Tamoxifen and its metabolites cause acute vasorelaxation of aortic rings by inducing vasodilator prostanoid synthesis

Marcelo F. Montenegro, Carla S. Ceron, Maria C O Salgado, Zeruesenay Desta, David A. Flockhart, Jose E. Tanus-Santos

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

The vascular effects of tamoxifen (Tam) and its metabolites are poorly known. We compared the vasorelaxation induced by Tam and its metabolites (N-desmethyl-Tam, 4-hydroxy-Tam, and endoxifen) in aortic rings from rats using standardized organ bath procedures, and we investigated the mechanisms involved in this effect. Tam and its metabolite-induced vasorelaxation in a concentration-dependent manner. Although 4-hydroxy-Tam and Tam had similar potency (pD2 = 8.5 ± 0.1 vs. 8.8 ± 0.1, respectively) and maximum effect (Emax = 88.5% ± 1.3% vs. 92.6% ± 1.3%, respectively), N-desmethyl-Tam and endoxifen were more potent and showed higher E max than Tam did (pD2 = 9.0 ± 0.1 and 8.9 ± 0.1; E max = 101.1% ± 1.8% and 101.0% ± 1.8% for N-desmethyl-Tam and endoxifen, respectively). Although preincubation of aortic rings with the estrogen receptor antagonist ICI 182780 or with the nitric oxide synthase inhibitor N ω-nitro-L-arginine methyl ester hydrochloride induced no changes in the vasorelaxation induced by Tam or 4-hydroxy-Tam, both drugs significantly reduced Emax in response to N-desmethyl-Tam or to endoxifen. Inhibition of cyclooxygenase with indomethacin or the incubation with the prostaglandin D2 and E2 receptor antagonist AH6809 reduced the vasorelaxation-induced Tam and its metabolites by approximately 50%. Preincubation with Nω-nitro-L-arginine methyl ester hydrochloride combined with indomethacin abolished the vasorelaxation-induced Tam and its metabolites. These results show that Tam and its metabolites cause acute vasorelaxation by inducing vasodilator prostanoids synthesis.

Original languageEnglish
Pages (from-to)647-653
Number of pages7
JournalJournal of Cardiovascular Pharmacology
Volume58
Issue number6
DOIs
StatePublished - Dec 2011

Fingerprint

Tamoxifen
Vasodilator Agents
Vasodilation
Prostaglandins
Indomethacin
Arginine
Prostaglandin-Endoperoxide Synthases
Baths
Dinoprostone
Nitric Oxide Synthase
Blood Vessels

Keywords

  • metabolites
  • prostanoids
  • tamoxifen
  • vascular

ASJC Scopus subject areas

  • Pharmacology
  • Cardiology and Cardiovascular Medicine

Cite this

Tamoxifen and its metabolites cause acute vasorelaxation of aortic rings by inducing vasodilator prostanoid synthesis. / Montenegro, Marcelo F.; Ceron, Carla S.; Salgado, Maria C O; Desta, Zeruesenay; Flockhart, David A.; Tanus-Santos, Jose E.

In: Journal of Cardiovascular Pharmacology, Vol. 58, No. 6, 12.2011, p. 647-653.

Research output: Contribution to journalArticle

Montenegro, Marcelo F. ; Ceron, Carla S. ; Salgado, Maria C O ; Desta, Zeruesenay ; Flockhart, David A. ; Tanus-Santos, Jose E. / Tamoxifen and its metabolites cause acute vasorelaxation of aortic rings by inducing vasodilator prostanoid synthesis. In: Journal of Cardiovascular Pharmacology. 2011 ; Vol. 58, No. 6. pp. 647-653.
@article{424939440220410bae4b50308438fcdf,
title = "Tamoxifen and its metabolites cause acute vasorelaxation of aortic rings by inducing vasodilator prostanoid synthesis",
abstract = "The vascular effects of tamoxifen (Tam) and its metabolites are poorly known. We compared the vasorelaxation induced by Tam and its metabolites (N-desmethyl-Tam, 4-hydroxy-Tam, and endoxifen) in aortic rings from rats using standardized organ bath procedures, and we investigated the mechanisms involved in this effect. Tam and its metabolite-induced vasorelaxation in a concentration-dependent manner. Although 4-hydroxy-Tam and Tam had similar potency (pD2 = 8.5 ± 0.1 vs. 8.8 ± 0.1, respectively) and maximum effect (Emax = 88.5{\%} ± 1.3{\%} vs. 92.6{\%} ± 1.3{\%}, respectively), N-desmethyl-Tam and endoxifen were more potent and showed higher E max than Tam did (pD2 = 9.0 ± 0.1 and 8.9 ± 0.1; E max = 101.1{\%} ± 1.8{\%} and 101.0{\%} ± 1.8{\%} for N-desmethyl-Tam and endoxifen, respectively). Although preincubation of aortic rings with the estrogen receptor antagonist ICI 182780 or with the nitric oxide synthase inhibitor N ω-nitro-L-arginine methyl ester hydrochloride induced no changes in the vasorelaxation induced by Tam or 4-hydroxy-Tam, both drugs significantly reduced Emax in response to N-desmethyl-Tam or to endoxifen. Inhibition of cyclooxygenase with indomethacin or the incubation with the prostaglandin D2 and E2 receptor antagonist AH6809 reduced the vasorelaxation-induced Tam and its metabolites by approximately 50{\%}. Preincubation with Nω-nitro-L-arginine methyl ester hydrochloride combined with indomethacin abolished the vasorelaxation-induced Tam and its metabolites. These results show that Tam and its metabolites cause acute vasorelaxation by inducing vasodilator prostanoids synthesis.",
keywords = "metabolites, prostanoids, tamoxifen, vascular",
author = "Montenegro, {Marcelo F.} and Ceron, {Carla S.} and Salgado, {Maria C O} and Zeruesenay Desta and Flockhart, {David A.} and Tanus-Santos, {Jose E.}",
year = "2011",
month = "12",
doi = "10.1097/FJC.0b013e31823171ba",
language = "English",
volume = "58",
pages = "647--653",
journal = "Journal of Cardiovascular Pharmacology",
issn = "0160-2446",
publisher = "Lippincott Williams and Wilkins",
number = "6",

