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* From the Section of Respiratory Medicine, Division of Clinical Sciences (Drs. Higenbottam, Laude, and Bee, and Ms. Marriott), Sheffield University, Sheffield, UK; and the S. Maugeri Foundation, Institute for Clinical Care and Research (Dr. Cremona), Veruna, Italy.
Correspondence to: Timothy Higenbottam, MD, FCCP; Section of Respiratory Medicine, Division of Clinical Sciences, Sheffield University Medical School, Beech Hill Rd, Sheffield S10 2RX, UK; e-mail: t.higenbottam{at}sheffield.ac.uk
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Design: For the human study, tissue was obtained from patients who had undergone lung and heart-lung transplantation. The effect of dFen was studied in seven isolated colloid perfused human lungs and in rings of human pulmonary artery (PA) dissected from the lungs of a further 19 patients. For the porcine study, regional pulmonary vascular resistances (PVRs) were measured in isolated perfused porcine lungs. Vasoconstriction was assessed following dFen alone and in combination with hypoxia, cyclo-oxygenase blockade (indomethacin, 10-5 mol/L), or nitric oxide synthase (NOS) blockade (NG-nitro-L-arginine, 10-5 mol/L).
Results: In the human study, 5-HT and dFen
caused only limited increases in tension of isolated rings of PA. The
concentration of dFen, 10-4 mol/L, that was needed to
increase tension was higher than that found normally in treated
patients where peak levels are 3.3 x 10-7 mol/L. Other
vasoconstrictors such as prostaglandin F2
,
10-5 mol/L, and the thromboxane analog U46619,
10-6 mol/L, produced far greater increases in tension.
Ketanserin, 10-4 mol/L, attenuated the constrictor
response to 5-HT but had no effect on the constrictor response to dFen.
Removal of the endothelium did not influence the response to dFen. In
the isolated ventilated and perfused lungs, dFen caused an increase in
PVR again only at a comparatively high concentration, 10-4
mol/L. In the porcine study, dFen, 10-4 mol/L, did not
increase any PVR during normoxia or following NOS blockade. Small
insignificant increases in PVR occurred during hypoxia and after
cyclo-oxygenase blockade.
Conclusion: These results do not support the view that dFen would act as a direct vasoconstrictor when given in the usual doses. However, delayed elimination of dFen could raise tissue concentrations to high levels and give rise to vasoconstriction and pulmonary hypertension.
Key Words: dexfenfluramine • human • isolated perfused lung • pulmonary hypertension • porcine • serotonin
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dFen is a halogen-substituted ß-phenylethylamine that inhibits the
uptake of 5-HT in presynaptic nerve terminals in the paraventricular
nuclei of the brain and enhances its release from these cells. It is
thought that its anorectic effect results from a rise in 5-HT levels at
these sites.11
The action of dFen differs from the
unsubstituted ß-phenylethylamines, such as amphetamine, that achieve
their anorectic effect through stimulation of
2-sympathomimetic receptors and are therefore
responsible for the abuse potential of this drug.12
dFen,
unlike other phenylamines such as cocaine and amphetamine, has
minimal catecholinergic effects that lead to ad-diction.
The inhibition of 5-HT uptake by dFen is not confined to neuronal cells,13 but is also seen in platelets that express the 5-HT transporter 14 and causes a rise in circulating plasma levels of 5-HT.15 A similar fall in the 5-HT levels of platelets has been observed with other specific inhibitors of 5-HT uptake, such as the antidepressant imipramine.16
There are a number of serotonergic receptor subtypes, most of which have now been cloned and their structures identified.17 The receptors involved in the control of appetite are 5-HT1B and 5-HT2C in the rat,18 and probably 5-HT2C and 5-HT1D in humans.19 The affinity of dFen for these receptors is low, and receptor binding is not thought to contribute to its anorectic actions.20
5-HT itself increases vascular tone by acting principally on the 5-HT2 receptor,21 but also involved in vascular smooth muscle contraction are the 5-HT1D receptors that are found in bovine coronary and pulmonary arteries.22 23 It is possible that dFen acts on these 5-HT receptors. In man, dFen causes a fall in systemic arterial pressure in the obese,24 possibly from the release of prostacyclin (PGI2) from endothelial cells.25
An alternate mechanism might involve the inhibition of the potassium
current as produced by dFen and aminorex in cultured rodent pulmonary
vascular smooth muscle cells. This would lead to depolarization and
subsequent smooth muscle contraction.26
The concentrations
of dFen that were required to achieve this were high
(10-4 mol/L), far higher than the reported
plasma levels seen during treatment (0.3 mg/kg/d;
3.03 x 10-7 mol/L). However, in human
normotensive pulmonary artery smooth muscle cells treated with
fenfluramine (fen), Wang et al27
showed a reduced
expression, and protein, of the Kv1.5 subunit of a delayed
rectifying Kv potassium channel that stabilizes membrane potential.
