CLINICAL PERSPECTIVE

This Article Abstract Full Text (PDF) All Versions of this Article: 112/10/1494    most recent CIRCULATIONAHA.105.556704v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Hong, Z. Articles by Weir, E. K. Search for Related Content PubMed PubMed Citation Articles by Hong, Z. Articles by Weir, E. K. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Hazardous Substances DB CALCIUM COMPOUNDS CALCIUM, ELEMENTAL Related Collections Pulmonary biology and circulation Pulmonary circulation and disease

(Circulation. 2005;112:1494-1499.)
© 2005 American Heart Association, Inc.

Vascular Medicine

Pergolide Is an Inhibitor of Voltage-Gated Potassium Channels, Including Kv1.5, and Causes Pulmonary Vasoconstriction

Zhigang Hong, MD, PhD; Andrew J. Smith, MD; Stephen L. Archer, MD; Xi-Chen Wu, PhD; Daniel P. Nelson, BS; Douglas Peterson, MD, PhD; Gerhard Johnson, MD; E. Kenneth Weir, MD

From the Department of Medicine, Veterans Affairs Medical Center and University of Minnesota, Minneapolis (Z.H., A.J.S., D.P.N., D.P., G.J., E.K.W.); and Departments of Medicine, Division of Cardiology, and Physiology, University of Alberta, Edmonton, Alberta, Canada (S.L.A., X.W.).

Correspondence to E. Kenneth Weir, MD, Veterans Affairs Medical Center 111C, One Veteran’s Dr, Minneapolis, MN 55417. E-mail weirx002{at}umn.edu

Received April 18, 2005; revision received May 19, 2005; accepted May 31, 2005.

	Abstract

Top Abstract Introduction Methods Results Discussion References

 
Background— Pergolide produces clinical benefit in Parkinson disease by stimulating dopamine D₁ and D₂ receptors. An increased incidence of carcinoid-like heart valve disease (CLHVD) has been noted in pergolide users, reminiscent of that induced by certain anorexigens used for weight reduction. Anorexigens that modulate serotonin release and reuptake, such as dexfenfluramine, were withdrawn from sale because of CLHVD. Interestingly, the anorexigens also caused pulmonary arterial hypertension (PAH). Anorexigens were shown to enhance hypoxic pulmonary vasoconstriction, in part by inhibiting voltage-gated K⁺ channels (Kv) in pulmonary artery smooth muscle cells (PASMCs). Although PAH has not been associated with pergolide use, we hypothesized that pergolide might have similar effects on hypoxic pulmonary vasoconstriction and Kv channels.

Methods and Results— Pergolide enhanced hypoxic pulmonary vasoconstriction in the isolated perfused rat lung compared with control lungs (mean pulmonary artery pressure 32±3 versus 21±2 mm Hg; P<0.01). Pergolide also caused vasoconstriction in rat pulmonary artery rings. Pergolide inhibited PASMC potassium current density, resulting in membrane depolarization (from –51±2 to –44±1 mV) and increased cytosolic calcium in both rat and human PASMCs. Pergolide directly inhibited heterologously expressed Kv1.5 and K_Ca channels.

Conclusions— Pergolide causes Kv channel inhibition and, despite being from a different class of drugs, has pulmonary vascular effects reminiscent of dexfenfluramine. Coupled with their shared proclivity to induce CLHVD, these findings suggest that clinical monitoring for pergolide-induced PAH should be considered.

Key Words: drugs • hypertension, pulmonary • ion channels • muscle, smooth • vasoconstriction

	Introduction

Top Abstract Introduction Methods Results Discussion References

 
Pergolide is an ergot alkaloid–derived medication designed to alleviate the effects of Parkinson disease by stimulating the dopamine D₁ and D₂ receptors.¹ Although the drug has been helpful clinically, there have recently been reports of associated carcinoid-like heart valve disease (CLHVD), as well as pulmonary and retroperitoneal fibrosis.^2,3 The valvulopathy associated with the use of pergolide is similar to that seen with the ergot alkaloid drugs and the anorectic agents fenfluramine and aminorex.⁴ Fenfluramine and aminorex are also known to be associated with an increased incidence of pulmonary hypertension.⁵ Despite the observation that pergolide may cause CLHVD, no clinically significant increase in the incidence of pulmonary hypertension has been recognized. We have shown previously that dexfenfluramine, fenfluramine, and aminorex inhibit potassium current (I_K) in PASMCs, leading to membrane depolarization, calcium entry, and vasoconstriction.⁶ Given that pergolide and fenfluramine both cause CLHVD, we wished to determine whether pergolide might also be a K⁺ channel blocker and cause pulmonary artery (PA) vasoconstriction, in which case it might pose a risk of pulmonary arterial hypertension (PAH). The present study shows that pergolide is an inhibitor of voltage-gated K⁺ channels (Kv) and causes pulmonary vasoconstriction by a mechanism similar to that initiated by dexfenfluramine.

