(Circulation. 1997;96:1847-1852.)
© 1997 American Heart Association, Inc.
Articles |
Direct Vascular Effects of Furosemide in Humans
From the Division of General Internal Medicine, Department of Medicine (P.P., T.T., P.S.) and Department of Pharmacology (P.P., T.P.J.D., F.G.M.R., P.S.), University of Nijmegen, Netherlands; the Department of Clinical Pharmacology, St Mary's Hospital Medical School, Imperial College of Science, Technology, and Medicine, London, UK (A.D.H.); and the Department of Endocrinology, University of Maastricht, Netherlands (N.S.).
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Background In humans, hemodynamic changes observed within minutes after systemic administration of furosemide are often referred to as direct vasoactivity. However, these immediate changes do not per se imply a direct vascular effect. We examined the genuine direct vascular effects of furosemide on the human forearm vascular bed and dorsal hand vein.
Methods and Results Forearm blood flow in response to infusion of increasing dosages of furosemide into the brachial artery was recorded by venous occlusion plethysmography. Local plasma concentrations of furosemide reached a maximum of 234±40 µg/mL during the highest infused dose but did not significantly affect the ratio of flow in the infused/noninfused arms. Venous distensibility of a dorsal hand vein was measured with a linear variable differential transformer. During precontraction with norepinephrine, five increasing dosages of furosemide (1 to 100 µg/min) were administered locally. Additional experiments using local administration of indomethacin or NG-monomethyl-L-arginine (L-NMMA) were carried out to determine whether effects were dependent on local prostaglandin or nitric oxide synthesis, respectively. Also, the effects of systemic administration of furosemide were examined. Local administration of furosemide led to a dose-dependent venorelaxation of 18±6% at the first to 72±16% at the last dose. Indomethacin almost completely abolished furosemide-induced venorelaxation, whereas L-NMMA had no effect. Systemic administration of furosemide resulted in a time-dependent increase of hand vein distensibility, reaching 45±11% after 8 minutes.
Conclusions Furosemide does not exert any direct arterial vasoactivity in the human forearm, even at supratherapeutic concentrations. In contrast, at concentrations estimated to be in the therapeutic range, we observed a dose-dependent direct venodilator effect on the dorsal hand vein that appears to be mediated by local vascular prostaglandin synthesis.
Key Words: furosemide • pharmacology • vasodilation • blood flow • prostaglandins
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Introduction |
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The loop-active diuretic furosemide has been the standard treatment for heart failure for several decades. Apart from its primary diuretic action, furosemide is also thought to have effects on the cardiovascular system. In heart failure, systemic administration of a loop-active diuretic has been reported to relieve the symptoms of pulmonary edema immediately, even before diuresis sets in.1 2 Although these effects are referred to as "direct" vascular effects, systemic administration of a drug does not permit distinction between a direct action on the vascular wall versus changes induced by cardiovascular reflexes or regulatory systems.
It is well established that furosemide itself stimulates the release of renin, thereby increasing levels of angiotensin II3 4 5 as well as of prostaglandins from the kidney.6 The effects on these two vasoactive hormonal systems have been associated with arterial vasoconstriction and venous vasodilation observed after systemic administration of the drug.3 4 Conversely, various in vitro experiments indicate that furosemide, sometimes at rather high concentrations, does exert a direct vasodilator effect on isolated arterial7 8 and venous vessels.9 In the in vivo situation, this furosemide-induced direct arterial vasodilation could be blunted by the vasoconstrictive effects of angiotensin II after systemic administration, and it is not clear whether the previously reported in vivo venodilation1 3 10 is the result of a direct or indirect effect of furosemide on venous smooth muscle cells. Thus, up to now it is unknown whether furosemide-induced effects on systemic hemodynamics are the result of a direct or indirect action of the drug on the vasculature in vivo.
In the present study, we thoroughly investigated the genuine direct vascular effects of furosemide on resistance arteries in the forearm and on the dorsal hand vein of healthy subjects. To this end, we used the perfused forearm technique and the LVDT technique, respectively. With these methods, interpretation of the results will not be confounded by direct effects on kidney or reflex effects secondary to changes in blood pressure or total plasma volume.
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Subjects
Several protocols using two techniques were conducted for this study, all approved by the local ethics committee. Before participation, written informed consent was obtained from a total of 60 healthy volunteers. Participants were asked to refrain from drinking alcohol or caffeine-containing beverages for at least 24 hours before their studies. Salt intake was not restricted. None of the participants smoked or used any medication (including analgesics). All experiments were performed in a single-blind fashion in a temperature-controlled laboratory (23°C to 24°C for the perfused forearm experiments and 28°C to 29°C for the venous distensibility measurements) with the subject in the supine position.
Demographic characteristics of the participants are summarized in the
Table
.
