(Stroke. 1999;30:1949-1954.)
© 1999 American Heart Association, Inc.
Original Contributions |
Fluoxetine Dilates Isolated Small Cerebral Arteries of Rats and Attenuates Constrictions to Serotonin, Norepinephrine, and a Voltage-Dependent Ca2+ Channel Opener
From the Institutes of Pathophysiology and Pharmacology, Semmelweis University of Medicine, PO Box 370, H-1445 Budapest, Hungary (Z.U., P.P., V.K., A.K.), and the Department of Physiology, New York Medical College, Valhalla, NY (A.K.).
Correspondence to Akos Koller, MD, PhD, Department of Physiology, New York Medical College, Valhalla, New York 10595. E-mail kolako{at}net.sote.hu
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Abstract |
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Background and Purpose—Recent clinical observations question that the antidepressant effect of fluoxetine (Prozac) can be explained solely with serotonin reuptake inhibition in the central nervous system. We hypothesized that fluoxetine affects the tone of vessels and thereby modulates cerebral blood flow.
Methods—A small branch of rat anterior cerebral artery (195±15 µm in diameter at 80 mm Hg perfusion pressure) was isolated, cannulated, and pressurized (at 80 mm Hg), and changes in diameter were measured by videomicroscopy.
Results—Fluoxetine dilated small cerebral arteries with an EC50 of 7.7±1.0x10-6 mol/L, a response that was not affected by removal of the endothelium or application of 4-aminopyridine (an inhibitor of aminopyridine-sensitive K+ channels), glibenclamide (an inhibitor of ATP-sensitive K+ channels), or tetraethylammonium (a nonspecific inhibitor of K+ channels). The presence of fluoxetine (10-6 to 3x10-5 mol/L) significantly attenuated constrictions to serotonin (10-9 to 10-5 mol/L) and norepinephrine (10-9 to 10-5 mol/L). Increasing concentrations of Bay K 8644 (a voltage-dependent Ca2+ channel opener, 10-10 to 10-6 mol/L) elicited constrictions, which were markedly reduced by 2x10-6 and 10-5 mol/L fluoxetine, whereas 3x10-5 mol/L fluoxetine practically abolished the responses.
Conclusions—Fluoxetine elicits substantial dilation of isolated small cerebral arteries, a response that is not mediated by endothelium-derived dilator factors or activation of K+ channels. The finding that fluoxetine inhibits constrictor responses to Ca2+ channel opener, as well as serotonin and norepinephrine, suggests that fluoxetine interferes with the Ca2+ signaling mechanisms in the vascular smooth muscle. We speculate that fluoxetine increases cerebral blood flow in vivo, which contributes to its previously described beneficial actions in the treatment of mental disorders.
Key Words: calcium channels • cerebral arteries • dilation • fluoxetine • smooth muscle
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferencesIntroduction |
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Previous studies suggest that 5-hydroxytryptaminergic (serotonergic) pathways in the central nervous system are involved in the pathogenesis of human depression.1 It is thought that by blocking 5-hydroxytryptamine (5-HT) reuptake from nerve terminals, newer antidepressant drugs, such as fluoxetine (Prozac), enhance 5-serotonergic transmission, which is regarded as the primary therapeutic action of these compounds.
Several recent studies suggested that fluoxetine has additional effects that are apparently not related to the inhibition of the neuronal 5-HT reuptake. For example, in neuronal tissue, fluoxetine has been reported to antagonize nicotinic acetylcholine2 and 5-HT3 4 receptors and to block sodium5 and voltage-dependent potassium channels.6 Moreover, fluoxetine was reported to inhibit both voltage-dependent and 5-HT–induced increases in [Ca2+]i in rat and human cortical neurons.7 8 9 Fluoxetine has also been shown to affect the function of smooth muscle. It antagonized 5-HT–induced contraction of isolated rat intestinal preparation,10 affected potassium channels in isolated intestinal smooth muscle cells,11 and inhibited the high potassium–induced contraction of uterine preparations.12 In isolated pulmonary arterial smooth muscle cells, fluoxetine inhibited the 5-HT–induced [Ca2+]i increase,13 suggesting that fluoxetine interferes with the generation of vascular tone. However, the possible effects of fluoxetine on the function of cerebral arteries is not known, and their possible contribution to the therapeutic action of fluoxetine has not been considered.