	Methods

Top Abstract Introduction Methods Results Discussion References

 
All studies were approved by the Institutional Animal Care and Use Committee of the Minneapolis Veterans Affairs Medical Center and conform to current National Institutes of Health and American Physiological Society guidelines for the use and care of laboratory animals.

Isolated Perfused Rat Lung
Lungs were isolated en bloc from adult male Sprague-Dawley rats (weight, 250 to 350 g) after the rats were anesthetized with pentobarbital (50 mg/kg body wt IP), as previously described.⁷ Lungs were then perfused at a constant flow so that changes in pressure reflect changes in pulmonary vascular resistance. The perfusate was Krebs’ salt solution, balanced for osmotic potential with Ficoll to reduce the possible effects of pergolide binding to protein, such as albumin. Lungs were ventilated with humidified gases containing 21% O₂/5% CO₂/balance N₂ (normoxia) or 2.5% O₂/5% CO₂/balance N₂ (hypoxia). The lung chamber and perfusate were maintained at 37°C. Respiration was set to physiological values (frequency 70 breaths per minute, tidal volume 1.5 mL), with a positive end-respiratory pressure of 2.5 cm H₂O. To determine lung reactivity, we subjected the lungs to 10 minutes of normoxia and a 6-minute hypoxic challenge, without the use of angiotensin II or other vasoconstrictors. After return to baseline, the lungs were given a nitric oxide synthase inhibitor (N-nitro-L-arginine methyl ester, 50 µmol/L) and perfused for 20 minutes before 2 additional hypoxic challenges. Eight lungs then received pergolide 10 µmol/L, and 8 received the vehicle before a final hypoxic challenge.

Large Resistance PAs
Male Sprague-Dawley rats were anesthetized with pentobarbital (50 mg/kg IP). Large resistance PAs (third and fourth division, internal diameter 400 to 800 µm) were dissected and placed immediately in ice-cold Earle’s balanced salt solution of the following composition (in mmol/L): 1.8 CaCl₂, 0.8 MgSO₄, 5.4 KCl, 116.2 NaCl, 1.0 NaH₂PO₄, 5.6 glucose, and 26.2 NaHCO₃. The vessels were cleaned of connective tissue, and 4-mm-long rings were suspended in stirrups in organ chambers (Radnoti) for measurement of isometric force, as previously described.⁸ For some experiments the endothelium was mechanically denuded with the removal of endothelium, demonstrated by the absence of the normal relaxation response to acetylcholine (0.1 to 10 µmol/L). Chambers were filled with Earle’s balanced salt solution and bubbled with 21% O₂/5% CO₂/balance N₂ (normoxic) and 2.5% O₂/5% CO₂/balance N₂ (hypoxic) gases. Temperature was kept at 37°C, and pH was 7.35 to 7.45. The rings were equilibrated at a resting tension of 900 mg for at least 60 minutes and then exposed 3 times to phenylephrine (1 µmol/L) at 30-minute intervals. The optimal resting tension was that which permitted the maximal constriction to 80 mmol/L KCl in preliminary experiments. After an additional 30 minutes, pergolide was given at a concentration of 10 µmol/L.

Small Resistance PAs
Small resistance PAs (internal diameter 150 to 400 µm) were dissected free of adventitia, and the rings were mounted in a temperature-controlled myograph at 37°C (Multi Myograph System-610M, Danish Myo Technology A/S). They were bubbled continuously with 21% O₂/5% CO₂ (pH 7.35 to 7.45). The rings were equilibrated to give a transmural pressure of 400 mg. After at least 60 minutes of this tone, the viability of the endothelium was assessed, as determined by relaxation in response to 1 µmol/L acetylcholine. At this point the effect of pergolide (10 µmol/L) was observed.

