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(Circulation. 1996;94:2216-2220.)
© 1996 American Heart Association, Inc.

Articles

Anorexic Agents Aminorex, Fenfluramine, and Dexfenfluramine Inhibit Potassium Current in Rat Pulmonary Vascular Smooth Muscle and Cause Pulmonary Vasoconstriction

E. Kenneth Weir, MD; Helen L. Reeve, PhD; James M.C. Huang, PhD; Evangelos Michelakis, MD; Daniel P. Nelson, BS; Vaclav Hampl, PhD; Stephen L. Archer, MD

the Department of Medicine, Veterans Affairs Medical Center and University of Minnesota, Minneapolis, Minn.

Correspondence to Dr E. Kenneth Weir, Department of Medicine, VA Medical Center (111C), One Veterans Dr, Minneapolis, MN 55417.

	Abstract

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Background The appetite suppressant aminorex fumarate is thought to have caused an epidemic of pulmonary hypertension in Europe in the 1960s. More recently, pulmonary hypertension has been described in some patients taking other amphetamine-like, anorexic agents: fenfluramine and its d-isomer, dexfenfluramine. No mechanism has been demonstrated that might account for the association between anorexic drugs and pulmonary hypertension.

Methods and Results Using the whole-cell, patch-clamp technique, we found that aminorex, fenfluramine, and dexfenfluramine inhibit potassium current in smooth muscle cells taken from the small resistance pulmonary arteries of the rat lung. Dexfenfluramine causes reversible membrane depolarization in these cells. These actions are similar to those of hypoxia, which initiates pulmonary vasoconstriction by inhibiting a potassium current in pulmonary vascular smooth muscle. In the isolated, perfused rat lung, aminorex, fenfluramine, and dexfenfluramine induce a dose-related increase in perfusion pressure. When the production of endogenous NO is inhibited by N-nitro-L-arginine methyl ester, the pressor response to dexfenfluramine is greatly enhanced.

Conclusions These observations indicate that anorexic agents, like hypoxia, can inhibit potassium current, cause membrane depolarization, and stimulate pulmonary vasoconstriction. They suggest one mechanism that could be responsible for initiating pulmonary hypertension in susceptible individuals. It is possible that susceptibility is the result of the reduced production of an endogenous vasodilator, such as NO, but this remains speculative.

Key Words: hypertension, pulmonary • obesity • muscle, smooth • vasoconstriction

	Introduction

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Between 1967 and 1969, a marked increase in the incidence of what appeared to be primary pulmonary hypertension occurred in Switzerland, Austria, and Germany. This was associated with the use of the amphetamine-like, appetite-suppressant drug aminorex fumarate (2-amino-5-phenyl-2-oxazoline).^{1 2} Another appetite suppressant, fenfluramine, and its d-isomer, dexfenfluramine (a phenyl-ethylamine derivative), have also been linked in case reports to the development of pulmonary hypertension.^{3 4 5 6 7 8 9 10 11} In one case, the pulmonary hypertension regressed when fenfluramine was discontinued and recurred with a subsequent fenfluramine challenge.³ Fenfluramine is reported to have been used by 50 million patients worldwide.¹² The results of the International Primary Pulmonary Hypertension Study show that there is at least an eightfold increase in the risk of developing pulmonary hypertension in patients who have taken dexfenfluramine for >3 months (L. Abenhaim, unpublished data, 1995).

The mechanism by which aminorex or fenfluramine might cause pulmonary hypertension is unknown but might resemble that responsible for hypoxic pulmonary vasoconstriction, in which K⁺ channel inhibition leads to membrane depolarization and Ca²⁺ entry through the voltage-dependent Ca²⁺ channels.¹³ Vasoconstriction is important in both hypoxic pulmonary hypertension¹³ and primary pulmonary hypertension.¹⁴ We hypothesized that inhibition of an I_K, which initiates hypoxic pulmonary vasoconstriction in pulmonary vascular smooth muscle,^{13 15} might play a role in the pulmonary hypertension sometimes associated with aminorex and fenfluramine ingestion.

