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The Fenfluramine Metabolite ()-Norfenfluramine Is Vasoactive 0022-3565/04/3092-845–852$20.00 THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS Vol. 309, No. 2 Copyright © 2004 by The American Society for Pharmacology and Experimental Therapeutics 60806/1144303 JPET 309:845–852, 2004 Printed in U.S.A. The Fenfluramine Metabolite (ϩ)-Norfenfluramine Is Vasoactive Wei Ni, Melissa W. Li, Keshari Thakali, Gregory D. Fink, and Stephanie W. Watts Department of Pharmacology and Toxicology, Michigan State University, East Lansing, Michigan Received October 1, 2003; accepted January 29, 2004 ABSTRACT ϩ ϩ The anorexigen ( )-fenfluramine was used for treatment of 5-HT2A receptors and independence of ( )-norfenfluramine- obesity until the association of use with valvular heart disease induced contraction from stimulation of ␣-adrenergic receptors and primary pulmonary hypertension. (ϩ)-Fenfluramine has and the sympathetic nervous system was validated by demon- Downloaded from been found in Chinese and Korean slimming pills. The hepatic strating 1) unchanged contraction to (ϩ)-norfenfluramine in ar- metabolite of (ϩ)-fenfluramine, (ϩ)-norfenfluramine, has affinity teries from chemically denervated rats; 2) a minimal effect of ␣ for 5-hydroxytryptamine (5-HT)2A and 5-HT2B receptors. We the 1-adrenergic receptor antagonist prazosin (100 nM) on tested the hypothesis that (ϩ)-norfenfluramine contracts arte- contraction; and 3) antagonism by [6-methyl-l-(1-methylethy)- rial smooth muscle in a 5-HT receptor-dependent manner and ergoline-8␤-carboxylic acid 2-hydroxy-1 methylpropyl ester acts as a pressor in the conscious rat. Isometric contraction maleate] LY53857 [6-methyl-1-(1-methylethy)-ergoline-8␤-car- ϩ ␮ jpet.aspetjournals.org experiments showed that ( )-norfenfluramine (10 nM, 100 M) boxylic acid 2-hydroxy-1 methylpropyl ester maleate], a 5-HT2 but not (ϩ)-fenfluramine nor the isomer (Ϫ)-norfenfluramine receptor antagonist without ␣-receptor affinity. (ϩ)-Norfenflu- caused concentration-dependent contraction in arteries [Ϫlog ramine (10–300 ␮g/kg i.v.) caused a dose-dependent increase ϭ Ϯ EC50 (moles per liter), thoracic aorta 5.77 0.09; renal in mean arterial blood pressure in conscious rats, the maximum artery ϭ 6.29 Ϯ 0.02; mesenteric resistance artery ϭ 5.70 Ϯ of which could be virtually abolished by ketanserin (3 mg/kg i.v.) 0.06]. Contraction was dependent on the 5-HT2A receptor be- but not prazosin (0.2 mg/kg i.v.). Our findings demonstrate for cause ketanserin (10 nM) rightward shifted (ϩ)-norfenfluramine the first time that (ϩ)-norfenfluramine is vasoactive and has the response curves (aorta ϭ 16-fold, renal artery ϭ 26-fold, and potential to increase blood pressure. resistance artery ϭϾ100-fold). Dependence on activation of at ASPET Journals on June 8, 2015 The highly effective anorexigen (ϩ)-fenfluramine (Redux) valvulopathy. Recently, the Food and Drug Administration was approved as an individual agent by the Food and Drug warned that two Chinese diet pills contain fenfluramine (http:// Administration for long-term use in the medical management of www.fda.gov/bbs/topics/NEWS/2002/NEW00826.html). Un- obesity in 1996. American health care practitioners used (ϩ)- doubtedly, there are still individuals ingesting (ϩ)-fenflura- fenfluramine either alone or in combination with a noradrener- mine; thus, it is important for potential serious side effects of gic appetite suppressant, phentermine (combination of fenflu- this drug to be highlighted. ramine and phentermine, “fen-phen”); the combination was (ϩ)-Fenfluramine is a 5-hydroxytryptamine transporter never approved by Food and Drug Administration (www. substrate and potent 5-HT releaser (Garattini, 1995). The fda.gov/cder/news/phen/phenfen.htm). The effectiveness of the hepatic deethylated metabolite of (ϩ)-fenfluramine is (ϩ)- combination (fen-phen) in reducing body weight was similar to norfenfluramine, which also possesses the ability to release use of each individual drug alone, but lower doses of each drug 5-HT. Important for this study is the knowledge that (ϩ)- could be used with the intent of reducing side effects. However, norfenfluramine has been described as a 5-HT receptor ago- (ϩ)-fenfluramine was pulled from the market in 1997 because nist. Radioligand binding experiments show (ϩ)-fenflura- Ͼ ␮ of the incidence of pulmonary hypertension (Abenhaim et al., mine has a weak affinity (Ki 2 M) for the 5-HT2A, 5-HT2B, ϩ 1996) and aortic valvular disease (Connolly et al., 1997). Phen- and 5-HT2C receptor, whereas ( )-norfenfluramine has high ϭ termine was not withdrawn because it was not associated with affinity at the 5-HT2B receptor (Ki 11.2 nM), 5-HT2C re- ϭ ceptor (Ki 324 nM), and lesser affinity at the 5-HT2A This study was supported by National Institutes of Health Grant ϭ receptor (Ki 1516 nM) (Rothman et al., 2000). 