Cell Dispersal
PA smooth muscle cells (PASMCs) were dispersed freshly on the day of electrophysiological study. Sprague-Dawley rats were anesthetized, and the lungs were removed and perfused with Ca²⁺-free Hanks’ solution. The Hanks’ solution contained (in mmol/L) 140 NaCl, 4.2 KCl, 1.2 KH₂PO₄, 0.5 MgCl₂, 10 HEPES, and 0.1 EGTA (pH 7.4). Fourth division PAs were dissected and placed in the Hanks’ solution for 10 minutes at 4°C. The arteries were then placed in Hanks’ solution containing 1 mg/mL of papain, 0.75 mg/mL bovine albumin, and 0.85 mg/mL of dithiothreitol without EGTA and digested at 4°C for 30 minutes and then at 37°C for 13 minutes. Finally, the arteries were washed thoroughly with Hanks’ solution without EGTA ("low-Ca^2+") for at least 10 minutes and maintained on ice in Hanks’ solution supplemented with 1 mg/mL glucose. This digestion protocol consistently produced high yields of viable, relaxed SMCs.

Cell Electrophysiology
Gentle trituration produced a cell suspension that was divided into aliquots and placed in a perfusion chamber on the stage of an inverted microscope (Diaphot 200, Nikon) for conventional whole-cell patch-clamp studies. After a brief period to allow adherence to the bottom of the recording chamber, cells were perfused with a normoxic solution of the following composition (in mmol/L): 115 NaCl, 25 NaHCO₃, 4.5 KCl, 1 KH₂PO₄, 1.5 CaCl₂, 0.5 MgCl₂, 10 HEPES, and 10 glucose (pH 7.4 with NaOH, PO₂ 120 mm Hg by bubbling with 21% O₂/5% CO₂/balance N₂). Electrode resistances ranged from 3 to 5 mol/L after fire polishing and when filled with a solution of composition (in mmol/L) 140 KCl, 1.0 MgCl₂, 10 HEPES, 1 EGTA, 1 KATP (pH 7.2 with KOH).

The patch-clamp amplifier was Axopatch 200B (Axon Instruments) in all voltage- and current-clamp experiments. Offset potentials were nulled directly before formation of a seal. Capacitance and series resistance were corrected (usually 80%). No leak subtraction was made. Leakage current was monitored with the use of hyperpolarizing steps (–30 mV) from the holding potential, a procedure that did not activate ion channels but allowed measurement of passive membrane properties and leak during the experiments. Cells expressing holding current at –70 mV of >20 pA before or during the recordings were discarded. The extracellular perfusate perfusion rate was 2 mL/min. Cells were voltage clamped at a holding potential of –70 mV, and currents were evoked by 20-mV steps to more positive potentials with test pulses of 250-ms duration at a rate of 0.1 Hz. Currents were filtered at 1 kHz and sampled at 2 or 4 kHz. For resting membrane potential (E_m) experiments, cells were held in current clamp at their resting E_m (without current injection). Series resistance and leak were checked at the beginning and end of each E_m experiment to eliminate artificial changes in potential. Data were recorded and analyzed with pClamp 8 software (Axon Instruments).

CHO Cells Transfected With Kv1.5 or KCa
Kv1.5 from human PA or BK_Ca cloned from rat PA was placed in serotype 5 adenovirus with a green fluorescent protein reporter under a CMV promoter. CHO cells were transfected with these vectors, and whole-cell patch clamp was performed on green cells, as previously described.⁹

Human PASMC Cell Culture
Cultured human PASMCs (fourth passage) were obtained from Clonetics (Walkersville, Md) and plated in smooth muscle growth medium (Clonetics) supplemented with gentamicin (50 µg/mL), human epidermal (0.5 µg/mL) and fibroblast growth factors (1.0 µg/mL), insulin (5 µg/mL), and 5% fetal bovine serum. Cells were grown at 37°C in a humidified atmosphere of 5% CO₂. After they reached confluence, cells were dislodged from the dish by treatment with Accutase (TCS Biologicals) and transferred to T75 flasks for further passage.

Calcium Imaging
Dual-excitation imaging with fura 2 was used to measure cytosolic Ca²⁺. Dispersed PASMCs were loaded with fura 2-AM following a standard protocol. Cells were then transferred to imaging plates (Molecular Probes) and incubated in low-Ca²⁺ Hanks’ solution. The plates were washed in the same solution and placed on the microscope stage. All drugs were given as a bolus by direct microinjection. Volumes were limited to 10 µL, and similar volumes of saline had no effect on [Ca²⁺]_i. Changes in [Ca²⁺]_i were recorded in individual cells with a MetaFluor-driven 340/380 filter imaging system (Universal Imaging) and cooled charge-coupled device camera (Photometrics).