	Methods

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Cell Dispersal
Rat pulmonary artery smooth muscle cells were freshly dissociated for electrophysiological studies each day. Male Sprague-Dawley rats (body weight, 300 to 400 g) were anesthetized with 50 mg/kg sodium pentobarbital, and the lungs were removed after perfusion of the pulmonary artery with Ca²⁺-free Hanks' solution. The third divisions of the pulmonary arteries were then dissected and placed in a Ca²⁺-free Hanks' solution for 10 minutes. The Hanks' solution contained (in mmol/L) NaCl 145, KCl 4.2, KH₂PO₄ 1.2, MgCl₂ 1.0, glucose 10, and EGTA 0.1 (pH 7.3). Arteries were then transferred to Hanks' solution without EGTA, containing 1 mg/mL papain and 0.25 mg/mL bovine albumin, and kept at 4°C for 20 minutes. After this incubation period, arteries were placed in the same papain solution supplemented with 0.85 mg/mL dithiothreitol for 40 to 60 minutes at 4°C and then 15 minutes at 37°C. Arteries were washed thoroughly in Hanks' solution for at least 10 minutes and then maintained on ice. Gentle trituration produced a suspension of single cells that were then aliquoted into a perfusion chamber on the stage of an inverted microscope for patch-clamp studies.¹⁶ After a brief period to allow partial adherence to the bottom of the recording chamber, cells were perfused with a solution composed of (in mmol/L) NaCl 145, KCl 5.4, MgCl₂ 1.0, CaCl₂ 1.5, HEPES 10, and glucose 10 (pH 7.4, 32°C). For whole-cell, patch-clamp recordings, electrodes were filled with a solution containing (in mmol/L) KCl 140, MgCl₂ 1.0, HEPES 10, EGTA 5, phosphocreatine 2, and ATP (disodium salt) 5 (pH 7.2). For perforated patch-clamp recordings, ATP was omitted from the pipette solution, and amphotericin B was included at a final concentration of 120 µg/mL. All drugs were dissolved in the extracellular perfusate and applied to the cells via gravity perfusion at a rate of 2 mL/min. Electrode resistances ranged from 3 to 4 M after the application of Sylgard coating and fire polishing.

Cell Electrophysiology
Currents were evoked from a holding potential of -70 mV using test pulses of 200-msec duration at a rate of 0.033 to 0.1 Hz. Series resistance was generally compensated by 90% to 95%. Currents were filtered at 1 kHz and sampled at 4 kHz. All data were recorded and analyzed using pClamp 6.02 software (Axon Instruments). Experiments using the perforated-patch configuration were performed at low light intensity. Results are presented as mean±SEM.

In the aminorex (n=5) and fenfluramine (n=5) dose-response experiments, whole-cell I_K were elicited by 20-mV step depolarizations (500-msec pulse duration) from a holding potential of -70 mV. The cells were characterized by recording I-V curves in the presence of 4-AP (2 mmol/L) and TEA (10 mmol/L). In the whole-cell technique, the cytoplasm of the cell is dialyzed by the larger volume of the solution in the electrode. In the perforated-patch technique, the patch is permeable to monovalent ions, but cytosolic factors are not lost. This might be considered more physiological. Consequently, in the dexfenfluramine experiments (n=23), I_K was recorded using the amphotericin-perforated patch-clamp technique¹⁷ by +10-mV step depolarizations from -70 to +40 mV. Membrane depolarization caused by dexfenfluramine was recorded using current-clamp mode. Cells were monitored in current-clamp mode at their resting potential, and controls were recorded for >1 minute before application of the drug to ensure membrane potential stability. All patch-clamp experiments were performed at 32°C. In four additional cells, the inhibition of I_K induced by 4 mmol/L 4-AP was compared with that induced by 4 mmol/L 4-AP plus 100 µmol/L dexfenfluramine (amphotericin-perforated patch technique).