Thus, in the present study we aimed to characterize the effects of fluoxetine on the myogenic tone of small cerebral arteries of rats. To avoid the masking effect of neural and hormonal regulation of the vascular tone, experiments were conducted on isolated rat cerebral arteries. To elucidate the underlying mechanisms responsible for the vascular action of fluoxetine, the possible roles of endothelium, opening of K+ channels, inhibition of voltage-dependent Ca2+ channels, and the responses to 5-HT and norepinephrine were assessed.
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Materials and Methods |
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Isolation of Arterioles
Experiments were conducted on isolated rat small cerebral arteries (
195 µm in diameter at 80 mm Hg). The methods
for isolation of vessels have been described in detail
previously.14 The procedures followed were in accord with
institutional guidelines. Male Wistar rats (weighing 350±30 g) were
anesthetized with pentobarbitone (75 mg/kg IP). The brain was
removed immediately after decapitation and placed in a silicone-lined
Petri dish containing cold (0°C to 4°C)
physiological salt (PS) solution composed of
(in mmol/L) NaCl 110, KCl 5.0, CaCl2 2.5,
MgSO4 1.0,
KH2PO4 1.0, dextrose 10.0,
and NaHCO3 24.0 and was equilibrated with a gas
mixture of 10% O2 and 5%
CO2, balanced with nitrogen, at pH 7.4. With
microsurgical instruments and an operating microscope, a 1.5-mm segment
of a first daughter branch of the anterior cerebral artery running
superficially was isolated and transferred into an organ chamber
containing 2 glass micropipettes filled with PS solution. One artery
was used from each rat. The vessel chamber (15 mL) was continuously
supplied with PS solution from a reservoir at a rate of 40 mL/min.
After the vessel had been mounted on the proximal micropipette and
secured with sutures, the perfusion pressure was raised to 20
mm Hg to clear the debris from the lumen. Then the other end of the
vessel was mounted on the distal pipette. Both micropipettes were
connected with silicone tubing to an adjustable PS solution reservoir.
Pressure on both sides was measured by an electromanometer. The
perfusion pressure was slowly increased to 80 mm Hg. The
temperature was set at 37°C by a temperature controller (Grant
Instruments), and the vessel was allowed to equilibrate for 1
hour.
Experimental Protocols
Only those vessels that developed spontaneous tone in response
to perfusion pressure were used, and thus, no vasoactive agent was
added to the PS solution to establish arterial tone. After
the equilibration period, the diameter of vessels was measured at
80 mm Hg perfusion pressure under zero-flow conditions. At the
conclusion of each experiment, the suffusion solution was changed to a
Ca2+-free PS solution that contained sodium
nitroprusside (SNP, 10-4 mol/L) and EGTA
(1.0 mmol/L). The vessel was incubated for 10 minutes, and the
passive diameter at 80 mm Hg pressure was obtained. The diameter
was measured with a microangiometer and recorded with a chart
recorder.
