Effects of fluoxetine, phentermine, and venlafaxineon pulmonary arterial pressure and electrophysiology
HELEN L. REEVE,1,2 DANIEL P. NELSON,3 STEPHEN L. ARCHER,4AND E. KENNETH WEIR2,3Departments of
2Medicine, University of Minnesota, Minneapolis 55455;
3Department of Cardiology, Veterans Affairs Medical Center, Minneapolis, Minnesota 55417;and
4Department of Medicine, University of Alberta, Edmonton, Alberta, Canada T6G 2R7
Reeve, Helen L., Daniel P. Nelson, Stephen L. Archer,
PPH by an odds ratio of 23 (1). In 1996, it was reported
and E. Kenneth Weir.
Effects of fluoxetine, phentermine,
that the total number of prescriptions for the anorexic
and venlafaxine on pulmonary arterial pressure and electro-
combination of fenfluramine and another anorexic
physiology. Am. J. Physiol.
276 (Lung Cell. Mol. Physiol.
agent, phentermine (Fen-Phen), was .18 million in the
L213–L219, 1999.—The anorexic agents dexfenfluramine
United States (8). Unfortunately, despite the wide-
and fenfluramine plus phentermine have been associated
spread use of anorexic agents, the mechanism by which
with outbreaks of pulmonary hypertension. The fenflur-
they may cause PPH remains unclear. The fenflur-
amines release serotonin and reduce serotonin reuptake in
amines cause serotonin release from neurons (21) and
neurons. They also inhibit potassium current (I
reduce reuptake, whereas phentermine inhibits seroto-
membrane potential depolarization in pulmonary arterialsmooth muscle cells. The recent withdrawal of the fenflur-
nin metabolism (27). It has been proposed that high
amines has led to the use of fluoxetine and phentermine as an
levels of serotonin might initiate pulmonary hyperten-
alternative anorexic combination. Because fluoxetine and
venlafaxine reduce serotonin reuptake, we compared the
Weir et al. (31) reported that aminorex, fenfluramine,
effects of these agents with those of phentermine and dexfen-
and dexfenfluramine cause dose-dependent inhibition
fluramine on pulmonary arterial pressure, I
K, and membrane
of the outward potassium current (I
K) in isolated
potential. Fluoxetine, venlafaxine, and phentermine caused
pulmonary arterial (PA) smooth muscle cells (SMCs)
minimal increases in pulmonary arterial pressure at concen-
and that dexfenfluramine depolarizes the cell mem-
trations , 100 µM but did cause a dose-dependent inhibition
brane potential. More recently, it has been shown that
K. The order of potency for inhibition of I
K at 150 mV was
dexfenfluramine inhibits the voltage-dependent potas-
fluoxetine . dexfenfluramine 5 venlafaxine . phentermine.
Despite the inhibitory effect on I
V) channel Kv2.1 (25), which may contribute to
K at more positive membrane
resting membrane potential (RMP) in PASMCs (6). The
potentials, fluoxetine, venlafaxine, and phentermine, in con-trast to dexfenfluramine, had minimal effects on the cell
same doses that inhibit I
K also cause pulmonary vaso-
resting membrane potential (all at a concentration of 100
constriction in isolated rat lungs, which is further
µM). However, application of 100 µM fluoxetine to cells that
enhanced after the inhibition of nitric oxide (NO)
had been depolarized to 230 mV by current injection elicited
synthase (31). Because inhibition of I
a further depolarization of .18 mV. These results suggest
depolarization, and the resulting increase in intracellu-
that fluoxetine, venlafaxine, and phentermine do not inhibit
lar Ca21 concentration are thought to underlie hypoxic
K at the resting membrane potential. Consequently, they
pulmonary vasoconstriction (30), Weir et al. (31) sug-
may present less risk of inducing pulmonary hypertension
gested that these drugs might initiate anorexic-induced
than the fenfluramines, at least by mechanisms involving
pulmonary hypertension in susceptible patients by a
anorexic; serotonin; potassium channels; pulmonary hyperten-
Despite the recent withdrawal of fenfluramine and
sion; membrane potential
dexfenfluramine because of their association with carci-noid syndrome-like cardiac valve disease (8), there hasalready been a move to replace them with new agentssuch as the combination of fluoxetine (Prozac) and
THE AMPHETAMINE-LIKE ANOREXIC AGENT aminorex was
phentermine (Pro-Phen). Fluoxetine is a serotonin reup-
associated with an epidemic of pulmonary hyperten-
take inhibitor (28) and venlafaxine inhibits reuptake of
sion in Austria, Germany, and Switzerland between
serotonin and norephinephrine (17). To determine
1967 and 1972 (13, 22). More recently, a similar epi-
whether these agents might have membrane effects
demic of primary pulmonary hypertension (PPH) oc-
similar to the fenfluramines, we investigated the effects
curred after the use of two other chemically related
of fluoxetine, venlafaxine, and phentermine on PA
anorexic agents, fenfluramine and its D-isomer dexfen-
pressures in isolated, perfused rat lungs and on I
fluramine (7). An epidemiologic study carried out in
membrane potential recorded from isolated rat PASMCs
Europe between 1992 and 1994 showed that the use of
and compared them with those with dexfenfluramine.