Isolated, Perfused Lungs
For pressure studies, lungs that had been surgically removed from adult Sprague-Dawley rats were perfused at a constant flow rate with a physiological salt solution containing albumin (4%) and meclofenamate (1.7x10^-5 mol/L) as previously described.¹⁸ Initially, two cycles of Ang II followed by hypoxia were performed to assess the reactivity of the lungs. For each cycle, a bolus injection of 0.15 µg of Ang II was made into the pulmonary artery line, followed after 8 minutes by a 6-minute hypoxic challenge (FIO₂ 2.5%). In one series of lungs (n=6), increasing bolus injections of aminorex were made at 18-minute intervals during normoxia, and the resulting changes in pressure were measured. In the second series of lungs (n=6), increasing bolus injections of fenfluramine were made at the same time intervals. In the third series of lungs (n=5), increasing bolus injections of dexfenfluramine were made at 5-minute intervals. (Doses are shown in the figure legends.) In the fourth series of lungs (n=5), L-NAME (5x10^-5 mol/L) was added to the reservoir, and the same succession of increasing bolus doses of dexfenfluramine was made as in the third series. The experimental protocols were approved by the institutional animal studies committee.

Statistical Analysis
Data are expressed as mean±SEM. The effects of drugs on I_K and pulmonary arterial pressure were compared using a repeated measures ANOVA (StatView II, Version 4.0, Abacus Concepts). A value of P<.05 was considered significant.

	Results

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The whole-cell I_K in pulmonary artery smooth muscle cells from resistance vessels was markedly reduced by aminorex (Fig 1A) and by fenfluramine (Fig 1B). Fenfluramine (2.0 mmol/L) reduced I_K as much as an equimolar dose of the classic K⁺ channel blocker 4-AP (Fig 1B). Dexfenfluramine was also found to cause a dose-dependent inhibition of I_K (Fig 2A) and to depolarize the smooth muscle cell (Fig 2B). The mean resting membrane potential was -40.3±3.2 mV. Mean depolarization in response to 100 µmol/L dexfenfluramine in four cells was 12.6±1.7 mV. Bath application of 4 mmol/L 4-AP inhibited I_K at +40 mV, and no further decrease was induced by the additional application of 100 µmol/L dexfenfluramine (n=4), suggesting that dexfenfluramine may be acting on 4-AP–sensitive channels. This dose of dexfenfluramine, given in the absence of 4-AP, decreased I_K by 36.6±4.0% (n=11).

View larger version (8K): [in this window] [in a new window]   Figure 1. Aminorex and fenfluramine inhibit whole-cell IK. A, Aminorex (10 mmol/L) and 4-AP (2 mmol/L) inhibit whole-cell IK in five rat pulmonary artery smooth muscle cells (P<.05 compared with control). TEA (10 mmol/L) had no effect. B, FFA (0.5 and 2.0 mmol/L) and 4-AP (2 mmol/L) inhibit IK in five rat pulmonary artery smooth muscle cells (P<.05 compared with control). TEA (10 mmol/L) and FFA (0.1 mmol/L) had no effect.

View larger version (8K): [in this window] [in a new window]   Figure 2. Electrophysiological effects of dexfenfluramine (amphotericin-perforated patch-clamp). A, Dexfenfluramine causes dose-dependent inhibition of IK induced in isolated rat pulmonary artery smooth muscle cells by stepping from a holding potential of -70 mV to +40 mV. Inhibition is seen as a reduction in IK compared with the current elicited by the same protocol before the application of dexfenfluramine. Values are mean±SEM, and the number of cells is given in parentheses. B, Dexfenfluramine (100 µmol/L) reversibly depolarizes a rat pulmonary vascular smooth muscle cell.