Statistical Analysis
Data are expressed as mean±SE. The effects of drugs on I_K and PA pressure were compared with repeated-measures ANOVA (Statview II, version 4.0, Abacus Concepts). Membrane potential data were compared with the Student paired t test. A value of P<0.05 was considered significant.

	Results

Top Abstract Introduction Methods Results Discussion References

 
Isolated Perfused Lung
Pergolide (10 µmol/L) increased normoxic PA pressure from 10.3±1.5 to 15.6±3.7 mm Hg (P<0.01) and also increased hypoxic pulmonary vasoconstriction from control hypoxic pulmonary vasoconstriction of 20.8±2.0 mm Hg to 32.2±3.1 mm Hg (n=8 each; P<0.01) (Figure 1).

View larger version (15K): [in this window] [in a new window]   Figure 1. Pergolide increases PA pressure (Pap) and enhances hypoxic pulmonary vasoconstriction in isolated lungs. Three control hypoxic challenges are given to demonstrate that the pulmonary vascular reactivity of the 2 groups of lungs is the same. n=8 for each group; **P<0.01 compared with control group. BL indicates baseline; L-NAME, NG-nitro-L-arginine methyl ester.

PA Rings
Pergolide (10 µmol/L) caused contraction in rings from both large- and small resistance PAs. Whereas phenylephrine-induced contraction of large proximal PA rings was 380.1±27.5 mg, 10 µmol/L pergolide caused a vasoconstriction of 134.5±16.7 mg, which is 38.5±4.8% when expressed as a percentage of the phenylephrine contraction (n=15) (Figure 2A). The constriction caused by pergolide was inhibited by an L-type calcium channel blocker, nifedipine (1 µmol/L: 73.2±7.9%, n=5; 3 µmol/L: 99.3±2.3%, n=5) (Figure 2B). Pergolide 10 µmol/L also caused potent vasoconstriction in small resistance PAs, which was 54.9±6.8% of phenylephrine contraction (n=8) (Figure 2B).

View larger version (15K): [in this window] [in a new window]   Figure 2. Nifedipine inhibits pergolide constriction. A, Representative tension tracing of large resistance PA ring showing that 10 µmol/L pergolide causes a strong contraction that can be almost completely reversed by 1 µmol/L nifedipine (NIF). B, The contraction caused by 10 µmol/L pergolide on large resistance PA (n=15) and small resistance PA (n=8) compared with 1 µmol/L phenylephrine (PE).

Electrophysiology
Pergolide (10 µmol/L) inhibited I_K in resistance PASMCs from 166.3±33.8 to 69.0±10.5 pA/pF at 50 mV (Figure 3) (n=5). The effect was rapidly reversed when the drug was washed out. Pergolide (10 µmol/L) depolarized PASMC membrane potential from –51.1±1.5 to –44.0±0.8 mV in resistance PASMCs (Figure 4) (n=5). In CHO cells, pergolide (10^–7 to 10^–5 mol/L) inhibited heterologously expressed rat BK_Ca channels in a dose-dependent manner (n=5) (Figure 5A). It is also clear that pergolide inhibited heterologously expressed human Kv1.5 (n=6), an important O₂-sensitive Kv channel expressed in PASMCs (Figure 5B).

View larger version (15K): [in this window] [in a new window]   Figure 3. Pergolide inhibits K+ current in resistance PASMCs. A, Representative tracings demonstrate that K+ current can be inhibited by 10 µmol/L pergolide and can completely recover after washout. Currents were evoked from a holding potential of –70 to 50 mV in incremental depolarizing 20-mV steps (n=5). B, Current recording, with the use of repeated steps from a holding potential of –70 to 0 mV, demonstrates that the K+ current inhibition of 10 µmol/L pergolide takes effect rapidly and washes out completely. C, Average whole-cell current-voltage plots of K+ current. **P<0.01. The plots are normalized to the control current at 50 mV, shown as 1.0.

View larger version (17K): [in this window] [in a new window]   Figure 4. Pergolide depolarizes resistance PASMC membrane potential. A, Representative membrane potential tracing demonstrates that 10 µmol/L pergolide depolarizes cell membrane potential. B, Pergolide (10 mmol/L) causes membrane potential depolarization (n=5). **P<0.01 compared with control.