fenfluramine for .3 mo increased the risk of developing
Isolated perfused rat lungs.
Male Sprague-Dawley rats
The costs of publication of this article were defrayed in part by the
payment of page charges. The article must therefore be hereby
6 5 g; n
5 59) were anesthetized with pentobarbital
marked ‘ advertisement
' in accordance with 18 U.S.C. Section 1734
sodium (50 mg/kg body wt ip). The rats were intubated with
solely to indicate this fact.
PE-200 tubing (ID 1.44 mm, OD 1.90 mm), a thorocatomy was
ELECTROPHYSIOLOGY AND PULMONARY VASOCONSTRICTION
performed, and the animal was heparinized (100 units). The
potential, the cells were held in current clamp at either their
pulmonary artery was cannulated with a double-lumen can-
RMP (244 6 3 mV; n
5 21) or a potential of 230 mV. The
nula so perfusion and pressure measurements could be
baseline was recorded for at least 1 min to ensure stability.
obtained simultaneously. The left atrium was cannulated for
Data were recorded and analyzed with pClamp 6.04 software
efferent flow in a recirculating manner at a rate of 0.04 ml ·
(Axon Instruments, Foster City, CA).
min21 · g body wt21. Fifty milliliters of Krebs solution contain-
Dexfenfluramine, phentermine, fluoxetine,
ing 4% albumin and 5 µg/ml of meclofenamate were used for
and ketanserin were obtained from RBI (Natick, MA). Venla-
the perfusate. The lungs were ventilated with humidified
faxine (Effexor) was a gift from Knoll Pharmaceutical (Mt.
gases containing 20% O
Olive, NJ). The drugs were dissolved in normal saline, except
2-5% CO2-balance N2 (normoxia) or
ketanserin that was dissolved in 1 part ethanol to 4 parts
2-5% CO2-balance N2 (hypoxia). The lung chamber and
perfusate were maintained at 37°C. Respiration was set to
normal saline. All other drugs and salts were obtained from
physiological values (frequency 70 breaths/min; tidal volume
Sigma (St. Louis, MO). Vehicle controls were done for all
1.5 ml), with a positive end-respiratory pressure of 2.5
Data are expressed as means 6 SE. The effects
2O. To determine lung reactivity, the lungs were sub-
jected to two consecutive cycles, each consisting of 10 min of
of drugs on I
K and PA pressure were compared with a
normoxia, a bolus injection of angiotensin II (0.15 µg) into the
repeated-measures ANOVA (Staview II, version 4.0, Abacus
afferent line, and, after 8 min, a 6-min hypoxic challenge.
Concepts). Membrane potential data were compared with
Lungs were only accepted for study if they had a pressor
Student's paired t
-test. A value of P
, 0.05 was considered
response . 8 mmHg to hypoxia. After a return to baseline, the
lungs were given an NO synthase inhibitor [N
arginine methyl ester (L-NAME); 50 µM] and perfused for afurther 20 min. At this point, increasing doses of the test
Fluoxetine, phentermine, and venlafaxine effects on
drugs (0.1, 1, and 10 µM) were administered at 5-min
There was minimal effect on PA pressure
intervals. The type 2 5-hydroxytryptamine (5-HT2)-receptor
at concentrations of ,10 µM for all drugs tested.