In the isolated, perfused rat lung, aminorex, fenfluramine, and dexfenfluramine caused a modest dose-dependent increase in pulmonary arterial pressure (Figs 3 and 4). However, in the presence of the NO synthase inhibitor L-NAME, dexfenfluramine caused a much greater pressor response (Fig 4). There was a correlation between the severity of the maximal pressor response to dexfenfluramine, in the absence of L-NAME, and the pressor response to the preceding hypoxic challenge (P<.05) but not between the pressor response to dexfenfluramine and that to Ang II.

View larger version (20K): [in this window] [in a new window]   Figure 3. In the isolated, perfused rat lung, fenfluramine and aminorex cause dose-dependent increases in pulmonary artery pressure (P<.05 for increase in pressure with fenfluramine and aminorex*; n=6 for each drug).

View larger version (28K): [in this window] [in a new window]   Figure 4. In the isolated, perfused rat lung, dexfenfluramine causes dose-dependent increases in pulmonary artery pressure, which is markedly enhanced by L-NAME. Values are mean±SEM (n=5 for control and L-NAME groups).

	Discussion

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Aminorex is thought to have been responsible for the epidemic of pulmonary hypertension that occurred in Europe in the late 1960s.^{1 2} Only 1% to 2% of those who ingested the drug developed significant pulmonary hypertension.² This limited susceptibility to the drug is similar to that noted after exposure to toxic oil, when only 1.5% of those exposed to contaminated rapeseed oil had pulmonary hypertension on follow-up 4 years later.¹⁹ It is not known whether those who develop pulmonary hypertension metabolize aminorex more slowly and consequently have higher tissue levels or whether their pulmonary arteries are more susceptible in some way, such as a lower endogenous production of NO. In more recent years, the anorexic agents fenfluramine and dexfenfluramine have been widely used for weight reduction^{12 20} and have also been associated with sporadic cases of pulmonary hypertension.^{3 4 5 6 7 8 9 10 11} Despite many studies, the mechanism by which these drugs might initiate pulmonary hypertension is unknown.

The patch-clamp experiments show that aminorex, fenfluramine. and dexfenfluramine cause a dose-dependent inhibition of whole-cell I_K in smooth muscle cells freshly dispersed from resistance arteries of the rat lung. Dexfenfluramine produces membrane depolarization in these cells, indicating that the inhibition of I_K has a physiological effect (Fig 2). Thus, like hypoxia,¹³ these drugs may initiate pulmonary vasoconstriction by permitting Ca²⁺ entry through voltage-gated Ca²⁺ channels. The K⁺ channel or channels blocked by dexfenfluramine appear to be sensitive to low-dose 4-AP, suggesting that they include a delayed rectifier. It is important to note that fenfluramine is as effective in reducing whole-cell I_K as 4-AP, a classic K⁺ channel blocker (Fig 1). It is also possible that dexfenfluramine, like 4-AP,²¹ could have actions in addition to K⁺ channel blockade, such as inhibition of the Ca²⁺-ATPase in the sarcoplasmic reticulum.

The sustained plasma concentration of fenfluramine that "correlates with the best rate of weight loss" is said to be 1 µmol/L.²² This is slightly less than the 10 and 100 µmol/L concentrations of dexfenfluramine that acutely inhibited I_K but comparable to the 100 nmol/L and 1 µmol/L concentrations that increased pulmonary artery pressure in the presence of L-NAME. The somewhat higher concentration of dexfenfluramine found necessary to inhibit I_K, compared with the plasma concentration in patients, may reflect the difference between the effects of chronic drug administration in a susceptible patient and acute exposure of a single cell taken from an unselected rat. In the chronic hypoxia model of pulmonary hypertension, NO activity is upregulated.^{23 24 25 26} In this study, the acute inhibition of NO synthesis by L-NAME markedly enhanced the vasoconstriction caused by dexfenfluramine. It is possible that the patients who develop pulmonary hypertension while taking an anorexic agent have diminished NO activity. The actual reason for susceptibility remains to be established.