View larger version (15K): [in this window] [in a new window]   Figure 5. Pergolide inhibits heterologously expressed BKCa and Kv1.5 channels. A, Effect of pergolide on K+ current CHO cells transfected with rat BKCa channels (n=5). **P<0.01 compared with control. B, Effect of pergolide on K+ current in CHO cells transfected with human Kv1.5 channels (n=6). **P<0.01 compared with control.

Calcium Imaging
Average resting [Ca²⁺]_i in freshly isolated rat PASMCs was calculated to be 167±16 nmol/L (n=12). Pergolide 10 µmol/L caused an increase in [Ca²⁺]_i to 231±18 nmol/L (P<0.001) (Figure 6). Average resting [Ca²⁺]_i in cultured human PASMCs was calculated to be 41±6 nmol/L (n=11). Pergolide 10 µmol/L caused an increase in [Ca²⁺]_i to 156±55 nmol/L in cultured human PASMCs (P=0.06) (Figure 6).

View larger version (13K): [in this window] [in a new window]   Figure 6. Pergolide increases calcium concentration in freshly isolated rat PASMC (n=11) and cultured human PASMC (n=11). ***P<0.001 compared with control.

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
During the 15 years since it was introduced, >1.7 million patients with Parkinson disease have been treated with pergolide. These patients have displayed evidence of some serious side effects, including retroperitoneal and pericardial fibrosis. However, it was only in 2002 that CLHVD was recognized as a possible drug effect.^10,11 Since then, an increased incidence of valvular heart disease has been described in 3 additional echocardiography studies.^12–14 In one of these, there was a major suspicion of restrictive valvular disease in 19% of those taking pergolide, as compared with 0% in the control group.¹⁴

In the case of the drug dexfenfluramine, longer use led to CLHVD and was also associated with pulmonary hypertension.^5,15 PAH has not been recognized to be a complication of the use of pergolide. However, in clinical observations the estimated PA pressure was significantly higher in 15 patients treated with pergolide than in controls. The systolic PA pressure in 1 patient was estimated to be as high as 71 mm Hg.¹⁴ The cause of the observed elevated pressure is not clear. It could be the result of pulmonary fibrosis, valvular regurgitation, or several other etiologies, but PA systolic pressure was still elevated when patients with significant mitral regurgitation were excluded.¹⁴ However, in view of the present observations and our previous findings on the mechanism of dexfenfluramine-induced pulmonary hypertension, it is possible that pergolide has a direct effect on the pulmonary vasculature. The concentration of pergolide (10 µmol/L) that we used in most of these studies is likely to be in the range of the plasma concentration in patients taking the drug. After a single oral dose of 0.138 mg in healthy volunteers, the peak plasma concentration was 4.4 µmol/L.¹⁶ The mean therapeutic dose of pergolide is 1 mg given 3 times per day,¹⁷ suggesting that the plasma concentration would be significantly higher. However, pergolide is >90% bound to plasma proteins, and therefore the free concentration is uncertain. There is also evidence of rapid uptake by tissues, raising the possibility of protracted activity.¹⁶

These experiments demonstrate that pergolide causes an increase in PA pressure in isolated perfused lungs and contraction of resistance PA rings. The cellular electrophysiology suggests that the mechanism involves inhibition of I_K, membrane depolarization, and Ca²⁺ entry through voltage-gated L-type Ca²⁺ channels. The specific potassium channel was further defined by examining the effect of pergolide on Kv1.5 and K_Ca channels transfected into CHO cells. The drug inhibited both channels. The conclusion that calcium influx is responsible for the vasoconstriction is suggested by the observation that the vasoconstriction was almost completely reversed by nifedipine. Dexfenfluramine causes pulmonary vasoconstriction by the same mechanism.^6,7 However, the major metabolite of dexfenfluramine, nordexfenfluramine, causes pulmonary vasoconstriction predominantly through the release of Ca²⁺ from the sarcoplasmic reticulum.^18,19 Given the impressive effect of nifedipine, this does not seem to play a significant role in the case of pergolide. The proposed mechanism by which pergolide may cause pulmonary vasoconstriction is shown in Figure 7. It is interesting that pergolide has been reported to block hERG K⁺ current and shorten the potential duration of Purkinje fibers.²⁰ Another mechanism that could be invoked to explain pergolide-related valve disease and possible pulmonary hypertension involves the serotonin 5-HT_2B receptor. Pergolide activates this receptor,²¹ which has been implicated in fenfluramine-induced valvular disease^22,23 and in pulmonary hypertension.²⁴ However, this mechanism could not explain the inhibition of I_K or the entry of calcium through L-type calcium channels in the PASMCs. Is there a connection between the serotonin receptor–mediated effect and the K⁺ channel effect of pergolide? Activation of the bone morphogenetic protein 2 (BMP2) receptor is thought to have an inhibitory effect on serotonin signaling. Some patients with idiopathic PAH have a "loss of function" mutation of the BMP2 receptor.²⁵ It has recently been reported that BMP2 increases K⁺ channel function/expression.²⁶ Consequently, loss of BMP2 signaling may permit serotonin proliferative signals to be unopposed by K⁺ channel effects. Because fenfluramine and pergolide both stimulate serotonin receptors and inhibit K⁺ channel function/expression, it is not surprising that vasoconstriction, proliferation, and a decrease in apoptosis might follow in PASMCs.