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Arterial Vascular Activity Measurements
Two protocols were conducted in a total of 22 subjects to assess
the direct arterial vasoactivity of loop-active
diuretics. First, we examined the direct arterial
vasoactivity of furosemide and bumetanide and second, the effect of
locally administered furosemide on norepinephrine-induced
vasoconstriction. The perfused forearm technique was used for both
protocols. For this technique, the left brachial artery was cannulated
with a 20-gauge catheter (Angiocath, Deseret Medical, Becton Dickinson)
after induction of local anesthesia (lidocaine 2%). This
catheter was used for drug infusion (automatic syringe infusion pump,
type STC-521, Terumo) and blood pressure monitoring (Hewlett Packard
GmbH). At least 30 minutes after intra-arterial
cannulation, baseline values of FBF were measured in both arms three
times per minute by ECG-triggered venous occlusion plethysmography with
mercury-in-Silastic strain gauges (Hokanson EC4, DE
Hokanson).11 To ensure that FBF recordings
referred predominantly to the forearm skeletal muscle resistance
arteries, the hand circulation was occluded during all FBF
recordings by a wrist cuff inflated 100 mm Hg above the
systolic pressure.12 The upper arm collecting
cuffs were simultaneously inflated to 45 to 50 mm Hg
with a rapid cuff inflator (Hokanson E-20). In all experiments, we also
inserted a catheter into a deep ipsilateral forearm vein. During the
last minute of each drug infusion period of 10 minutes, a venous blood
sample was taken and drug concentrations were measured by
high-performance liquid chromatography assay as
previously described.13
Direct Arterial Vasoactivity of Loop-Active
Diuretics
Dosages of furosemide were normalized to forearm volume (water
displacement method). Total infusion rate was kept constant at 100
µL·min-1·100 mL forearm
volume-1. Furosemide was infused at 1, 3, 10,
30, and 100
µg·min-1·dL-1
in 8 subjects. In another 6 subjects, furosemide was infused at 1000
µg·min-1·dL-1
for 6 minutes. In 4 subjects, we administered bumetanide (0.025, 0.075,
0.25, 0.75, and 2.5 µg·
min-1·dL-1)
instead of furosemide to perceive possible differences in vasoactivity
between these two loop-active diuretics.
Effect of Furosemide on Norepinephrine-Induced
Vasoconstriction
Animal data suggest that furosemide may exert an
antivasoconstrictor effect, because the drug did not directly dilate
mesenteric resistance vessels but rather inhibited the vasoconstrictor
effect of norepinephrine and angiotensin
II.14 To study this possible mechanism in humans, we
measured the reduction of FBF in response to cumulative
intra-arterial norepinephrine infusions in the
absence and presence of local furosemide administration. In 4 subjects,
norepinephrine was infused at 10, 30, and 100 ng ·
min-1 · dL-1
before and after local administration of furosemide (10 µg ·
min-1 · dL-1
for 20 minutes, preceded by a 30-minute interval after the first
norepinephrine dose-response curve). Previous experiments
revealed that intrabrachial infusion of this dose of furosemide led to
clinically relevant concentrations in the infused forearm.
Venous Vascular Activity Measurements
Four protocols were carried out to determine the venous
vasoactivity of furosemide. The direct venous effect of locally
administered furosemide was examined, after which involvement of
vascular prostaglandin and NO synthesis was assessed. Also,
the venous effect of systemic administration of furosemide was
examined. All protocols were conducted by the LVDT technique, in which
venous distensibility of a dorsal hand vein was measured with the LVDT
as described by Aellig15 and evaluated by Alradi and
Carruthers.16 A total of 51 experiments were performed in
28 young and 10 elderly subjects. Regression analysis
established that there was no significant correlation between age and
percentage venodilation (r=.18, P=NS), after
which all data were pooled.
With the subject in the supine position in a temperature-controlled laboratory (28°C to 29°C), the arm under investigation was placed on a rigid support at an angle of 30° from the horizontal to allow complete emptying of the superficial hand veins. A sphygmomanometer cuff placed on the upper arm was then inflated to 45 mm Hg. A suitable large superficial vein with no apparent tributaries in the immediate area of examination was chosen, and a 23-gauge butterfly needle was inserted into the vein. The lightweight (0.2-g) probe of the LVDT was placed over the summit of the chosen vein 10 mm downstream from the tip of the needle. Under these conditions, dorsal hand vein distensibility is maximal during venous occlusion. When the venous pressure remains constant at 45 mm Hg, changes in venous diameter are proportional to changes in venous tone.
Owing to the low venous tone present under these
conditions,17 venodilator effects can be quantified only
on veins that have been preconstricted. To examine furosemide-induced
venodilation, we used continuous infusion of increasing concentrations
of norepinephrine to precontract the veins. Infusion of the
norepinephrine concentration that achieved a precontraction
of 
30% of maximal vein diameter was sustained throughout the
experiment. Previous experiments from our laboratory showed that this
method has a good reproducibility: In 15 subjects, the coefficient of
variation of the maximal vasoconstrictor response to
norepinephrine (before and after an interval of 2 hours)
was 9%. In addition, norepinephrine dose-response curves
on different days did not differ significantly from each other.