Chronic administration of aminorex to small numbers of monkeys,²⁷ calves,²⁸ and rats²⁹ has not been found to cause pulmonary hypertension. In dogs, three chronic studies failed to show pulmonary hypertension,^{29 30 31} but another study, in which aminorex was fed for 2 years, resulted in an increase in pulmonary arterial pressure and resistance.³² The authors postulated that precapillary vasoconstriction induced by aminorex might lead to more fixed pulmonary hypertension. Plasma membrane depolarization and consequent Ca²⁺ influx can stimulate DNA synthesis and cell proliferation in osteoblasts,^{33 34} so it is possible that this mechanism might also be involved in the intimal proliferation observed in the pulmonary hypertension caused by anorexic agents.

Acute administration of fenfluramine has been observed to increase pulmonary artery pressure in the dog.²⁹ In pigs rendered more susceptible to pulmonary hypertension by prior left pulmonary artery ligation, ingestion of fenfluramine for 3 months increased pulmonary vascular resistance.³⁵ In the present study, aminorex, fenfluramine, and dexfenfluramine produced a dose-related increase in pressure in the isolated, perfused rat lung. The fact that these agents mimic hypoxia by inhibiting I_K in smooth muscle cells, and causing pulmonary vasoconstriction, suggests the possibility of a similar mechanism. This analogy is supported by the observation that dexfenfluramine restores acute hypoxic pulmonary vasoconstriction in dogs that otherwise do not respond to hypoxia, while leaving unchanged the hypoxic vasoconstriction in responders.³⁶

Dexfenfluramine inhibits the cellular uptake of 5-HT.³⁷ 5-HT causes pulmonary vasoconstriction through its action on 5-HT₂ receptors, which can be blocked by ketanserin. It might be considered that dexfenfluramine could inhibit I_K through a mechanism involving 5-HT. However, because single cells are studied in the patch-clamp experiments, this would mean that the smooth muscle cell would also have to be the source of the 5-HT. In addition, in the experiment cited above, in which dexfenfluramine restored hypoxic pulmonary vasoconstriction in the dog, ketanserin did not affect the vasoconstriction.³⁶ These observations make it unlikely that 5-HT is involved.

In the future, it would seem wise to consider that drugs that block K⁺ channels, such as these anorexic agents, might be able to cause pulmonary hypertension in susceptible individuals. The illegal drug Ecstasy (3,4-methylenedioxymethamphetamine) is known to block neuronal K⁺ channels³⁸ and has been associated with pulmonary hypertension.³⁹ The anorexic agents may give us insight into the origins of pulmonary hypertension. Because aminorex and fenfluramine cause a histological picture that is indistinguishable from that of primary pulmonary hypertension, information on the etiologic mechanisms of drug-induced pulmonary hypertension may provide clues to the causes of primary pulmonary hypertension.

	Selected Abbreviations and Acronyms

 

4-AP = 4-aminopyridine 5-HT = 5-hydroxytryptamine Ang II = angiotensin II I-V = current-voltage IK = K+ current L-NAME = N-nitro-L-arginine methyl ester TEA = tetraethylammonium

	Acknowledgments

 
This work was supported by the Department of Veterans Affairs (NIH 1R29-HL-45735 [Dr Archer]), the Minnesota Medical Foundation, and the American Heart Association, Minnesota Affiliate.

	Footnotes

 
Presented in part at the American Thoracic Society Annual Conference, Seattle, Wash, May 24, 1995.

Received January 17, 1996; revision received May 31, 1996; accepted June 7, 1996.