antagonist ketansarin (1 µM) or vehicle was then adminis-
Dexfenfluramine caused a small constriction at 10 µM,
tered. We have found that this concentration of ketanserin
whereas venlafaxine, fluoxetine, and phentermine had
prevents the vasoconstriction caused by 100 µM serotonin(data not shown). After a further 10 min, drugs were given
minimal effect on baseline pressures at this concentra-
again at concentrations of 10 and 100 µM. To determine
tion (Fig. 1A
). At a dose of 100 µM, dexfenfluramine
responsiveness of the lungs to a combination of phentermine
and fluoxetine caused significant constriction. Pretreat-
and dexfenfluramine (to mimic the use of Fen-Phen), the
ment of the lungs with the 5-HT2 blocker ketanserin
lungs were given two consecutive doses of phentermine (10
(1 µM) caused no significant reduction in the response
and 100 µM) or vehicle after L-NAME, followed by two doses
to dexfenfluramine (Fig. 1A
). Lungs treated with phen-
of dexfenfluramine (10 and 100 µM).
termine (10 and 100 µM) constricted significantly more
Rat PASMCs were obtained fresh on each
to subsequent doses of dexfenfluramine (10 and 100
day of experimentation. Male Sprague-Dawley rats (316 6
µM) than control lungs given vehicle before dexfenflur-
14 g; n
5 30) were anesthetized with 50 mg/kg of pentobarbi-
amine (Fig. 1B
tal sodium, and the heart and lungs were removed en bloc.
Whole cell I
Fourth-, fifth-, and sixth-generation pulmonary arteries were
K recorded from PASMCs with the conven-
dissected free and placed in Ca21-free Hanks' solution com-
tional and perforated-patch clamp. I
K recorded from
posed of (in mM) 145 NaCl, 4.2 KCl, 1.0 MgCl
single PASMCs (average cell capacitance 8.6 6 0.2 pF;
10 HEPES, and 0.1 EGTA (pH 7.4) for 10 min at 4°C. The
5 67) with the conventional whole cell configuration
arteries were then transferred to Hanks' solution containing
were typically fast activating and slowly inactivating,
1 mg/ml of papain, 0.75 mg/ml of albumin, and 0.85 mg/ml of
with an average current amplitude of 2,326 6 183 pA at
dithiothreitol without EGTA and kept at 4°C for 17 min. After
150 mV (n
5 27 cells). Currents recorded with the
this time, the arteries were incubated at 36°C for 10 min. The
perforated-patch clamp, which prevents dialysis of the
arteries were washed in enzyme-free Hanks' solution and
cell cytosol, displayed similar kinetics and were not
maintained at 4°C. Several digestions were done each day to
significantly different in amplitude (n
5 7 cells). Cur-
ensure cell viability. Gentle trituration produced a cell suspen-
rents were inhibited by 1 and 2 mM 4-aminopyridine
sion that was divided into aliquots in a perfusion chamber on
(4-AP), suggesting that they were primarily due to
the stage of an inverted microscope (Diaphot 200, Nikon) forwhole cell patch-clamp studies (14). The cells were allowed to
activation of 4-AP-sensitive KV channels (Fig. 2A
adhere to the bottom of the organ bath for several minutes
Fluoxetine, phentermine, and venlafaxine inhibition
before perfusion with a solution composed of (in mM) 145
Fluoxetine and venlafaxine caused dose-depen-
NaCl, 5.4 KCl, 1.0 MgCl
dent and reversible inhibition of I
2, 1.5 CaCl2, 10 HEPES, and 10
K recorded from single
glucose (pH 7.4 with NaOH). For conventional whole cell
PASMCs. Dose-response curves (1–100 µM) were con-
recordings, electrodes were filled with a solution of (in mM)
structed for both drugs and compared with those
140 KCl, 1.0 MgCl2, 5 HEPES, 1 EGTA, and 1 ATP (dipotas-
obtained with dexfenfluramine (Fig. 2B
). Because phen-
sium salt) (pH 7.2 with KOH). For perforated-patch record-