5-HT2A HL58489.Article, publication date, and citation information can be found at http://jpet.aspetjournals.org. receptors mediate contraction to 5-HT in many arteries and DOI: 10.1124/jpet.103.060806. veins, especially conduit vessels (Martin, 1994). The 5-HT2B 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 sys- tem; NE, norepinephrine; RX8821002, 2-methoxyidazoxan; LY53857, 6-methyl-1-(1-methylethyl)-ergoline-8␤-carboxylic acid 2-hydroxy-1 meth- ylpropyl ester maleate; UK14304, 5-bromo-N-[4,5-dihydro-1H-imidazol-2-yl]-6-quinoxalinamine. 845 846 Ni et al. receptor was cloned in rat stomach fundus in 1992 (Foguet et Myograph Protocol al., 1992; Kursar et al., 1992) and plays an important role in The whole intestine was placed in a silastic-filled petri dish in cold mediating arterial contraction in deoxycorticosterone ace- PSS and pinned down. Second and third order arteries (200–300 ␮m, tate-salt hypertensive rats (Watts, 1998). Thus, we hypothe- inner diameter) were carefully dissected from the vein and placed in sized that (ϩ)-norfenfluramine may activate 5-HT receptors cold PSS. Two tungsten wires (California Wire, Grover Beach, CA) and be a vasoactive substance. were threaded through the lumen of the artery. One wire was Few studies have tested whether (ϩ)-fenfluramine can al- mounted to a micrometer and the other to a microtransducer. All ter smooth muscle contractility (Desta et al., 1998), and it has arteries were examined with an intact endothelium. Baths, filled never been determined whether (ϩ)-norfenfluramine con- with PSS, were warmed by a water-circulated jacket around the bath and are aerated with 95% O ,5%CO. Tissues equilibrated for 30 tracts smooth muscle. We investigated whether (ϩ)-norfen- 2 2 min before an optimal passive tension of 400 mg (determined previ- fluramine causes a concentration-dependent contraction in ously; Watts, 2002) was applied using the micrometer. Tissues equil- three isolated arteries and whether the contraction depends ibrated another 30 min with frequent buffer changes before chal- on 5-HT receptors, sympathetic nerves [a site of potential lenge with a maximal concentration of PE (10 ␮M). Experimental uptake of (ϩ)-norfenfluramine], or ␣-adrenergic receptors. protocols are as described above. We then investigated whether and the mechanism by which (ϩ)-norfenfluramine could alter mean arterial blood pressure Denervation Experiment Protocol in conscious normal rats, with the intent of connecting our Sympathetic neuronal denervation was induced by 6-hydroxydo- data derived from in vitro experiments to the whole animal. pamine (6-OHDA) injections (McCafferty et al., 1997). Rats were treated with four doses of 6-OHDA over 7 days (50 mg/kg on days 1 Downloaded from and 2 and 100 mg/kg on days 6 and 7; 0.1% ascorbic acid in physio- Materials and Methods logical saline as vehicle i.p.). Rats were euthanized (pentobarbital, 60 mg/kg i.p.), and arteries were removed on day 8. Contractility exper- Animal Use iments were performed on the aorta, renal artery, and mesenteric The normal male Sprague-Dawley rats (0.225–0.300 kg; Charles resistance arteries from vehicle-treated and denervated rats. River Laboratories, Inc., Portage, MI) were used in these experi- ments. Glyoxylic Acid Protocol jpet.aspetjournals.org Aorta and mesenteric resistance arteries were removed and placed Isolated Tissue Bath Protocol in normal PSS. After fat was trimmed off, arteries were immersed Thoracic aorta and renal artery were removed and placed in nor- into glyoxylic acid (2%) for 5 min. Blood vessels were mounted on a mal physiological salt solution (PSS) containing 130 mM NaCl, 4.7 microscope slide and placed in an oven (100°C) for 5 min. The slides ⅐ were removed and blood vessels mounted in mineral oil and cover- mM KCl, 1.18 mM KH2PO4, 1.17 mM MgSO4 7H2O, 1.6 mM ⅐ slipped. Vessels were viewed using a fluorescence microscope (Nikon CaCl2 2H2O, 14.9 mM NaHCO3, 5.5 mM dextrose, and 0.03 mM LABOPHOT) and UV illumination (G-1A; excitation, 546/10 nm; at ASPET Journals on June 8, 2015 CaNa2EDTA (pH 7.2). Vessels were trimmed of fat and cut into helical strips (aorta, 1 ϫ 10 mm; renal artery, 1 ϫ 5 mm). We used barrier filter, BA580). The absence of a fluorescent network of stain- endothelium-intact arteries in our experiments. ing of catecholamines in arteries confirms the effectiveness of Tissues were attached to a fixed, stainless steel rod at one end and 6-OHDA in causing sympathetic denervation. Method is according to to a force transducer (FT03; Grass Instruments, Quincy, MA) at the Ruijtenbeek et al. (2000). Only pictures of small resistance arteries other. Baths were filled with PSS, warmed to 37°C, and aerated with are shown as validation of this protocol, because no sympathetic 95% oxygen and 5% carbon dioxide. Each strip was placed under network was readily discernible in the aorta.
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