Responses to increasing concentrations of fluoxetine
(10-7 to 3x10-5 mol/L)
were obtained before and after removal of endothelium
or in the presence of 10-6 mol/L glibenclamide
(an inhibitor of ATP-dependent K+
channel15 ), tetraethylammonium
(TEA, 3x10-3 mol/L, a nonspecific
inhibitor of various K+
channels15 ), or 10-4 mol/L
4-aminopyridine (4-AP, an inhibitor of
aminopyridine-sensitive K+
channels15 ). The endothelium of arteries
was removed by perfusion of the vessel with air for 1 minute at a
perfusion pressure of 20 mm Hg as described
previously.14 The artery was then perfused with PS
solution to clear the debris. The perfusion pressure was then raised to
80 mm Hg for 30 minutes to establish a stable tone. The efficacy
of endothelial denudation was ascertained by
arterial responses to acetylcholine
(10-7 mol/L, an
endothelium-dependent agent) and SNP
(10-7 mol/L, an
endothelium-independent agent) before and after the
administration of the air bolus. The infusion of air resulted in loss
of function of the endothelium, as indicated by the
absence of dilation to acetylcholine, whereas dilation to SNP remained
intact.
In a second series of experiments, responses of vessels to cumulative doses 5-HT (10-9 to 10-5 mol/L) and norepinephrine (10-9 to 10-5 mol/L) were obtained. The vessel was then incubated with fluoxetine (10-6, 2x10-6, 5x10-6, 10-5, or 3x10-5 mol/L) for 5 minutes, and vasoactive responses were reassessed. In separate experiments, responses to 5-HT were obtained in the presence and absence of ketanserin (10-6 mol/L), a known 5-HT2A receptor antagonist. Also, after removal of the endothelium, changes in diameter to cumulative doses of Bay K 8644 (an opener of voltage-dependent Ca2+ channels, 10-10 to 10-6 mol/L) were assessed before and after preincubation with fluoxetine (2x10-6, 5x10-6, and 10-5 mol/L) for 5 minutes. All drugs were added to the vessel chamber, and final concentrations are reported. After responses to each drug subsided, the system was flushed with PS solution.
Materials
Fluoxetine was obtained from Research Biochemicals International
Co. All other salts and chemicals were obtained from Sigma-Aldrich
Co and were prepared on the day of the experiment. A
10-2 mol/L stock of glibenclamide was prepared
by dissolving the substance in 30% wt/vol
(2-hydroxypropyl)-(-cyclodextrin) (Cyclolab R&D Ltd), adding a small
volume of 40% vol/vol ethanol, and dissolving in buffer. Fluoxetine
was dissolved in PS solution. Bay K 8644 was dissolved in ethanol and
protected from light; experiments were carried out in the dark. The
vehicle did not have vasoactive effects.
Statistical Analysis
Dilations were expressed as a percentage of the maximal dilation
of the vessel, defined as the passive diameter at 80 mm Hg
perfusion pressure in Ca2+-free medium containing
10-3 mol/L EGTA and 10-4
mol/L SNP. Constrictions were expressed as a percentage of the baseline
diameter. The 50% effective concentrations
(EC50) were calculated from the logarithmic
regressions of the cumulative dose-response curves of vasoactive
agents. In the graphs, the arithmetic mean±SEM values were used.
Statistical analyses were performed by ANOVA for repeated
measures followed by Tukey's post hoc test or Student's t
test. A value of P<0.05 was considered statistically
significant.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferencesIntroduction |
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Rat small cerebral arteries developed a spontaneous myogenic tone in response to an increase in the perfusion pressure to 80 mm Hg without the use of any vasoactive agents. The active inner diameter of arterioles was 195±15 µm. The passive diameter of arterioles obtained in the same conditions but in the absence of Ca2+ (see Methods) was 270±17 µm.
Responses to Fluoxetine: Role of Endothelium
In a dose-dependent manner, fluoxetine
(10-6 to 5x10-5 mol/L)
elicited substantial dilations in arteries, with an
EC50 of 7.7±1.0x10-6
mol/L (Figure 1A
). We have also found
that removal of the endothelium had no significant
effect on the dilation of arteries to fluoxetine
(EC50=6.9±0.8x10-6
mol/L, P=NS; Figure 1A).
