The fenfluramine metabolite (+)-norfenfluramine is vasoactive.
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.
Ni
Wei
W
Department of Pharmacology and Toxicology, Michigan State University, East Lansing, MI 48824-1317, USA. niwei@msu.edu
Li
Melissa W
MW
Thakali
Keshari
K
Fink
Gregory D
GD
Watts
Stephanie W
SW
D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000502:physiology; D001794:Blood Pressure / Q000187:drug effects; D004873:Ergolines / Q000494:pharmacology; D005277:Fenfluramine / Q000378:metabolism* / Q000494:pharmacology; D066298:In Vitro Techniques; D007650:Ketanserin / Q000494:pharmacology; D008297:Male; D009642:Norfenfluramine / Q000494:pharmacology*; D011224:Prazosin / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D044402:Receptor, Serotonin, 5-HT2A / Q000378:metabolism; D044405:Receptor, Serotonin, 5-HT2C / Q000378:metabolism; D011942:Receptors, Adrenergic, alpha / Q000502:physiology; D058830:Serotonin 5-HT2 Receptor Antagonists; D012702:Serotonin Antagonists / Q000494:pharmacology; D013562:Sympathectomy; D013564:Sympathetic Nervous System / Q000187:drug effects / Q000502:physiology; D014661:Vasoconstriction / Q000187:drug effects* / Q000502:physiology
D004873:Ergolines; D044402:Receptor, Serotonin, 5-HT2A; D044405:Receptor, Serotonin, 5-HT2C; D011942:Receptors, Adrenergic, alpha; D058830:Serotonin 5-HT2 Receptor Antagonists; D012702:Serotonin Antagonists; D009642:Norfenfluramine; D005277:Fenfluramine; D007650:Ketanserin; C032663:LY 53857; D011224:Prazosin