide levels (37% and 62%, respectively; both P < 0.05), its metabolites significantly decreased lipid peroxide levels (by approximately 50%; P < 0.05). While treatment with tamoxifen decreased the concentrations of markers of nitric oxide formation by approximately 50% (P < 0.05), tamoxifen metabolites had no effect on these parameters (P > 0.05). These results suggest that while tamoxifen produces detrimental effects, its metabolites produce counteracting beneficial effects on the vascular system and on nitric oxide/reactive oxygen species formation.

Original languageEnglish
Pages (from-to)400-407
Number of pages8
JournalBasic and Clinical Pharmacology and Toxicology
Volume104
Issue number5
DOIs
StatePublished - May 2009

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Tamoxifen
Metabolites
Blood Vessels
Rats
Nitrites
Plasmas
Acetylcholine
Blood
Chemiluminescence
Thiobarbituric Acid Reactive Substances
Lipid Peroxides
Ozone
Nitroprusside
Nitrates
Luminescence
Assays
Reactive Oxygen Species
Nitric Oxide
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Pharmacology
  • Toxicology

Cite this

Assessment of vascular effects of tamoxifen and its metabolites on the rat perfused hindquarter vascular bed. / Montenegro, Marcelo F.; Pessa, Lisandra R.; Gomes, Valéria A.; Desta, Zeruesenay; Flockhart, David A.; Tanus-Santos, Jose E.

In: Basic and Clinical Pharmacology and Toxicology, Vol. 104, No. 5, 05.2009, p. 400-407.

Research output: Contribution to journalArticle

Montenegro, Marcelo F. ; Pessa, Lisandra R. ; Gomes, Valéria A. ; Desta, Zeruesenay ; Flockhart, David A. ; Tanus-Santos, Jose E. / Assessment of vascular effects of tamoxifen and its metabolites on the rat perfused hindquarter vascular bed. In: Basic and Clinical Pharmacology and Toxicology. 2009 ; Vol. 104, No. 5. pp. 400-407.
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