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-HT2B 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 μM) but not (+)-fenfluramine nor the isomer (-)-norfenfluramine caused concentration-dependent contraction in arteries [-log EC50 (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-HT2A 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-HT2A receptors and independence of (+)-norfenfluramine-induced contraction from stimulation of α-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 α1-adrenergic receptor antagonist prazosin (100 nM) on contraction; and 3) antagonism by [6-methyl-l-(1-methylethy)ergoline-8β-carboxylic acid 2-hydroxy-1 methylpropyl ester maleate] LY53857 [6-methyl-1-(1-methylethy)-ergoline-8β-carboxylic acid 2-hydroxy-1 methylpropyl ester maleate], a 5-HT2 receptor antagonist without α-receptor affinity. (+)-Norfenfluramine (10-300 μg/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.
Footnotes
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This study was supported by National Institutes of Health Grant HL58489.
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DOI: 10.1124/jpet.103.060806.
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ABBREVIATIONS: 5-HT, 5-hydroxytryptamine; PSS, physiological salt solution; PE, phenylephrine; 6-OHDA, 6-hydroxydopamine 6-OHDA; LY272015, 6-methyl-1,2,3,4-tetrahydro-1-[3,4-dimethoxyphenyl)methyl]-9H-pyrido[3,4-b]indole hydrochloride; SNS, sympathetic nervous system; NE, norepinephrine; RX8821002, 2-methoxyidazoxan; LY53857, 6-methyl-1-(1-methylethyl)-ergoline-8β-carboxylic acid 2-hydroxy-1 methylpropyl ester maleate; UK14304, 5-bromo-N-[4,5-dihydro-1H-imidazol-2-yl]-6-quinoxalinamine.
- Received October 1, 2003.
- Accepted January 29, 2004.
- The American Society for Pharmacology and Experimental Therapeutics
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