View larger version (22K): [in this window] [in a new window]   Figure 7. Pergolide inhibits PASMC K+ channels, depolarizes cell membrane potential, and causes the calcium influx through voltage-gated calcium channels (VGCC).

The pathophysiology of idiopathic PAH includes vasoconstriction, cellular proliferation, and thrombosis in small vessels. This work shows that pergolide can cause significant vasoconstriction. In addition, the observed intracellular effects might also initiate cellular proliferation. Pergolide may cause vascular remodeling through 2 separate mechanisms. Increased intracellular potassium, induced by the inhibition of potassium channels, has been shown to be antiapoptotic,²⁷ and increased intracellular calcium has been shown to promote cellular proliferation.²⁸ Further evaluation of the clinical safety of pergolide is indicated, with special attention to the possibility that PAH might occur in chronic users.

	Acknowledgments

 
Dr Weir is supported by Veterans Affairs Merit Review Funding and National Institutes of Health grant RO1-HL65322. Dr Archer is supported by the Canadian Institutes for Health Research, Canada Foundation for Innovation, National Institutes of Health grant RO1-HL071115, the Canadian Institutes for Health Research (CIHR), and ABACUS, the Alberta Cardiovascular and Stroke Research Centre. Dr Archer is a Canada Research Chair in Oxygen Sensing and Translational Cardiovascular Research.

	References

Top Abstract Introduction Methods Results Discussion References

 
1. Fuller RW, Clemens JA. Pergolide: a dopamine agonist at both D₁ and D₂ receptors. Life Sci. 1991; 49: 925–930.[CrossRef][Medline] [Order article via Infotrieve]

2. Horvath J, Fross RD, Kleiner-Fisman G, Lerch R, Stalder H, Liaudat S, Raskoff WJ, Flachsbart KD, Rakowski H, Pache JC, Burkhard PR, Lang AE. Severe multivalvular heart disease: a new complication of the ergot derivative dopamine agonists. Mov Disord. 2004; 19: 656–662.[CrossRef][Medline] [Order article via Infotrieve]

3. Mondal BK, Suri S. Pergolide-induced retroperitoneal fibrosis. Int J Clin Pract. 2000; 54: 403.[Medline] [Order article via Infotrieve]

4. Connolly HM, Crary JL, McGoon MD, Hensrud DD, Edwards BS, Edwards WD, Schaff HV. Valvular heart disease associated with fenfluramine-phentermine. N Engl J Med. 1997; 337: 581–588.[Abstract/Free Full Text]

5. Abenhaim L, Moride Y, Brenot F, Rich S, Benichou J, Kurz X, Higenbottam T, Oakley C, Wouters E, Aubier M, Simonneau G, Begaud B, for the International Primary Pulmonary Hypertension Study Group. Appetite-suppressant drugs and the risk of primary pulmonary hypertension. N Engl J Med. 1996; 335: 609–616.[Abstract/Free Full Text]

6. Weir EK, Reeve HL, Huang JM, Michelakis E, Nelson DP, Hampl V, Archer SL. Anorexic agents aminorex, fenfluramine, and dexfenfluramine inhibit potassium current in rat pulmonary vascular smooth muscle and cause pulmonary vasoconstriction. Circulation. 1996; 94: 2216–2220.[Abstract/Free Full Text]

7. Reeve HL, Nelson DP, Archer SL, Weir EK. Effects of fluoxetine, phentermine, and venlafaxine on pulmonary arterial pressure and electrophysiology. Am J Physiol. 1999; 276: L213–L219.[Medline] [Order article via Infotrieve]

8. Olschewski A, Hong Z, Peterson DA, Nelson DP, Porter VA, Weir EK. Opposite effects of redox status on membrane potential, cytosolic calcium and tone in pulmonary arteries and ductus arteriosus. Am J Physiol. 2004; 286: L15–L22.