Loss of functional Kv channels would lead to depolarization and smooth
muscle contraction.
However, as PPH seems to be a complication of dFen use, a first step in uncovering the mechanism is to determine if it causes constriction of pulmonary arteries. As pulmonary vascular responses to 5-HT show marked species variations,28 we elected to study human as well as porcine tissue.
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The recipients and lobectomy patients were premedicated with IM morphine sulfate, 0.2 mg/kg, and midazolam, 80 mg/kg. Anesthesia was induced with IV fentanyl, 1 mg/kg, and sodium methohexitone, 1.5 mg/kg; patients were paralyzed with IV vecuronium, 10 mg.
A lateral thoracotomy was performed in the lobectomy patients. The heart-lung recipients underwent a median sternotomy, after which IV heparin was administered and cardiopulmonary bypass was established. The recipient's heart and then lungs were removed in sequence. In the course of the resection, the bronchial arteries were ligated and the main bronchi divided just distal to the carina. A few centimeters of extrapulmonary artery were retained, but only a few millimeters of pulmonary vein remained outside the lung surface.
The preservation procedure for whole lungs was adapted from that used in lung transplantation.29 In brief, before perfusion of the cold preservation solution, PGI2 in normal saline solution was infused into the pulmonary artery (20 ng/10 mL). The extracellular solution contained in mmol/L included the following: Na+, 130; K+, 5; Ca2+, 2; Cl-1, 111; lactate, 29; glucose, 12; mannitol, 66; and citrate, 10, together with bovine serum albumin, 5g/L, and heparin, 1,000 U/L. The pH was adjusted to between 7.3 and 7.4 by adding a small quantity of sodium bicarbonate solution (1 mol/L). The lungs were continuously ventilated throughout the procedure. Under gravity, 2 L of the cold 10°C perfusate solution was infused into the pulmonary artery until the effluent was completely clear of blood. The left atrium was incised to prevent pulmonary venous overload. The lungs were then inflated to a tracheal pressure of 10 mm Hg and clamped. The inflated lungs were stored at 4°C in perfusate.
Isolated Rings Studies: For the organ bath studies, pulmonary arteries were dissected from lung tissue as described previ-ously.30 31 In brief, the lungs or lobes were kept in cold (4°C) Krebs Ringer solution that had been pregassed with 95% O2 and 5% CO2. Segmental and subsegmental arteries were then dissected and cleaned. Pairs of rings 2 to 5 mm in length and 2 to 4 mm in diameter were cut and mounted in the organ baths filled with 20 mL of Krebs Ringer solution at 37°C and continuously bubbled with 95% O2 and 5% CO2. From one of each pair of rings, endothelium was carefully removed with a pipe cleaner. Confirmation of endothelial removal was tested in random samples by noting the response to acetylcholine, 10-6 mol/L. The rings were repeatedly washed until a stable tension was obtained, and then an optimal length tension relationship was determined.
Response to 5-HT and dFen:
The rings, with and without
endothelium, were first stabilized, and then 5-HT or dFen was added to
give cumulative dose responses over the range 10-8 to
10-4 mol/L bath concentration. At the end of the dose
response study, the preparation was washed repeatedly and allowed to
regain a stable resting tension (RT). Responses to either prostaglandin
F2 (PGF2) or the thromboxane analog
U46619 were then undertaken at a bath concentration of
10-5 mol/L. These concentrations were chosen because
earlier studies had established that these gave maximum contraction in
human pulmonary artery.
Response to 5-HT and dFen After Ketanserin Pretreatment:
Once baseline relaxation had been achieved, the separate arterial rings
were pretreated with ketanserin, 10-4 mol/L. After a
stable RT was established, a dose response to either 5-HT or dFen was
performed as in previous protocols. After washout and a return to RT, a
final response to PGF2, 10-5 mol/L, was
undertaken to test the viability of the rings.