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				A. Cogolludo, L. Moreno, F. Lodi, G. Frazziano, L. Cobeno, J. Tamargo, and F. Perez-Vizcaino Serotonin Inhibits Voltage-Gated K+ Currents in Pulmonary Artery Smooth Muscle Cells: Role of 5-HT2A Receptors, Caveolin-1, and KV1.5 Channel Internalization Circ. Res., April 14, 2006; 98(7): 931 - 938. [Abstract] [Full Text] [PDF]

				E. K. Weir, J. Lopez-Barneo, K. J. Buckler, and S. L. Archer Acute Oxygen-Sensing Mechanisms. N. Engl. J. Med., November 10, 2005; 353(19): 2042 - 2055. [Full Text] [PDF]

				W. K. P. Wong, J. A. Knowles, and J. H. Morse Bone Morphogenetic Protein Receptor Type II C-Terminus Interacts with c-Src: Implication for a Role in Pulmonary Arterial Hypertension Am. J. Respir. Cell Mol. Biol., November 1, 2005; 33(5): 438 - 446. [Abstract] [Full Text] [PDF]

				Z. Hong, A. J. Smith, S. L. Archer, X.-C. Wu, D. P. Nelson, D. Peterson, G. Johnson, and E. K. Weir Pergolide Is an Inhibitor of Voltage-Gated Potassium Channels, Including Kv1.5, and Causes Pulmonary Vasoconstriction Circulation, September 6, 2005; 112(10): 1494 - 1499. [Abstract] [Full Text] [PDF]

				S. Rezaie-Majd, J. Murar, D. P. Nelson, R. F. Kelly, Z. Hong, I. M. Lang, A. Varghese, and E. K. Weir Increased release of serotonin from rat ileum due to dexfenfluramine Am J Physiol Regulatory Integrative Comp Physiol, November 1, 2004; 287(5): R1209 - R1213. [Abstract] [Full Text] [PDF]

				J. H. Newman, B. L. Fanburg, S. L. Archer, D. B. Badesch, R. J. Barst, J. G.N. Garcia, P. N. Kao, J. A. Knowles, J. E. Loyd, M. D. McGoon, et al. Pulmonary Arterial Hypertension: Future Directions: Report of a National Heart, Lung and Blood Institute/Office of Rare Diseases Workshop Circulation, June 22, 2004; 109(24): 2947 - 2952. [Full Text] [PDF]

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				E. K. Weir, Z. Hong, and A. Varghese The Serotonin Transporter: A Vehicle to Elucidate Pulmonary Hypertension? Circ. Res., May 14, 2004; 94(9): 1152 - 1154. [Full Text] [PDF]

				J. Lopez-Barneo, R. del Toro, K. L. Levitsky, M. D. Chiara, and P. Ortega-Saenz Regulation of oxygen sensing by ion channels J Appl Physiol, March 1, 2004; 96(3): 1187 - 1195. [Abstract] [Full Text] [PDF]

				Z. Hong, A. Olschewski, H. L. Reeve, D. P. Nelson, F. Hong, and E. K. Weir Nordexfenfluramine causes more severe pulmonary vasoconstriction than dexfenfluramine Am J Physiol Lung Cell Mol Physiol, March 1, 2004; 286(3): L531 - L538. [Abstract] [Full Text] [PDF]

				Z. I. Pozeg, E. D. Michelakis, M. S. McMurtry, B. Thebaud, X.-C. Wu, J. R.B. Dyck, K. Hashimoto, S. Wang, R. Moudgil, G. Harry, et al. In Vivo Gene Transfer of the O2-Sensitive Potassium Channel Kv1.5 Reduces Pulmonary Hypertension and Restores Hypoxic Pulmonary Vasoconstriction in Chronically Hypoxic Rats Circulation, April 22, 2003; 107(15): 2037 - 2044. [Abstract] [Full Text] [PDF]

				S. Eddahibi, N. Morrell, M-P. d'Ortho, R. Naeije, and S. Adnot Pathobiology of pulmonary arterial hypertension Eur. Respir. J., December 1, 2002; 20(6): 1559 - 1572. [Abstract] [Full Text] [PDF]