}

TY - JOUR

T1 - Tamoxifen and its metabolites cause acute vasorelaxation of aortic rings by inducing vasodilator prostanoid synthesis

AU - Montenegro, Marcelo F.

AU - Ceron, Carla S.

AU - Salgado, Maria C O

AU - Desta, Zeruesenay

AU - Flockhart, David A.

AU - Tanus-Santos, Jose E.

PY - 2011/12

Y1 - 2011/12

N2 - The vascular effects of tamoxifen (Tam) and its metabolites are poorly known. We compared the vasorelaxation induced by Tam and its metabolites (N-desmethyl-Tam, 4-hydroxy-Tam, and endoxifen) in aortic rings from rats using standardized organ bath procedures, and we investigated the mechanisms involved in this effect. Tam and its metabolite-induced vasorelaxation in a concentration-dependent manner. Although 4-hydroxy-Tam and Tam had similar potency (pD2 = 8.5 ± 0.1 vs. 8.8 ± 0.1, respectively) and maximum effect (Emax = 88.5% ± 1.3% vs. 92.6% ± 1.3%, respectively), N-desmethyl-Tam and endoxifen were more potent and showed higher E max than Tam did (pD2 = 9.0 ± 0.1 and 8.9 ± 0.1; E max = 101.1% ± 1.8% and 101.0% ± 1.8% for N-desmethyl-Tam and endoxifen, respectively). Although preincubation of aortic rings with the estrogen receptor antagonist ICI 182780 or with the nitric oxide synthase inhibitor N ω-nitro-L-arginine methyl ester hydrochloride induced no changes in the vasorelaxation induced by Tam or 4-hydroxy-Tam, both drugs significantly reduced Emax in response to N-desmethyl-Tam or to endoxifen. Inhibition of cyclooxygenase with indomethacin or the incubation with the prostaglandin D2 and E2 receptor antagonist AH6809 reduced the vasorelaxation-induced Tam and its metabolites by approximately 50%. Preincubation with Nω-nitro-L-arginine methyl ester hydrochloride combined with indomethacin abolished the vasorelaxation-induced Tam and its metabolites. These results show that Tam and its metabolites cause acute vasorelaxation by inducing vasodilator prostanoids synthesis.

AB - The vascular effects of tamoxifen (Tam) and its metabolites are poorly known. We compared the vasorelaxation induced by Tam and its metabolites (N-desmethyl-Tam, 4-hydroxy-Tam, and endoxifen) in aortic rings from rats using standardized organ bath procedures, and we investigated the mechanisms involved in this effect. Tam and its metabolite-induced vasorelaxation in a concentration-dependent manner. Although 4-hydroxy-Tam and Tam had similar potency (pD2 = 8.5 ± 0.1 vs. 8.8 ± 0.1, respectively) and maximum effect (Emax = 88.5% ± 1.3% vs. 92.6% ± 1.3%, respectively), N-desmethyl-Tam and endoxifen were more potent and showed higher E max than Tam did (pD2 = 9.0 ± 0.1 and 8.9 ± 0.1; E max = 101.1% ± 1.8% and 101.0% ± 1.8% for N-desmethyl-Tam and endoxifen, respectively). Although preincubation of aortic rings with the estrogen receptor antagonist ICI 182780 or with the nitric oxide synthase inhibitor N ω-nitro-L-arginine methyl ester hydrochloride induced no changes in the vasorelaxation induced by Tam or 4-hydroxy-Tam, both drugs significantly reduced Emax in response to N-desmethyl-Tam or to endoxifen. Inhibition of cyclooxygenase with indomethacin or the incubation with the prostaglandin D2 and E2 receptor antagonist AH6809 reduced the vasorelaxation-induced Tam and its metabolites by approximately 50%. Preincubation with Nω-nitro-L-arginine methyl ester hydrochloride combined with indomethacin abolished the vasorelaxation-induced Tam and its metabolites. These results show that Tam and its metabolites cause acute vasorelaxation by inducing vasodilator prostanoids synthesis.

KW - metabolites

KW - prostanoids

KW - tamoxifen

KW - vascular

UR - http://www.scopus.com/inward/record.url?scp=83155172381&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=83155172381&partnerID=8YFLogxK

U2 - 10.1097/FJC.0b013e31823171ba

DO - 10.1097/FJC.0b013e31823171ba

M3 - Article

C2 - 21885992

AN - SCOPUS:83155172381

VL - 58

SP - 647

EP - 653

JO - Journal of Cardiovascular Pharmacology

JF - Journal of Cardiovascular Pharmacology

SN - 0160-2446

IS - 6

ER -