Isolated Perfused Lungs: Lungs for isolated perfused and ventilated preparations were obtained at the time of explantation as described above, and the studies were performed as described in our earlier work.26 The perfusion of the lungs was established within 20 min of excision, having being transported inflated and maintained cold at 4°C. They were suspended by the hilar structures from a gravimetric balance (model 235; Salter; London, UK) and enclosed in a Perspex hood to conserve humidity. The temperature was maintained by infrared lamps (Phillips; Eindhoven, Holland) placed around the chamber. The lungs were ventilated with a gas mixture containing 20% O2, 5% CO2, and 75% N2 using a ventilator (Manley; Blease Medical; Bucks, UK) set at a rate of 15 breaths/min and a tidal volume of 5 to 6 mL/kg body weight. The maximum airway pressure was 10 mm Hg, which was monitored through a side arm in the endobronchial tube connected to a pressure transducer (model P50; Spectromed; Coventry, UK). Periodically, a deep breath was simulated to prevent atelectasis of the lung. A positive end-expiratory pressure of 3 mm Hg was maintained.
A recirculating circuit provided a controlled-flow perfusion. A roller pump (model 16670; American Optical; MA) delivered the perfusate to the lung at 800 mL/min through a cannula in the left main pulmonary artery. The venous drainage was free, and the effluent ran into a constant-temperature (37°C) reservoir through a filter. The perfusate consisted of 2 L of buffered Krebs-Henseleit solution with dextran, 35g/L, and bovine serum albumin, 5g/L.
Pulmonary artery pressure (Ppa) was recorded with a transducer (model P50; Spectromed) referenced to the level of the hilum, through a catheter with an outer diameter of 2 mm that was placed in the main pulmonary artery. Pulmonary flow (Q) was recorded by a Doppler ultrasound probe (model T101D; Transonic Systems; Ithaca, NY) placed on the inflow cannula. Flow and pressure signals were displayed on a chart recorder (model 404; W&W Scientific Instruments; Basel, Switzerland). The analog pressure and flow signals were digitized at a sample rate of 500 Hz (MP100; Biopac Systems; Goleta, CA), and the data was stored on a microcomputer (Macintosh SE30; Apple Computer; Cupertino, CA).
Perfusate was sampled using a pulmonary artery cannula for gas tensions that were measured using a blood gas analyzer (model 1312; Instrumentation Laboratory; Milano, Italy). Samples were taken at the beginning of the experiment and subsequently before the addition of the treatments. The O2 tension was maintained at < 90 mm Hg, and the pH was kept between 7.3 and 7.4 by the addition of sodium bicarbonate solution, 1 mol/L.
A 20- to 30-min equilibration period was allowed before baseline Ppa and Q were measured. Measurements were made with the ventilator switched off at end-expiration and zero positive end-expiratory pressure. With the airway pressure at atmospheric pressure, the perfused lobes should be under zone III conditions.32 To detect the development of pulmonary edema sufficient to affect vascular responses, the weight of the lung was continuously monitored. The experiment was terminated after a 50% weight gain.
Cumulative dose responses to dFen (reservoir concentration, 10-9 to 10-4 mol/L ) were carried out. At the end of the study, U46619, 10-9 mol/L, was added to provide an assessment of the responsiveness of the preparation. A dose response study of U46619 was performed in two lungs over the range 10-11 to 10-8 mol/L.
Porcine Study
Isolated Perfused Porcine Lungs:
Eleven pigs of either sex
weighing from 28 to 44 kg were sedated with IM droperidol, 0.5 mg/kg,
and midazolam, 0.3 mg/kg, and were anaesthetized with IV sodium
pentobarbital, up to 25 mg/kg. A tracheotomy was performed, and the
animals were intubated and ventilated using the Manley ventilator
(Blease Medical) with 40% O2 and 60% N2.
Systemic arterial BP was monitored through a cannula inserted into the
left carotid artery connected to a transducer (model P50; Spectramed).
After a median sternotomy, the pericardium was opened and heparin, 1,000 U kg-1), was administered through the right atrium. Cannulae with an inner diameter (ID) of 5 mm (Portex; UK) were placed in the inferior vena cava, and in the right ventricle through an incision in the right atrium. The animal was exsanguinated via the cannula in the inferior vena cava while 1 to 2 L of buffered Krebs-Ringer solution containing 40 g/L of dextran 70 was concurrently infused into the right ventricle. The rate of infusion was adjusted to keep systemic arterial BP stable until 3 L of blood was obtained.
