(+)-Norfenfluramine-induced arterial contraction is not dependent on endogenous 5-HT or 5-HTT

Item Type:	Article
Title:	(+)-Norfenfluramine-induced arterial contraction is not dependent on endogenous 5-HT or 5-HTT
Creators Name:	Ni, W. and Wilhelm, C.S. and Bader, M. and Murphy, D.L. and Lookingland, K.J. and Watts, S.W.
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 μM) but not by fluvoxamine (1 μM). Tryptophan hydroxylase (TPH)-deficient (Tph1-/-) mice lack peripheral 5-HT. (+)-Norfenfluramine (10 nM-100 μM)-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 μM) (wild type = 22.4, Tph1-/- = 28.8-fold rightward shift versus control). To further test the role of 5-HTT in (+)-norfenfluramineinduced 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 μM). 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.
Keywords:	Aorta, Fluoxetine, Fluvoxamine, Inbred C57BL Mice, Ketanserin, Membrane Glycoproteins, Membrane Transport Proteins, Nerve Tissue Proteins, Norfenfluramine, Serotonin, Serotonin Plasma Membrane Transport Proteins, Serotonin Uptake Inhibitors, Tryptophan Hydroxylase, Vasoconstriction, Animals, Mice
Source:	Journal of Pharmacology and Experimental Therapeutics
ISSN:	0022-3565
Publisher:	Amer Soc Pharmacology Experimental Therapeutics
Volume:	314
Number:	3
Page Range:	953-960
Date:	18 May 2005
Official Publication:	https://doi.org/10.1124/jpet.105.087080
PubMed:	View item in PubMed

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