9. Pozeg ZI, Michelakis ED, McMurtry MS, Thebaud B, Wu XC, Dyck JR, Hashimoto K, Wang S, Moudgil R, Harry G, Sultanian R, Koshal A, Archer SL. 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. 2003; 107: 2037–2044.[Abstract/Free Full Text]

10. Rahimtoola SH. Drug-related valvular heart disease: here we go again: will we do better this time? Mayo Clin Proc. 2002; 77: 1275–1277.[Free Full Text]

11. Pritchett AM, Morrison JF, Edwards WD, Schaff HV, Connolly HM, Espinosa RE. Valvular heart disease in patients taking pergolide. Mayo Clin Proc. 2002; 77: 1280–1286.[Abstract/Free Full Text]

12. Baseman DG, O’suilleabhain PE, Reimold SC, Laskar SR, Baseman JG, Dewey RB Jr. Pergolide use in Parkinson disease is associated with cardiac valve regurgitation. Neurology. 2004; 63: 301–304.[Abstract/Free Full Text]

13. Van Camp G, Flamez A, Cosyns B, Goldstein J, Perdaens C, Schoors D. Heart valvular disease in patients with Parkinson’s disease treated with high-dose pergolide. Neurology. 2003; 61: 859–861.[Abstract/Free Full Text]

14. Van Camp G, Flamez A, Cosyns B, Weytjens C, Muyldermans L, Van Zandijcke M, De Sutter J, Santens P, Decoodt P, Moerman C, Schoors D. Treatment of Parkinson’s disease with pergolide and relation to restrictive valvular heart disease. Lancet. 2004; 363: 1179–1183.[CrossRef][Medline] [Order article via Infotrieve]

15. Teramae CY, Connolly HM, Grogan M, Miller FA Jr. Diet drug-related cardiac valve disease: the Mayo Clinic echocardiographic laboratory experience. Mayo Clin Proc. 2000; 75: 456–461.[Abstract]

16. Rubin A, Lemberger L, Dhahir P. Physiologic disposition of pergolide. Clin Pharmacol Ther. 1981; 30: 258–265.[Medline] [Order article via Infotrieve]

17. Physicians’ Desk Reference 2005. Montvale, NJ: Thomson PDR; 2005: 3276.

18. Reeve HL, Archer SL, Soper M, Weir EK. Dexfenfluramine increases pulmonary artery smooth muscle intracellular Ca²⁺, independent of membrane potential. Am J Physiol. 1999; 277: L662–L666.[Medline] [Order article via Infotrieve]

19. Hong Z, Olschewski A, Reeve HL, Nelson DP, Hong F, Weir EK. Nordexfenfluramine causes more severe pulmonary vasoconstriction than dexfenfluramine. Am J Physiol. 2004; 286: L531–L538.

20. Hurst RS, Higdon NR, Lawson JA, Clark MA, Rutherford-Root KL, McDonald WG, Haas JV, McGrath JP, Meglasson MD. Dopamine receptor agonists differ in their actions on cardiac ion channels. Eur J Pharmacol. 2003; 482: 31–37.[CrossRef][Medline] [Order article via Infotrieve]

21. Setola V, Hufeisen SJ, Grande-Allen KJ, Vesely I, Glennon RA, Blough B, Rothman RB, Roth BL. 3,4-Methylenedioxymethamphetamine (MDMA, "ecstasy") induces fenfluramine-like proliferative actions on human cardiac valvular interstitial cells in vitro. Mol Pharmacol. 2003; 63: 1223–1229.[Abstract/Free Full Text]

22. Rothman RB, Baumann MH, Savage JE, Rauser L, McBride A, Hufeisen SJ, Roth BL. Evidence for possible involvement of 5-HT_2B receptors in the cardiac valvulopathy associated with fenfluramine and other serotonergic medications. Circulation. 2000; 102: 2836–2841.[Abstract/Free Full Text]