				S. G Haworth PULMONARY HYPERTENSION IN THE YOUNG Heart, December 1, 2002; 88(6): 658 - 664. [Full Text] [PDF]

				V. Hampl, J. Bibova, Z. Stranak, X. Wu, E. D. Michelakis, K. Hashimoto, and S. L. Archer Hypoxic fetoplacental vasoconstriction in humans is mediated by potassium channel inhibition Am J Physiol Heart Circ Physiol, December 1, 2002; 283(6): H2440 - H2449. [Abstract] [Full Text] [PDF]

				Y. Mitani, A. Mutlu, J. C. Russell, D. N. Brindley, J. DeAlmeida, and M. Rabinovitch Dexfenfluramine protects against pulmonary hypertension in rats J Appl Physiol, November 1, 2002; 93(5): 1770 - 1778. [Abstract] [Full Text] [PDF]

				J. Malysz, G. Farrugia, Y. Ou, J. H. Szurszewski, A. Nehra, and S. J. Gibbons The Kv2.2 {alpha} Subunit Contributes to Delayed Rectifier K+ Currents in Myocytes From Rabbit Corpus Cavernosum J Androl, November 1, 2002; 23(6): 899 - 910. [Abstract] [Full Text] [PDF]

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				J. A. Caccitolo, H. M. Connolly, D. S. Rubenson, T. A. Orszulak, and H. V. Schaff Operation for anorexigen-associated valvular heart disease J. Thorac. Cardiovasc. Surg., October 1, 2001; 122(4): 656 - 664. [Abstract] [Full Text] [PDF]

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				G. Glazer Long-term Pharmacotherapy of Obesity 2000: A Review of Efficacy and Safety Arch Intern Med, August 13, 2001; 161(15): 1814 - 1824. [Abstract] [Full Text] [PDF]

				S. Belohlavkova, J. Simak, A. Kokesova, O. Hnilickova, and V. Hampl Fenfluramine-induced pulmonary vasoconstriction: role of serotonin receptors and potassium channels J Appl Physiol, August 1, 2001; 91(2): 755 - 761. [Abstract] [Full Text] [PDF]

				E. D. Michelakis, E. K. Weir, X. Wu, A. Nsair, R. Waite, K. Hashimoto, L. Puttagunta, H. G. Knaus, and S. L. Archer Potassium channels regulate tone in rat pulmonary veins Am J Physiol Lung Cell Mol Physiol, June 1, 2001; 280(6): L1138 - L1147. [Abstract] [Full Text] [PDF]

				S. Archer and S. Rich Primary Pulmonary Hypertension : A Vascular Biology and Translational Research "Work in Progress" Circulation, November 28, 2000; 102(22): 2781 - 2791. [Abstract] [Full Text] [PDF]

				V. Hampl and J. Herget Role of Nitric Oxide in the Pathogenesis of Chronic Pulmonary Hypertension Physiol Rev, October 1, 2000; 80(4): 1337 - 1372. [Abstract] [Full Text] [PDF]

				G. A. Bray and F. L. Greenway Current and Potential Drugs for Treatment of Obesity Endocr. Rev., December 1, 1999; 20(6): 805 - 875. [Abstract] [Full Text]

				E. D. Michelakis, E. K. Weir, D. P. Nelson, H. L. Reeve, S. Tolarova, and S. L. Archer Dexfenfluramine Elevates Systemic Blood Pressure by Inhibiting Potassium Currents in Vascular Smooth Muscle Cells J. Pharmacol. Exp. Ther., December 1, 1999; 291(3): 1143 - 1149. [Abstract] [Full Text]

				T. Higenbottam, H. Marriott, G. Cremona, E. Laude, and D. Bee The Acute Effects of Dexfenfluramine on Human and Porcine Pulmonary Vascular Tone and Resistance Chest, October 1, 1999; 116(4): 921 - 930. [Abstract] [Full Text] [PDF]