The heart was stopped by an intracoronary injection of potassium chloride, 10-3 mol/L, and the main pulmonary artery was cannulated using a 13-mm ID cannula. Through an incision in the left ventricle, another cannula (ID, 16 mm) was retrogradely inserted into the left atrium and secured by heavy ties that prevented ballooning of the atrial appendage. These cannulae were connected to an external perfusion system as used for human lungs. The time from cardiac arrest to the start of perfusion was never > 20 min.
The isolated lungs were ventilated with 21% O2, 74% N2, and 5% CO2 at a tidal volume of 12 mL/kg and a frequency of 8 to 12 breaths/min. For hypoxic tests, the lungs were ventilated with 10% O2, 5% CO2, and balance N2. An air-filled pressure transducer attached to the side port of the endotracheal tube was used to measure airway pressure. A positive end-expiratory tracheal pressure of 2 mm Hg was applied, and a deep inspiration was periodically simulated to prevent atelectasis.
The perfusion circuit and the measurement of pressures and flows were similar to the human setup. Pulmonary artery and left atrial pressures were measured by matched transducers (model P50; Spectramed) connected to side ports placed near the tips of the cannulae. Inflow and outflow rates were measured by Doppler flow probes. Data were recorded continuously on a chart recorder.
The perfusate consisted of autologous blood mixed with dextran to give a hematocrit from 0.19 to 0.25. The perfusion rate was increased slowly by 10 mL/kg/min steps over 1 h until a flow rate of 100 mL/kg/min was reached. The pH and the O2 and CO2 tensions of the perfusate were checked periodically with the blood gas analyzer (model 1312; Instrumentation Laboratory). The pH was maintained between 7.3 and 7.4 by the addition of small volumes of sodium bicarbonate, 1 mol/L. The blockers of PGI2 and nitric oxide (NO) production, indomethacin and NG-nitro-L-arginine (L-NA), were added to the reservoir to give circulating concentrations of 10-5 mol/L and 10-4 mol/L, respectively.
Occlusion Maneuvers
The arterial and venous cannulae were held firmly in place by
clamps in order to minimize vibration.33
Ventilation was
stopped at end expiration prior to each occlusion maneuver. Double
occlusion was carried out by simultaneously clamping the inflow and
outflow tubing for 6 s. During occlusion maneuvers, the analog
outputs of the three pressure transducers, the ultrasonic flowmeter,
and the occlusion markers were digitized at a sample rate of 500 Hz
(MP100; Biopac Systems), and the data stored on a personal computer
(Macintosh SE 30; Apple Computer). For the occlusion maneuver, 15
s of data were sampled that included several preocclusion cycles.
Statistical Analysis
Analysis of the Results From Isolated Human Pulmonary Artery
Rings:
The data are presented as mean ± SEM of the tension in
g. Statistical analysis was carried out using
analysis of variance (ANOVA) and, where applicable, paired and unpaired
t tests.
Analysis of the Results From Isolated Perfused Lungs (Human and Porcine): As the mean venous outflow pressure was taken as zero, the pulmonary vascular resistance (PVR) was calculated from the Ppa divided by the value of Q. The mean and SEM are presented. All results were subjected to ANOVA and, where necessary, Scheffe's f test for multiple comparisons or post hoc t tests.
Analysis of Occlusion Tracings:
To minimize the effect of
interference by the roller pump and the occlusion maneuver on the
pressure signals, the digitized signals were filtered via software
(Acknowledge; Biopac Systems) using low-pass Bessel filters with a
cut-off frequency of 50 Hz. From the double occlusion tracings, the
mean pressure for 2 s after equilibration was measured and taken
as pulmonary capillary pressure. From this measurement, the total
pressure drop across the pulmonary circulation could be partitioned
into arterial (
pulmonary arterial segmental pressure) and venous
( pulmonary venous segmental pressure) segments.
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Response to 5-HT and dFen: Dose responses to 5-HT were performed on rings with (n = 36) and without endothelium (n = 35). RT was not significantly different in the two groups. Increases in tension occurred with concentrations > 10-7 mol/L in both rings, with and without endothelium, and reached significance (p < 0.05) at 10-6 mol/L. Although the tension achieved was greater in rings with (1.99 ± 0.12g) endothelium than without (1.73 ± 0.10g), this was not significant (NS; Fig 1 , top). After 5-HT, the further addition of U46619 caused a rise in tension from 1.5 ± 0.3 to 2.7 ± 0.4g (n = 2) in rings with endothelium, and 1.3 ± 0.2 to 2.2 ± 0.4g (n = 2) in rings without endothelium.
