The fenfluramine metabolite (+)-norfenfluramine is vasoactive

J Pharmacol Exp Ther. 2004 May;309(2):845-52. doi: 10.1124/jpet.103.060806. Epub 2004 Jan 29.

Abstract

The anorexigen (+)-fenfluramine was used for treatment of obesity until the association of use with valvular heart disease and primary pulmonary hypertension. (+)-Fenfluramine has been found in Chinese and Korean slimming pills. The hepatic metabolite of (+)-fenfluramine, (+)-norfenfluramine, has affinity for 5-hydroxytryptamine (5-HT)(2A) and 5-HT(2B) receptors. We tested the hypothesis that (+)-norfenfluramine contracts arterial smooth muscle in a 5-HT receptor-dependent manner and acts as a pressor in the conscious rat. Isometric contraction experiments showed that (+)-norfenfluramine (10 nM, 100 microM) but not (+)-fenfluramine nor the isomer (-)-norfenfluramine caused concentration-dependent contraction in arteries [-log EC(50) (moles per liter), thoracic aorta = 5.77 +/- 0.09; renal artery = 6.29 +/- 0.02; mesenteric resistance artery = 5.70 +/- 0.06]. Contraction was dependent on the 5-HT(2A) receptor because ketanserin (10 nM) rightward shifted (+)-norfenfluramine response curves (aorta = 16-fold, renal artery = 26-fold, and resistance artery = >100-fold). Dependence on activation of 5-HT(2A) receptors and independence of (+)-norfenfluramine-induced contraction from stimulation of alpha-adrenergic receptors and the sympathetic nervous system was validated by demonstrating 1) unchanged contraction to (+)-norfenfluramine in arteries from chemically denervated rats; 2) a minimal effect of the alpha(1)-adrenergic receptor antagonist prazosin (100 nM) on contraction; and 3) antagonism by [6-methyl-l-(1-methylethy)ergoline-8beta-carboxylic acid 2-hydroxy-1 methylpropyl ester maleate] LY53857 [6-methyl-1-(1-methylethy)-ergoline-8beta-carboxylic acid 2-hydroxy-1 methylpropyl ester maleate], a 5-HT(2) receptor antagonist without alpha-receptor affinity. (+)-Norfenfluramine (10-300 microg/kg i.v.) caused a dose-dependent increase in mean arterial blood pressure in conscious rats, the maximum of which could be virtually abolished by ketanserin (3 mg/kg i.v.) but not prazosin (0.2 mg/kg i.v.). Our findings demonstrate for the first time that (+)-norfenfluramine is vasoactive and has the potential to increase blood pressure.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Aorta / drug effects
  • Aorta / physiology
  • Blood Pressure / drug effects
  • Ergolines / pharmacology
  • Fenfluramine / metabolism*
  • Fenfluramine / pharmacology
  • In Vitro Techniques
  • Ketanserin / pharmacology
  • Male
  • Norfenfluramine / pharmacology*
  • Prazosin / pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • Receptor, Serotonin, 5-HT2A / metabolism
  • Receptor, Serotonin, 5-HT2C / metabolism
  • Receptors, Adrenergic, alpha / physiology
  • Serotonin 5-HT2 Receptor Antagonists
  • Serotonin Antagonists / pharmacology
  • Sympathectomy
  • Sympathetic Nervous System / drug effects
  • Sympathetic Nervous System / physiology
  • Vasoconstriction / drug effects*
  • Vasoconstriction / physiology

Substances

  • Ergolines
  • Receptor, Serotonin, 5-HT2A
  • Receptor, Serotonin, 5-HT2C
  • Receptors, Adrenergic, alpha
  • Serotonin 5-HT2 Receptor Antagonists
  • Serotonin Antagonists
  • Norfenfluramine
  • Fenfluramine
  • Ketanserin
  • LY 53857
  • Prazosin