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				R. B. Rothman, M. A. Ayestas, C. M. Dersch, and M. H. Baumann Aminorex, Fenfluramine, and Chlorphentermine Are Serotonin Transporter Substrates : Implications for Primary Pulmonary Hypertension Circulation, August 24, 1999; 100(8): 869 - 875. [Abstract] [Full Text] [PDF]

				S. S. Salvi {alpha}1-Adrenergic Hypothesis for Pulmonary Hypertension Chest, June 1, 1999; 115(6): 1708 - 1719. [Abstract] [Full Text] [PDF]

				H. L. Reeve, D. P. Nelson, S. L. Archer, and E. K. Weir Effects of fluoxetine, phentermine, and venlafaxine on pulmonary arterial pressure and electrophysiology Am J Physiol Lung Cell Mol Physiol, February 1, 1999; 276(2): L213 - L219. [Abstract] [Full Text] [PDF]

				P. Egermayer, G I. Town, and A. J Peacock Role of serotonin in the pathogenesis of acute and chronic pulmonary hypertension Thorax, February 1, 1999; 54(2): 161 - 168. [Full Text]

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				S. G Haworth Primary pulmonary hypertension in childhood Arch. Dis. Child., November 1, 1998; 79(5): 452 - 455. [Full Text]

				J. X.-J. Yuan, A. M. Aldinger, M. Juhaszova, J. Wang, J. V. Conte Jr, S. P. Gaine, J. B. Orens, and L. J. Rubin Dysfunctional Voltage-Gated K+ Channels in Pulmonary Artery Smooth Muscle Cells of Patients With Primary Pulmonary Hypertension Circulation, October 6, 1998; 98(14): 1400 - 1406. [Abstract] [Full Text] [PDF]

				S. L. ARCHER, K. DJABALLAH, M. HUMBERT, E. KENNETH WEIR, M. FARTOUKH, J. DALL'AVA-SANTUCCI, J.-C. MERCIER, G. SIMONNEAU, and A. TUAN DINH-XUAN Nitric Oxide Deficiency in Fenfluramine- and Dexfenfluramine-induced Pulmonary Hypertension Am. J. Respir. Crit. Care Med., October 1, 1998; 158(4): 1061 - 1067. [Abstract] [Full Text] [PDF]

				A.-M. Gonzalez, A. P. L. Smith, C. J. Emery, and T. W. Higenbottam The Pulmonary Hypertensive Fawn-hooded Rat Has a Normal Serotonin Transporter Coding Sequence Am. J. Respir. Cell Mol. Biol., August 1, 1998; 19(2): 245 - 249. [Abstract] [Full Text]

				S. EDDAHIBI, B. RAFFESTIN, J.-M. LAUNAY, M. SITBON, and S. ADNOT Effect of Dexfenfluramine Treatment in Rats Exposed to Acute and Chronic Hypoxia Am. J. Respir. Crit. Care Med., April 1, 1998; 157(4): 1111 - 1119. [Abstract] [Full Text] [PDF]

				H. M. Connolly, J. L. Crary, M. D. McGoon, D. D. Hensrud, B. S. Edwards, W. D. Edwards, and H. V. Schaff Valvular Heart Disease Associated with Fenfluramine-Phentermine N. Engl. J. Med., August 28, 1997; 337(9): 581 - 588. [Abstract] [Full Text] [PDF]

				G. D. Curfman Diet Pills Redux N. Engl. J. Med., August 28, 1997; 337(9): 629 - 630. [Full Text]

				U. D. McCann, L. S. Seiden, L. J. Rubin, and G. A. Ricaurte Brain Serotonin Neurotoxicity and Primary Pulmonary Hypertension From Fenfluramine and Dexfenfluramine: A Systematic Review of the Evidence JAMA, August 27, 1997; 278(8): 666 - 672. [Abstract] [PDF]

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