termine had minimal effect on I
K even at 100 µM, a
ings (26), ATP was omitted from the pipette solution and
dose-response curve was not constructed. Venlafaxine
amphotericin B was included at a final concentration of 120
and dexfenfluramine inhibited a similar percentage of
µg/ml. The electrodes had a resistance of 2–3 MV after beingfire polished. All drugs were applied via the extracellular
K at all concentrations tested. Fluoxetine inhibited a
perfusate at a rate of 1–2 ml/min at room temperature
significantly greater percentage of the total I
K and, at a
(21–23°C). For voltage-clamp experiments, the cells were
membrane potential of 150 mV, almost completely
held at a potential of 270 mV and stepped to more depolar-
eliminated the current at 30 µM (79.8 6 3.0% inhibi-
ized potentials in 120-mV steps. For recordings of membrane
5 6 cells; Fig. 2B
), with no additional inhibition
ELECTROPHYSIOLOGY AND PULMONARY VASOCONSTRICTION
Fig. 1. A
: changes (D) in pulmonary arterial pressure(Ppa) measured after increasing doses of venlafaxine,
dexfenfluramine, and fluoxetine before and after admin-istration of ketanserin (arrow) in isolated perfused ratlungs. Values are means 6 SE; n
, no. of lungs. B
: Ppameasured during indicated interventions in isolatedperfused rat lungs. Control, vehicle treated; ANG II,angiotensin II (0.15 µg); L-NAME, N
-nitro-L-argininemethyl ester; Phen, phentermine; Dex, dexfenflur-amine. Values between interventions indicate baseline
measurements pre- and postintervention. Values aremeans 6 SE; n
, no of lungs. Note that ANG II andhypoxia have similar responses in both sets of lungs.
, 0.05 compared with control value.
at 100 µM. The EC50 of fluoxetine for the inhibition of I
). Venlafaxine (100 µM) had little or no effect on cells
at 150 mV was calculated as 4.3 µM. Inhibition of I
held either at their RMP (n
5 6; Fig. 3A
) or at 230 mV
dexfenfluramine (30 µM) with the perforated patch-
5 3; Fig. 3B
). One hundred micromolar phentermine
clamp technique was not significantly different from
had no effect on RMP (n
5 4; Fig. 3A
) but caused a small
that found with the conventional whole cell technique
depolarization if cells were predepolarized to 230 mV
(data not shown).
5 3; Fig. 3B
). Dexfenfluramine (100 µM) depolarized
Fluoxetine, phentermine, and venlafaxine modula-
PASMCs from their RMP by ,14 mV (n
5 4; Fig. 3A
tion of membrane potential.
The average RMP recorded
Cells that did not respond to the test drugs were
from fresh PASMCs was 244 6 3 mV (n
5 21). Cells
exposed to 1 mM 4-AP to ensure reactivity (16.2 6
could be consistently depolarized from RMP by applica-
4 mV; n
tion of 4-AP (1 mM; 18.6 6 4-mV depolarization; n
5 3)but not by tetraethylammonium (5 mM; data not
shown), suggesting that a KV channel controls RMP inthese cells as previously described (4, 5, 33). Despite
Obesity, which is estimated to contribute to 300,000
the significant inhibition of I
deaths annually, is a significant medical problem in the
K at 150 mV by 100 µM
fluoxetine, when this concentration was applied to cells
United States (19). Aminorex, fenfluramine, and dexfen-
held at their RMP, it had minimal effect on the mem-
fluramine were developed to treat obesity but have
brane potential (3-mV depolarization; n
5 7; Fig. 3A
been associated with epidemics of PPH (1, 7) and, more
In contrast, if cells were held at a more depolarized
recently, carcinoid-like cardiac valve disease (8). These
potential of 230 mV, 100 µM fluoxetine caused signifi-
drugs are inhibitors of potassium-channel activity in
cant membrane depolarization (,18 mV; n
5 3; Fig.
