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(+)-Norfenfluramine-induced arterial contraction is not dependent on endogenous 5-hydroxytryptamine or 5-hydroxytryptamine transporter.
J Pharmacol Exp Ther. 2005 Sep; 314(3):953-60.JP

Abstract

(+)-Norfenfluramine, the major metabolite of fenfluramine, causes vasoconstriction dependence on the 5-hydroxytryptamine (5-HT)(2A) receptor in rat. (+)-Norfenfluramine was reported as a 5-hydroxytryptamine transporter (5-HTT) substrate and 5-HT releaser. Because the arterial 5-HTT exists and is functional in the rat, we hypothesized that (+)-norfenfluramine causes vasoconstriction by releasing 5-HT from vascular smooth muscle via 5-HTT. The released 5-HT, in turn, activates the 5-HT(2A) receptor. Isometric contractility experiments showed that (+)-norfenfluramine-induced mouse aortic contraction was reduced by the 5-HTT inhibitor fluoxetine (1 micriM) but not by fluvoxamine (1 microM). Tryptophan hydroxylase (TPH)-deficient (Tph1-/-) mice lack peripheral 5-HT. (+)-Norfenfluramine (10 nM-100 microM)-contracted aorta from wild-type and Tph1-/- mice with equivalent potency (-log EC(50) [M], wild type = 5.73 +/- 0.02, Tph1-/- = 5.62 +/- 0.09), and these contractions were inhibited by the 5-HT(2A) receptor antagonist ketanserin (3 nM) by a similar magnitude in aorta from wild-type and Tph1-/- mice (wild type = 19.4, Tph1-/- = 15.4-fold rightward shift versus control), as did fluoxetine (1 microM) (wild type = 22.4, Tph1-/- = 28.8-fold rightward shift versus control). To further test the role of 5-HTT in (+)-norfenfluramine-induced aortic contraction, the 5-HTT-targeted mutation mouse was used. (+)-Norfenfluramine induced similar aortic contraction in wild-type and 5-HTT-targeted mutation mice, and these contractions were inhibited by fluoxetine (1 microM). Thus, (+)-norfenfluramine vasoconstriction is not dependent on 5-HTT-mediated release of endogenous 5-HT but by activating membrane 5-HT(2A) receptors directly. Understanding of the mechanism by which (+)-norfenfluramine induces vasoconstriction is important to characterize and understand the function of the serotonergic system in peripheral arterial vasculature.

Authors+Show Affiliations

Department of Pharmacology and Toxicology, Michigan State University, East Lansing, 48824-1317, USA. niwei@msu.eduNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

15901794

Citation

Ni, Wei, et al. "(+)-Norfenfluramine-induced Arterial Contraction Is Not Dependent On Endogenous 5-hydroxytryptamine or 5-hydroxytryptamine Transporter." The Journal of Pharmacology and Experimental Therapeutics, vol. 314, no. 3, 2005, pp. 953-60.
Ni W, Wilhelm CS, Bader M, et al. (+)-Norfenfluramine-induced arterial contraction is not dependent on endogenous 5-hydroxytryptamine or 5-hydroxytryptamine transporter. J Pharmacol Exp Ther. 2005;314(3):953-60.
Ni, W., Wilhelm, C. S., Bader, M., Murphy, D. L., Lookingland, K., & Watts, S. W. (2005). (+)-Norfenfluramine-induced arterial contraction is not dependent on endogenous 5-hydroxytryptamine or 5-hydroxytryptamine transporter. The Journal of Pharmacology and Experimental Therapeutics, 314(3), 953-60.
Ni W, et al. (+)-Norfenfluramine-induced Arterial Contraction Is Not Dependent On Endogenous 5-hydroxytryptamine or 5-hydroxytryptamine Transporter. J Pharmacol Exp Ther. 2005;314(3):953-60. PubMed PMID: 15901794.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - (+)-Norfenfluramine-induced arterial contraction is not dependent on endogenous 5-hydroxytryptamine or 5-hydroxytryptamine transporter. AU - Ni,Wei, AU - Wilhelm,Claudia S, AU - Bader,Michael, AU - Murphy,Dennis L, AU - Lookingland,Keith, AU - Watts,Stephanie W, Y1 - 2005/05/18/ PY - 2005/5/20/pubmed PY - 2005/10/22/medline PY - 2005/5/20/entrez SP - 953 EP - 60 JF - The Journal of pharmacology and experimental therapeutics JO - J Pharmacol Exp Ther VL - 314 IS - 3 N2 - (+)-Norfenfluramine, the major metabolite of fenfluramine, causes vasoconstriction dependence on the 5-hydroxytryptamine (5-HT)(2A) receptor in rat. (+)-Norfenfluramine was reported as a 5-hydroxytryptamine transporter (5-HTT) substrate and 5-HT releaser. Because the arterial 5-HTT exists and is functional in the rat, we hypothesized that (+)-norfenfluramine causes vasoconstriction by releasing 5-HT from vascular smooth muscle via 5-HTT. The released 5-HT, in turn, activates the 5-HT(2A) receptor. Isometric contractility experiments showed that (+)-norfenfluramine-induced mouse aortic contraction was reduced by the 5-HTT inhibitor fluoxetine (1 micriM) but not by fluvoxamine (1 microM). Tryptophan hydroxylase (TPH)-deficient (Tph1-/-) mice lack peripheral 5-HT. (+)-Norfenfluramine (10 nM-100 microM)-contracted aorta from wild-type and Tph1-/- mice with equivalent potency (-log EC(50) [M], wild type = 5.73 +/- 0.02, Tph1-/- = 5.62 +/- 0.09), and these contractions were inhibited by the 5-HT(2A) receptor antagonist ketanserin (3 nM) by a similar magnitude in aorta from wild-type and Tph1-/- mice (wild type = 19.4, Tph1-/- = 15.4-fold rightward shift versus control), as did fluoxetine (1 microM) (wild type = 22.4, Tph1-/- = 28.8-fold rightward shift versus control). To further test the role of 5-HTT in (+)-norfenfluramine-induced aortic contraction, the 5-HTT-targeted mutation mouse was used. (+)-Norfenfluramine induced similar aortic contraction in wild-type and 5-HTT-targeted mutation mice, and these contractions were inhibited by fluoxetine (1 microM). Thus, (+)-norfenfluramine vasoconstriction is not dependent on 5-HTT-mediated release of endogenous 5-HT but by activating membrane 5-HT(2A) receptors directly. Understanding of the mechanism by which (+)-norfenfluramine induces vasoconstriction is important to characterize and understand the function of the serotonergic system in peripheral arterial vasculature. SN - 0022-3565 UR - https://www.unboundmedicine.com/medline/citation/15901794/_+__Norfenfluramine_induced_arterial_contraction_is_not_dependent_on_endogenous_5_hydroxytryptamine_or_5_hydroxytryptamine_transporter_ L2 - https://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=15901794 DB - PRIME DP - Unbound Medicine ER -