Received for publication March 31, 2005.
Revised May 12, 2005.
Accepted for publication May 12, 2005.

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

Abstract

(+)-Norfenfluramine, the major metabolite of fenfluramine, causes vasoconstriction dependent on the 5-HT_2A receptor in rat. (+)-Norfenfluramine was reported as a 5-hydroxytryptamine transporter (5-HTT) substrate and 5-hydroxytryptamine (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). 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-/- (wild type=19.4, Tph1-/-=15.4-fold rightward shift vs. control), as did fluoxetine (1 µM) (wild type=22.4, Tph1-/-=28.8-fold rightward shift vs. 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. The 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.

Key words: 5-HT, 5-HTT, artery, fluoxetine, receptors, vasoconstriction

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