resistance PASMCs (31). In a susceptible population,
ELECTROPHYSIOLOGY AND PULMONARY VASOCONSTRICTION
Fig. 2. A
: actual representative traces of wholecell potassium currents recorded from a single pulmo-nary arterial smooth muscle cell (PASMC). Currents
were evoked from a holding potential of 270 mV to atest potential of 150 mV during control period and1-min application of 2 mM 4-aminopyridine (4-AP).A
: current (I
) relationship of effectof 4-AP shown on left
: dose-dependent inhibitionof potassium current (I
K) recorded at 150 mV byincreasing doses of fluoxetine, Dex, and venlafaxineand inhibition by 100 µM phentermine. [drug], Drugconcentration. Values are means 6 SE; n
this channel inhibition might result in membrane
antagonist ketanserin (Fig. 1A
). In 1996, there were
depolarization, increased levels of intracellular cal-
reported to be 18 million prescriptions for the anorexic
cium, and pulmonary vasoconstriction, hence contribut-
combination Fen-Phen (8). For this reason, we investi-
ing to pulmonary hypertension. Since the withdrawal
gated the effects of the combination of dexfenfluramine
of fenfluramine and dexfenfluramine, a new generation
and phentermine. In isolated lungs, in the presence of
of antiobesity drug regimens has already emerged,
phentermine, dexfenfluramine caused significantly
including fluoxetine (Prozac) in combination with phen-
greater pulmonary vasoconstriction than in lungs
termine (Pro-Phen) (2). Fluoxetine and other drugs like
treated with vehicle only (Fig. 1B
). It is possible that it
venlafaxine act, at least in part, through modulation of
might similarly enhance the slight vasoconstriction
the serotonergic system, leading to increased serotonin
caused by lower concentrations of the serotonin reup-
levels in the brain (28). In light of our previous data
(31), we tested the effects of fluoxetine, phentermine,
The patch-clamp studies show that all the drugs
and venlafaxine on PA pressure in isolated rat lungs
tested cause a dose-dependent inhibition of whole cell
and on I
K and membrane potential in single PASMCs.
K in resistance PASMCs. Interestingly, fluoxetine
All three drugs caused a slight increase in PA pressure
causes the most potent inhibition, with nearly 60% of
at a dose of 10 µM, but none constricted the lungs to the
the total current at 150 mV blocked by 10 µM com-
same extent as dexfenfluramine at the same concentra-
pared with only 10% by dexfenfluramine. This would
tion (Fig. 1A
). At the high dose of 100 µM, venlafaxine
appear to contradict the results in the whole lung,
and phentermine caused a slight, additional increase in
which indicate that fluoxetine has little effect on pulmo-
pressure, whereas fluoxetine constricted the lungs as
nary pressure at 10 µM. However, this may be ex-
effectively as dexfenfluramine. The vasoconstriction at
plained by considering the membrane potential data.
high concentrations of fluoxetine and dexfenfluramine
At RMP, fluoxetine causes virtually no inhibition of I
appeared to be via a mechanism independent of seroto-
even at 100 µM, and, consequently, does not initiate
nin because it could not be prevented by the 5-HT2
membrane depolarization. However, if the cell is held at
ELECTROPHYSIOLOGY AND PULMONARY VASOCONSTRICTION
through several subtypes of the KV channel (6, 25, 29),and it is possible that anorexic subjects inhibit differentsubtypes. Dexfenfluramine has recently been shown toinhibit the Kv2.1 channel (25), which may contribute toRMP (6). Because fluoxetine, venlafaxine, and phenter-mine do not appear to inhibit the subtypes that setRMP, this may account for their lack of effect onpulmonary pressure at lower concentrations. As dis-cussed above, fluoxetine causes a large depolarizationof membrane potential if the cell is predepolarized to
230 mV. This further suggests that its inhibitoryeffects may be primarily on channels that open at morepositive membrane potentials. Alternatively, the inter-action of fluoxetine with KV channels to cause IKinhibition may itself be voltage dependent.
Although the mortality and morbidity rates associ-
ated with PPH are high (9), the annual incidence of thedisease is low (1). This suggests that there is a geneticpredisposition to its development. The nature of thispredisposition is unknown. It may involve alteredexpression of ion channels, decreased production ofendogenous vasodilators, or increased production of
endogenous vasoconstrictors. We have shown that inhi-bition of endogenous NO with L-NAME dramaticallyincreases the pulmonary vasoconstrictor responses todexfenfluramine, with constrictions seen at concentra-tions as low as 0.1 µM (31). This raises the possibilitythat low NO production may increase patient suscepti-bility to PPH. Indeed, patients with anorexigen-induced PPH appear to have an NO deficiency yearsafter discontinuing anorexigen treatment (3). Alterna-
Fig. 3. Membrane potential (Em) data recorded in single PASMCs at
tively, a difference in potassium-channel expression
resting membrane potential (A) or at a potential of 230 mV (B). C,
may increase susceptibility similar to the ATP-depen-
control data for each group measured before 2-min application of
dent potassium-channel dysfunction found in hyperin-
either Dex, fluoxetine (Fluox), venlafaxine (Ven), or phentermine(Phen). Values are means
sulinemic hypoglycemia of infancy (10, 18). Indeed,
6 SE; nos. in parentheses, no. of cells. *P ,
0.05 compared with control value.