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10-5 mol/L, administered after dFen washout was
2.7 ± 0.4g. Response to 5-HT and dFen After Ketanserin Pre-treatment: The constrictor response to 5-HT was significantly attenuated in rings with endothelium (p < 0.01; n = 18) pretreated with ketanserin, 10-4 mol/L. Significant inhibition occurred at concentrations of 5-HT > 10-7 mol/L. In rings with the endothelium removed, mean values were reduced but significance was not achieved (n = 16; Fig 1 , top). In rings with intact endothelium, ketanserin pretreatment, 10-5 mol/L, did not inhibit the rise in tension induced by dFen (2.37 ± 0.26g vs 1.89 ± 0.16g in control subjects; Fig 1 , bottom) nor in rings with endothelium removed (1.73 ± 0.07g vs 1.69 ± 0.15g). Again, for comparison, U46619, 10-5 mol/L, caused a much greater increase in tension compared to that of dFen in rings with and without endothelium.
Isolated Perfused and Ventilated Lungs: A total of seven lungs were studied: four were from patients with CF, one from a patient with Bronch, and two from patients with Eis. The basal values for PVR were much higher in patients with Eis than in those with lung disease (Table 1 ) and were, therefore, analyzed separately.
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or the thromboxane
analog U46619 at concentrations < 10-8 mol/L
greatly exceeded that achieved with either 5-HT or dFen at a higher
concentration, 10-4 mol/L. The same was also
true for the isolated lung studies: U46619,
10-8 mol/L, caused a greater rise in PVR than
that observed with dFen. In isolated pulmonary artery rings, the
constriction induced by dFen appeared not to require the presence of
the endothelium and was not inhibited by the
5-HT2 receptor antagonist, ketanserin. We were able to confirm paucity of effect of dFen, 10-4 mol/L, in our porcine model, where no significant vasoconstriction occurred in the presence of normoxia and hypoxia. Constrictor activity could be attenuated by the release of vasorelaxants from the endothelium, eg, PGI2 or NO, but blockade of the production enzymes of these substances did not enhance the vasoconstriction and are, thus, unlikely to be masking the effect. Certainly, 5-HT2B- and 5-HT1C-like receptor antagonism causes the release of NO and could account for decreases in systemic BP seen with dFen.34 35
The importance of our observation is that the concentration of dFen, 10-4 mol/L, that is required to produce a significant constriction of both isolated rings of pulmonary artery and isolated ventilated and perfused lungs far exceeded the usual plasma concentrations of patients on regular treatment. Peak plasma concentrations of 3.03 x 10-7 mol/L of dFen are achieved with a daily dose of 0.3 mg/kg.36 The local accumulation in the lung of dFen, despite low plasma levels, is unlikely because the main sites of uptake are those where the 5-HT transporter is expressed. Specifically, the median raphe nucleus of the brain is the major site of uptake and not the lung.14 Despite this, the idea of prolongation of the half-life of dFen and the subsequent increase of local or circulating compound being a compromising event in the pathogenesis of pulmonary hypertension should not be dismissed.
Both fen and dFen are metabolized by the cytochrome P450 2D6. The enzyme exhibits a polymorphism with 7 to 10% of white patients expressing no functional enzyme (the phenotype known as "poor metabolizer"). These individuals are unable to efficiently break down certain classes of the compound, thus allowing them to accumulate. In a recent study, the poor metabolizer phenotype was found to be overrepresented in a group of 19 anorectic-associated primary pulmonary hypertensive patients (21%; personal communication).
It could be questioned whether it is valid to study specimens obtained from the explanted lungs of patients who have received heart-lung transplants. We have previously shown that explanted lungs from patients with COPD behave similarly to lungs assumed to have normal physiology.37 They exhibit normal contractile properties and respond to stimuli such as acetylcholine by releasing NO from the pulmonary endothelium. Indeed, similar responses are seen in undiseased lungs that are obtained from pigs and sheep.37 In addition to these past findings on endothelial function, we were able to show in this study that the thromboxane analog U46619 caused a marked increase in PVR at a concentration of 10-8 mol/L in explanted lungs, reaching values similar to that we have previously observed in normal lungs.
The lungs obtained from the two Eis patients had higher baseline values of PVR and responded to lower doses of dFen than the lungs from COPD patients, but these doses were still higher than would be expected during the usual therapeutic use of dFen. We suspect that this greater response in the lungs from the Eis patients resulted not from altered smooth muscle responses but from the extensive microscopic changes of the vasculature of such lungs. This is supported by the similarity of the responses to either 5-HT or dFen in rings of pulmonary artery obtained from Eis and COPD patients. It must be acknowledged that the tissue obtained was from donors whose pulmonary hypertension was not related to dFen use, and it is possible that the concentration range of responses in our study may differ from that of tissue from patients with PPH that is associated with anorectic use.