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Role of Potassium Channels
Next, we tested the possible role of K+
channels in the vasodilator action of fluoxetine. Fluoxetine-induced
dilations of arteries did not change significantly
(EC50=6.3± 1.5x10-6
mol/L, EC50=7.8±1.7x10-6
mol/L, and EC50=6.8±1.1x10-6
mol/L, respectively; Figure 1B
) after preincubation and in the
presence of the ATP-sensitive K+ channel
inhibitor glibenclamide (10-5
mol/L), 4-AP (10-4 mol/L), or TEA
(3x10-3 mol/L).
Responses to 5-HT and Norepinephrine
5-HT constricted the arteries in a concentration-dependent manner,
with an EC50 of 5.6±2.3x10-7
mol/L (Figure 2). In the presence of
ketanserin (10-6 mol/L), a 5-HT receptor
antagonist, 5-HT–induced constrictions were abolished
(data not shown). Fluoxetine (10-6,
2x10-6, and 10-5 mol/L)
significantly (P<0.01) reduced constrictor responses to
5-HT (Figure 2), whereas 3x10-5 mol/L
fluoxetine essentially abolished the response.
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In control conditions, norepinephrine constricted arteries
in a concentration-dependent manner with an EC50
of 4.25±0.9x10-7 mol/L (Figure 3). Increasing doses of fluoxetine
(2x10-6 and 3x10-6)
significantly (P<0.01) reduced responses to
norepinephrine, whereas 10-5 mol/L
completely abolished the response.
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Responses to Bay K 8644
We tested the arterial responses to Bay K 8644, a
voltage-dependent Ca2+ channel opener. Bay K 8644
(10-10 to 10-6 mol/L)
constricted arteries in a concentration-dependent manner with an
EC50 of 5.6±2.1
(0.42x10-9 mol/L) (Figure 4). Constrictions to Bay K 8644 were
significantly (P<0.01) reduced in the presence of
2x10-6 or 10-5 mol/L
fluoxetine (Figure 4), whereas 3x10-5
mol/L completely abolished the response.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferencesIntroduction |
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This study demonstrates for the first time that fluoxetine, a serotonin reuptake inhibitor, dilates isolated rat small cerebral arteries. This dilation is not mediated by 4-AP–, TEA-, or glibenclamide-sensitive K+ channels or endothelium-derived dilator factors. Fluoxetine antagonized arterial constrictions to 5-HT and norepinephrine and had a substantial inhibitory effect on constrictions elicited by opening of voltage-dependent Ca2+ channels.
Fluoxetine Dilates Small Cerebral Arteries
In the present study, fluoxetine elicited a substantial
concentration-dependent vasodilation in rat cerebral arteries (Figure 1). The vessels were isolated; thus, the effects of fluoxetine
were induced by local factors intrinsic to the arterial wall. The
concentrations of fluoxetine, which have a substantial cerebrovascular
effect, are close to the upper range of therapeutic plasma
concentrations (0.15 to 1.5 µmol/L).16 17 Previous
studies reported that similar concentrations of norfluoxetine, the
active metabolite of fluoxetine, are also present in the plasma of
fluoxetine-treated patients.16 17 In addition, recent data
indicate that fluoxetine can be accumulated in the tissues. During
chronic fluoxetine treatment, a concentration of fluoxetine 20 times
higher than that in plasma has been detected in human
brain,18 19 a finding that also indicates that fluoxetine
effectively crosses the blood-brain barrier. Collectively, these
findings suggest that during clinical treatments, the concentration of
fluoxetine in the brain can reach levels that can potentially affect
cerebral vascular tone and hence blood flow. Further studies are
needed, however, to clarify the effect of fluoxetine on cerebral blood
flow in patients with major depression. Nevertheless, our findings also
suggest that the mechanisms of the medicinal actions of fluoxetine are
more complicated than currently believed.
Possible Mechanisms of Action
Because there was no previous knowledge regarding the
cerebrovascular effects of fluoxetine, we aimed to characterize the
possible endothelial and smooth muscle mechanisms.
First, we aimed to elucidate whether the vasodilation to fluoxetine is
mediated by release of factors from the endothelium.