smooth muscle from PAs of PPH patients (unrelated toanorexic agents) has been shown to have decreased IK
230 mV, 100 µM fluoxetine causes a significant further values and depolarized membrane potentials compareddepolarization. The pathophysiological significance of
with control subjects (34).
this observation is that if the membrane potential is
Fluoxetine has previously been shown to inhibit IK in
already partially depolarized, fluoxetine might then
human and canine jejunal smooth muscle through a
cause vasoconstriction. By comparison, dexfenflur-
protein kinase C-dependent mechanism (11). In jejunal
amine at a concentration of 100 µM is able to elicit a
smooth muscle, one determinant of the role of a diffus-
depolarization from RMP. This concentration applied
ible second messenger in the inhibitory effect of fluox-
acutely to the PASMCs is considerably higher than the
etine on IK was that it could only be demonstrated with
plasma level measured in patients treated chronically
the perforated-patch clamp configuration where the
(,1 µM). It should be remembered, however, that the
cytosol of the cell remains intact. With the use of the
cells in this study are from rats that have not been
same rationale, the effects of fluoxetine observed in
selected for any genetic susceptibility to PPH and also
PASMCs may be independent of a cytosolic second
that it is possible that dexfenfluramine may be concen-
messenger because inhibition of IK was observed with
trated in the cell over time.
the conventional whole cell patch-clamp configuration.
4-AP has been shown to inhibit most of the IK and to
Because the inhibition of IK by dexfenfluramine was the
depolarize PASMCs from their RMP (see RESULTS),
same with the whole cell and perforated-patch tech-
suggesting that 1) the outward current in resistance
niques, we cannot confirm the necessity for a cytosolic
PASMCs is predominantly due to activation of KV
second messenger, at least in the SMC.
channels and 2) that KV channels are open and, at least
Dexfenfluramine induces the release of serotonin
in part, control RMP. Indeed, the data presented here
from neurons and inhibits its reuptake (21), whereas
show that 4-AP causes a significant membrane depolar-
fluoxetine and venlafaxine only inhibit reuptake (28).
ization after administration of noneffective doses of
Because serotonin itself is known to cause pulmonary
fluoxetine, venlafaxine, or phentermine. The whole cell
vasoconstriction (20, 23) and inhibition of potassium
IK in PASMCs is likely to be due to current flowing
channels (16, 24), the effects reported here could be
ELECTROPHYSIOLOGY AND PULMONARY VASOCONSTRICTION
attributed to increased levels of serotonin caused by the
Hampl. Molecular identification of the role of voltage-gated K1
drugs. This is unlikely to explain the electrophysiologi-
channels, Kv1.5 and 2.1, in hypoxic pulmonary vasoconstriction
cal changes because the patch-clamp studies were done
and control of resting membrane potentials in rat arterialmyocytes. J. Clin. Invest. 10: 1–12, 1998.
in single PASMCs that have no serotonergic innerva-
7. Brenot, F., P. Herve, P. Petitpretz, F. Parent, P. Duroux,
tion, and smooth muscle is not a recognized site of
and G. Simonneau. Primary pulmonary hypertension and
serotonin production (12). Furthermore, inhibition of
fenfluramine use. Br. Heart J. 70: 537–541, 1993.
8. Connolly, H., J. Crary, M. McGoon, D. Hensrud, B. Ed-
2 receptors by a concentration of ketanserin suffi-
cient to prevent serotonin-induced pulmonary vasocon-
wards, W. Edwards, and H. Schaff. Valvular heart disease is
associated with fenfluramine-phentermine. N. Engl. J. Med. 337:
striction had no effect on dexfenfluramine- or fluoxetine-
induced vasoconstriction (although it is acknowledged
9. D'Alonzo, G. E., R. J. Barst, and S. M. Ayres. Survival in
that this conclusion relies on a complete and specific
patients with primary pulmonary hypertension: results from a
block of all 5-HT
national prospective registry. Ann. Intern. Med. 115: 343–349,
2 receptors by ketanserin).