Endothelial cells could be involved in the pathogenesis of pulmonary hypertension. Excessive production of the vasoconstrictor endothelin 1 has been reported.38 A deficiency of the endothelial vasorelaxants PGI239 and NO30 have also been observed in pulmonary hypertension. We found that both 5-HT and dFen contracted arterial rings in the presence and absence of endothelium. Thus, the endothelium appeared to be unimportant in the vascular constrictor effects of dFen in the human pulmonary artery rings, while dFen did not significantly alter the PVR following the blockade of endothelial enzymes in porcine lungs. Previous studies of patients with secondary pulmonary hypertension have shown impaired endothelial NO release,31 but the smooth muscle cell contractile and relaxation responses that were observed appear to be normal. The rings of pulmonary artery from the two patients with lung cancer were similar to those of pulmonary hypertensive patients in their responses to dFen and 5-HT.
The rings of pulmonary artery that were used were of conduit large-diameter arteries that contribute little to the PVR.40 We found very similar results in isolated lungs where the PVR depends on resistance arteries. We conclude that dFen has a similar effect on both large and resistance arteries.
5-HT is a modest vasoconstrictor of the pulmonary arteries of a number of species. It is inhibited by the 5-HT2 receptor antagonist ketanserin.41 42 We found that ketanserin reduced the pulmonary vasoconstriction caused by 5-HT but did not affect the increased tone induced by dFen. We would argue that dFen is not acting through the 5-HT2 receptor. Alternative receptors could be involved, for example the 5-HT1D, which has been reported to cause constriction in both pulmonary and coronary arteries.23
dFen, Fen, and aminorex reduce the uptake of 5-HT in neurons, platelets, and endothelial cells,11 14 which might promote an increase in the circulating levels of 5-HT, although chronic dFen can decrease whole blood 5-HT while plasma levels remain unchanged.43 dFen acts similarly to other 5-HT transporter inhibitors,44 but unlike them, it causes leakage of 5-HT from cells,45 thus disturbing the turnover and metabolism of 5-HT. Prolonged, high local concentrations of plasma 5-HT in the lung and subsequently in the left heart (although other specific 5-HT uptake inhibitors show a greater degree of platelet 5-HT depletion46 47 48 ) might explain the left sided valvular heart lesions that are associated with the use of anorectics.10 49 There are conditions in which 5-HT levels are known to be elevated, eg, in carcinoid syndrome and after ergotamine overuse,43 50 and have been linked to similar valvular heart lesions on both the right and left sides of the heart in 3% of these patients, although the precise mechanism is unproven.51 52 53
Most of the circulating 5-HT is cleared by the liver, but the final modulation of the plasma levels involves the platelet and the pulmonary endothe-lium.54 Platelets regulate the circulating levels of 5-HT, while the pulmonary endothelium is involved in the clearance and metabolism. There is a familial platelet storage disorder where circulating levels of 5-HT are elevated and the platelet content is reduced.55 Patients with this condition have been reported as developing pulmonary hypertension.56
The fawn-hooded rat also has a platelet storage deficiency, low platelet levels, and elevated circulating plasma concentrations of 5-HT, and a predisposition to develop severe pulmonary hypertension on exposure to mild hypoxia.57 58 It appears that the disturbance of 5-HT metabolism in the fawn-hooded rat may be closely linked to the disposition to develop pulmonary hypertension.59 However, both in rats60 and in patients with carcinoid syndrome,43 diabetes,61 or autism,15 fen was shown to reduce circulating 5-HT. This was attributed to reduced platelet levels in the rats.60
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= prostaglandin F2;
PGI2 = prostacyclin; Ppa = pulmonary artery pressure;
PPH = primary pulmonary hypertension; PVR = pulmonary vascular
resistance; Q = perfusate flow (pulmonary); RT = resting tension This work was supported by the British Heart Foundation Grant 93/94043, the HC Roscoe award, and an educational grant from the Institut de Recherches Internationales Servier.
Received for publication August 24, 1998. Accepted for publication May 11, 1999.
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;
without endothelium 
; with endothelium in the presence of ketanserin
; without endothelium in the presence of ketanserin.