Removal of the endothelium, however, did not affect the
fluoxetine-induced dilation (Figure 1). Therefore, we conclude
that fluoxetine exerts its effect directly on the arterial
smooth muscle.
Next, we hypothesized that opening of vascular K+
channels may be responsible for the dilation of small cerebral arteries
to fluoxetine. Thus, we tested arterial responses to
fluoxetine in the presence of glibenclamide (an inhibitor
of ATP-sensitive K+ channels), 4-AP, or TEA
(which inhibits several vascular K+ channels).
However, the inhibition of these K+ channels did
not significantly affect the vasodilator action of fluoxetine (Figure 2).
Fluoxetine is known to interfere with 5-HT receptors and/or signal
transduction pathways in the central nervous
system.3 4 20 21 Although 5-HT has a complex action on the
cerebral vessels,22 the effect of fluoxetine on responses
of isolated cerebral arteries to 5-HT has not been clarified. In the
present study, first we confirmed previous
findings23 24 that 5-HT2A receptors
are functional in rat small cerebral arteries, because ketanserin was
able to antagonize arterial constrictions to 5-HT. We found
that fluoxetine inhibited constrictions to 5-HT in a dose-dependent
manner (Figure 2). Interestingly, fluoxetine inhibited
5-HT–induced contractions of rat intestinal preparations as
well.10 Previous studies demonstrated that other 5-HT
uptake inhibitors, femoxetine and paroxetine, also
antagonized 5-HT–induced contractions of isolated cat cerebral
arteries at similar concentrations (from 3x10-7
mol/L).25 On the basis of these findings and those of Ni
and Miledi4 showing that fluoxetine is a competitive and
reversible antagonist of 5-HT2C
receptors, one would conclude that fluoxetine inhibits 5-HT–induced
constrictions by inhibiting 5-HT receptors on cerebral arteries.
However, the finding that fluoxetine inhibited arterial
constriction to norepinephrine also suggests that
fluoxetine is not selective for 5-HT receptors and may affect
postreceptor sites as well.
Previous studies established that after the stimulation of vascular 5-HT2 and adrenergic receptors,24 26 27 an increase in [Ca2+]i takes place in the vascular smooth muscle, due at least in part to the opening of voltage-dependent Ca2+ channels. Therefore, it was logical to hypothesize that fluoxetine may attenuate 5-HT– and norepinephrine-mediated responses by inhibiting the influx of extracellular Ca2+. This hypothesis is supported by previous in vitro findings that fluoxetine at a similar concentration (10-6 mol/L) markedly attenuated the 5-HT–induced rise in [Ca2+]i in rat pulmonary arterial smooth muscle13 and human neuronal cells.9 Thus, the next logical step was to test the effect of fluoxetine on arterial responses to Ca2+ channel activation.
In the present study, small cerebral arteries developed spontaneous myogenic constriction in response to an increase in intraluminal pressure. Pressure-induced myogenic response is known to depend primarily on Ca2+ influx through voltage-dependent Ca2+ channels in the vascular smooth muscle cells.14 28 29 Thus, the finding that fluoxetine dilated cerebral arteries (inhibited myogenic tone) in an endothelium-independent manner suggests that fluoxetine interferes with Ca2+ signaling mechanisms. To further support this contention, we tested the effects of fluoxetine on cerebral arterial constrictions elicited by Bay K 8644, an opener of voltage-dependent Ca2+ channels. We found that fluoxetine, in a concentration-dependent manner, inhibited the constrictions evoked by the pharmacological stimulation of voltage-dependent Ca2+ channels. Thus, it is likely that fluoxetine inhibits Ca2+ entry by inhibiting voltage-dependent Ca2+ channels in arterial smooth muscle cells, thereby reducing the tone developed to pressure, ie, eliciting dilation. Previous studies support this hypothesis by demonstrating that fluoxetine antagonized voltage-dependent Ca2+ channels in the neuronal tissue.7 8 Fluoxetine also reduced the high potassium–induced contractions of uterine preparations,12 which may also suggest a role for inhibition of voltage-dependent Ca2+ channels in the smooth muscle. It is interesting to note that tricyclic antidepressants also seem to inhibit voltage-dependent Ca2+ channels in neuronal tissue,30 31 ventricular myocytes,32 and vascular smooth muscle33 34 and that several Ca2+ channel antagonists used to treat hypertension, especially dihydropyridine derivatives, were found to exert certain antidepressant effects.35 Nevertheless, future studies should further determine the possible involvement of inhibition of vascular and/or neural Ca2+ channels in the antidepressant action of fluoxetine.