In the case of dexfenfluramine, inhibition of I
membrane potential depolarization, and increases in
10. Dunne, M., C. Kane, R. Shepherd, and J. Sanchez. Familial
persistent hyperinsulinemic hypoglycemia of infancy and muta-
intracellular calcium may play a significant role in the
tions in the sulfonylurea receptor. N. Engl. J. Med. 336: 703–706,
mechanism of pulmonary hypertension. It is possible
that dexfenfluramine may also release sarcoplasmic
11. Farrugia, G. Modulation of ionic currents in isolated canine and
reticulum calcium directly. Fluoxetine is the most
human jejunal circular smooth muscle cells by fluoxetine. Gastro-
widely prescribed antidepressant in the world (32) and,
enterology 110: 1438–1445, 1996.
12. Frishman, W. H., S. Huberfield, S. Okin, Y. Wang, A. Kumar,
despite its potent inhibition of IK at positive potentials,
and B. Shareef. Serotonin and serotonin antagonism in cardio-
has not been associated with pulmonary hypertension.
vascular and non-cardiovascular disease. J. Clin. Pharmacol. 35:
This is consistent with its lack of effect on RMP in
PASMCs. Interestingly, at more depolarized membrane
13. Gurtner, H. Atiologie and haufigkeit der primer vaskularen
potentials, high concentrations of fluoxetine caused
formen des chronischen cor pulmonale. Dtsch. Med. Wochenschr.
further depolarization, perhaps indicating a potential
94: 850–852, 1969.
14. Hamill, O. P., A. Marty, E. Neher, B. Sakmann, and F. J.
to enhance pulmonary vasoconstriction at supraphar-
Sigworth. Improved patch-clamp techniques for high resolution
macological doses in susceptible patients. By contrast,
recording from cells and cell-free membrane patches. Pflu
venlafaxine and phentermine had minimal effects on
Arch. 391: 85–89, 1981.
membrane potential or pulmonary vasoconstriction
15. Herve, P., J.-M. Launay, M.-L. Scrobohaci, F. Brenot, G.
even at high concentrations, suggesting that they may
Simonneau, P. Petitpretz, P. Poubeau, J. Cerrina, P. Dur-
oux, and L. Drouet. Increased plasma serotonin in primary
have a lower risk of initiating pulmonary hypertension
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according to this model.
16. Hevers, W., and R. C. Hardie. Serotonin modulates the voltage-
dependence of delayed rectifier and Shaker potassium channels
We thank Knoll Pharmaceutical (Mt. Olive, NJ) for its interest and
in Drosophila photoreceptors. Neuron 14: 845–856, 1995.
support of this project.
17. Holliday, S. M., and P. Benfield. Venlafaxine. A review of its
H. L. Reeve was supported by National Heart, Lung, and Blood
pharmacology and therapeutic potential in depression. Drugs 49:
Institute Grant R29-HL-59182 and was the 1997 recipient of the
Giles F. Filley Award. E. K. Weir and S. L. Archer were supported by
18. Kane, C., R. Shepherd, P. Squires, P. Johnson, R. James, P.
Department of Veterans Affairs Merit Review Funding.
Milla, A. Aynsley-Green, K. Lindley, and M. Dunne. Loss of
Address for reprint requests: H. L. Reeve, Research 151, VA
functional KATP channels in b cells causes persistent hyperinsu-
Medical Center, Minneapolis, MN 55417.
linaemic hypoglycemia of infancy. Nat. Med. 2: 1344–1347, 1996.
Received 29 May 1998; accepted in final form 16 October 1998.
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Adenomyosis: A potentially missed, neglected and inappropriately managed condition By Dr Eisen Liang (Interventional Radiologist) www.sydneyfibroidclinic.com.au Adenomyosis is a benign disease of the uterus due to the presence of ectopic endometrial glands and stroma, deep within the myometrium with adjacent reactive myometrial hyperplasia. The disease can be diffuse or focal (adenomyoma).
Arch Dermatol Res (2005)DOI 10.1007/s00403-005-0584-6 A. Barel Æ M. Calomme Æ A. TimchenkoK. De. Paepe Æ N. Demeester Æ V. RogiersP. Clarys Æ D. Vanden Berghe Effect of oral intake of choline-stabilized orthosilicic acid on skin, nailsand hair in women with photodamaged skin Received: 10 January 2005 / Revised: 20 April 2005Accepted: 23 June 2005 Springer-Verlag 2005