23. Fitzgerald LW, Burn TC, Brown BS, Patterson JP, Corjay MH, Valentine PA, Sun JH, Link JR, Abbaszade I, Hollis JM, Largent BL, Hartig PR, Hollis GF, Meunier PC, Robichaud AJ, Robertson DW. Possible role of valvular serotonin 5-HT2B receptors in the cardiopathy associated with fenfluramine. Mol Pharmacol. 2000; 57: 75–81.[Abstract/Free Full Text]

24. Launay JM, Herve P, Peoc’h K, Tournois C, Callebert J, Nebigil CG, Etienne N, Drouet L, Humbert M, Simonneau G, Maroteaux L. Function of the serotonin 5-hydroxytryptamine 2B receptor in pulmonary hypertension. Nat Med. 2002; 8: 1129–1135.[CrossRef][Medline] [Order article via Infotrieve]

25. Newman JH, Wheeler L, Lane KB, Loyd E, Gaddipati R, Phillips JA III, Loyd JE. Mutation in the gene for bone morphogenetic protein receptor II as a cause of primary pulmonary hypertension in a large kindred. N Engl J Med. 2001; 345: 319–324.[Abstract/Free Full Text]

26. Remillard CV, Fantozzi I, Platoshyn O, Wong A, Petrauskene O, Zhang S, Yuan JX. Bone morphogenetic protein-2 enhances Kv channel expression and function in human pulmonary artery smooth muscle cells. Proc Am Thor Soc. 2005; 2: A723. Abstract.

27. Rimillard CV, Yuan JX. Activation of K⁺ channels: an essential pathway in programmed cell death. Am J Physiol. 2004; 286: L49–L67.

28. Platoshyn O, Golovina VA, Bailey CL, Limsuwan A, Krick S, Juhaszova M, Seiden JE, Rubin LJ, Yuan JX. Sustained membrane depolarization and pulmonary artery smooth muscle cell proliferation. Am J Physiol. 2000; 279: C1540–C1549.

---

 

CLINICAL PERSPECTIVE

Anorectic agents, such as fenfluramine, were associated with a carcinoid-like thickening and restriction of the heart valves, in addition to pulmonary hypertension. Recently, a dopamine receptor agonist, pergolide, used in the treatment of Parkinson disease, was described to cause a similar valvulopathy. It is important to know whether it might also have the potential to cause pulmonary hypertension. Patients with idiopathic pulmonary arterial hypertension have decreased expression/function of a specific potassium channel in the pulmonary arterial smooth muscle cells. The normal function of potassium channels helps to keep the small pulmonary arteries dilated and to inhibit cell proliferation. In this issue Hong et al report that pergolide causes inhibition of potassium channels, membrane depolarization, calcium entry, and vasoconstriction in a manner similar to that of fenfluramine. In view of these findings and the observation of elevated pulmonary artery pressures in some patients taking pergolide, attention should be paid to the possibility that pulmonary hypertension might occur in chronic users.

This article has been cited by other articles:

				S. Droogmans, P. R. Franken, C. Garbar, C. Weytjens, B. Cosyns, T. Lahoutte, V. Caveliers, M. Pipeleers-Marichal, A. Bossuyt, D. Schoors, et al. In vivo model of drug-induced valvular heart disease in rats: pergolide-induced valvular heart disease demonstrated with echocardiography and correlation with pathology Eur. Heart J., September 1, 2007; 28(17): 2156 - 2162. [Abstract] [Full Text] [PDF]

				C. V. Remillard, D. D. Tigno, O. Platoshyn, E. D. Burg, E. E. Brevnova, D. Conger, A. Nicholson, B. K. Rana, R. N. Channick, L. J. Rubin, et al. Function of Kv1.5 channels and genetic variations of KCNA5 in patients with idiopathic pulmonary arterial hypertension Am J Physiol Cell Physiol, May 1, 2007; 292(5): C1837 - C1853. [Abstract] [Full Text] [PDF]

				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]

This Article Abstract Full Text (PDF) All Versions of this Article: 112/10/1494    most recent CIRCULATIONAHA.105.556704v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Hong, Z. Articles by Weir, E. K. Search for Related Content PubMed PubMed Citation Articles by Hong, Z. Articles by Weir, E. K. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Hazardous Substances DB CALCIUM COMPOUNDS CALCIUM, ELEMENTAL Related Collections Pulmonary biology and circulation Pulmonary circulation and disease