In conclusion, we found that fluoxetine dilates small cerebral arteries. This response is not mediated by potassium channels or endothelium-derived dilator factors. The findings that fluoxetine inhibits not only responses to 5-HT and norepinephrine but also constrictions to a Ca2+ channel opener suggest that fluoxetine interferes with the Ca2+ signaling mechanisms in the vascular smooth muscle of small cerebral arteries. The dilation of cerebral vessels to fluoxetine (Prozac) can result in an increase in cerebral blood flow in vivo, which may have clinical importance, because considerable data support the existence of impaired regional cerebral blood flow in major depression.36 37 Thus, the augmentation of the cerebral blood flow could contribute to the therapeutic action of fluoxetine.
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Acknowledgments |
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This study was supported by grants OTKA T-023863 and T-019206 from the National Science Research Foundation; ETT 524/97 and ETT 469/96 from the Health Science Council, Hungary; and HL-46813 from the National Heart, Lung, and Blood Institute, Bethesda, Md.
Received February 3, 1999; revision received May 4, 1999; accepted June 7, 1999.
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Editorial Comment
Department of Internal Medicine, Virginia Commonwealth University, Medical College of Virginia Campus, Richmond, Virginia
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferencesIntroduction |
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Fluoxetine (Prozac) is widely used as an antidepressant in treating patients. The action of fluoxetine is presumably linked to its inhibition of central nervous system neuronal uptake of serotonin, thus making serotonin more available in the brain. Although serotonin is a chemical that affects mood, it is also a potent vasoconstrictor in the cerebral circulation. Despite extensive studies of the clinical pharmacological effects of the drug, the effect of fluoxetine on cerebral circulation remains essentially unexplored. In the accompanying article, Ungvari and coworkers demonstrated that fluoxetine causes dose-dependent vasodilation in the isolated branch of anterior cerebral arteries of rats. They provided the first evidence that fluoxetine diminishes the vasoconstrictor action of serotonin, norepinephrine, and Ca2+ channel openers. They concluded that fluoxetine interferes with the Ca2+ signaling mechanisms in the vascular smooth muscle. Findings from this in vitro study represent an important initial step in understanding the role of fluoxetine in the cerebral circulation.
Obviously, the vascular effect of fluoxetine needs to be further
assessed in in vivo animal models. The anterior cerebral artery in rat
is a conduit vessel, and its responses may not reflect those of the
smaller downstream arterioles. Therefore, it is not certain that the
dilator effect of fluoxetine on large vessels necessarily translates
into improved blood flow in the brain in vivo. Another issue is that
clinically, a low dose (20 mg/d) of fluoxetine is generally recommended
in treating depressed patients. Whether or not this therapeutic dosage
could consistently raise the plasma concentration of fluoxetine
in patients to micromolar levels remains to be tested. On the basis of
the findings of this study, below this level, fluoxetine seems to exert
little or no cerebrovascular effect. In humans, it was reported that
peak plasma concentrations of fluoxetine can reach 1 µmol/L
after a single oral 40-mg dose. Thus, it is not clear that at the usual
therapeutic doses, fluoxetine would have significant cerebrovascular
effects.
Received February 3, 1999; revision received May 4, 1999; accepted June 7, 1999.
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