QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: jpet.105.087080v1 314/3/953    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Ni, W. Articles by Watts, S. W. Search for Related Content PubMed PubMed Citation Articles by Ni, W. Articles by Watts, S. W.

CARDIOVASCULAR

(+)-Norfenfluramine-Induced Arterial Contraction Is Not Dependent on Endogenous 5-Hydroxytryptamine or 5-Hydroxytryptamine Transporter

Department of Pharmacology and Toxicology, Michigan State University, East Lansing, Michigan (W.N., K.L., S.W.W.); Max Delbrück Center for Molecular Medicine, Berlin-Buch, Germany (C.S.W., M.B.); and Laboratory of Clinical Science, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland (D.L.M.)

(+)-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 EC₅₀ [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 (+)-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 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.

Address correspondence to: Dr. Wei Ni, Department of Pharmacology and Toxicology, B445 Life Sciences Bldg., Michigan State University, East Lansing, MI 48824-1317. E-mail: niwei{at}msu.edu

This article has been cited by other articles:

				I. Morecroft, Y. Dempsie, M. Bader, D. J. Walther, K. Kotnik, L. Loughlin, M. Nilsen, and M. R. MacLean Effect of Tryptophan Hydroxylase 1 Deficiency on the Development of Hypoxia-Induced Pulmonary Hypertension Hypertension, January 1, 2007; 49(1): 232 - 236. [Abstract] [Full Text] [PDF]

				A. Cogolludo, L. Moreno, F. Lodi, G. Frazziano, L. Cobeno, J. Tamargo, and F. Perez-Vizcaino Serotonin Inhibits Voltage-Gated K+ Currents in Pulmonary Artery Smooth Muscle Cells: Role of 5-HT2A Receptors, Caveolin-1, and KV1.5 Channel Internalization Circ. Res., April 14, 2006; 98(7): 931 - 938. [Abstract] [Full Text] [PDF]