Sustained infusion of norepinephrine alone resulted in a
stable vasoconstrictor response (70±7% contraction after 10 minutes
and 73±6% after 60 minutes, n=10), indicating the absence of
tachyphylaxis to norepinephrine. During the experiment,
blood pressure and heart rate were monitored every 5 minutes by a
Dinamap 1846 SX attached to the contralateral arm.
Direct Venous Vasoactivity of Furosemide
In a total of 20 subjects, NaCl 0.9% (0.1 mL/min) was replaced
by five increasing doses of furosemide (1, 3, 10, 30, and 100
µg/min) at the same infusion rate for 10 minutes each. The
cuff was deflated for 30 seconds every 5 minutes. At the end of the
experiment, saline was infused again, still with concomitant
norepinephrine infusion.
Involvement of Vascular Prostaglandin Synthesis in the
Direct Venous Vasoactivity of Furosemide
In vivo, an increase in the venous capacitance induced by
systemically administered furosemide has been reported to be
inhibitable by indomethacin.3 This
observation suggests a role for prostaglandins as a
mediator of vasoactive effects of furosemide. The source of the
prostaglandins involved in this mechanism may be the
kidneys, because they may release prostaglandins into the
systemic circulation3 ; alternatively, local
production in the peripheral vasculature could be
involved.18 To determine the role of the nonrenal
prostaglandins in the venous vasoactive effects of
furosemide, we examined the effect of locally administered
indomethacin (12.5 µg/min, 10 minutes) on the
furosemide-induced venous vasoactivity. In 8 subjects, furosemide (100
µg/min) together with a placebo (NaCl 0.9%, 0.1 mL/min) was
locally infused into a preconstricted vein for 10 minutes. Venodilation
was assessed, after which placebo was replaced by
indomethacin for 10 minutes and venodilation was
assessed again.
To exclude a possible constrictor response by indomethacin alone, control experiments were performed in 4 subjects to determine the effect of indomethacin (12.5 and 125 µg/min) on baseline venous tone.
Involvement of Vascular NO Synthesis in the Direct Venous
Vasoactivity of Furosemide
NO is a potent vasodilator released by vascular
endothelial cells. Although the furosemide-induced
vascular effects in vitro appear to be independent of the
endothelium,7 a recent study showed that
furosemide augmented the NO production of isolated cultured
endothelial cells.18 To study the role of
NO in the furosemide-induced venous vasoactivity, we repeated the
protocol as described above, now using L-NMMA (60 µg/min)
instead of indomethacin to inhibit NO
production. Extensive studies have shown that this dose of
L-NMMA has no effect on basal venous tone19 and is able to
block the venodilation caused by acetylcholine.20
Effect of Systemic Administration of Furosemide on Dorsal Hand
Vein Distensibility
All previous reports concerning the effects of furosemide on
human vein capacitance used systemic
administration.1 3 4 10 To examine whether furosemide
administered systemically in therapeutic dosages exerts a vasodilator
activity comparable to that of locally administered furosemide, we
administered furosemide (40 mg) intravenously in the
contralateral arm in 15 subjects. Venous distensibility of the
precontracted hand vein was recorded during the following 8
minutes.
Drugs
Furosemide solutions were freshly prepared from 2-mL ampoules
containing 10 mg/mL furosemide as a disodium salt (Lasix,
Hoechst Marion Roussel) and were further diluted in
physiological saline immediately before each
experiment. Norepinephrine (1-mg/mL ampoules),
indomethacin (Indocid PDA, Merck Sharp and Dohme, 1
mg/mL), and L-NMMA acetate (Clinalfa) were dissolved in
physiological saline immediately before
use.
Data Analysis
Data are expressed as mean±SEM unless noted otherwise and were
analyzed by Student's t test or repeated measures
ANOVA for paired data if appropriate. If ANOVA showed that a
significant difference existed between conditions, it was followed by
post hoc t tests (including Bonferroni correction) to
determine dose dependency or time dependency. Linear regression
analysis was performed on the relation between age and
percentage furosemide-induced venodilation (correlation coefficient
according to Pearson). A value of P<.05 was considered to
indicate significance.
Direct arterial vasoactivity. To reduce the variability of blood flow data and to correct for systemic changes, the ratio of the FBF measurements in the infused and noninfused arms was calculated for each time point, with the noninfused arm used as a contemporaneous control for the infused arm.21 The FBF values of the last 3 minutes of each drug infusion were averaged to one value.
Direct venous vasoactivity. The response of norepinephrine-induced constriction was measured, and furosemide-induced effects were expressed as the percentage attenuation of the average control constriction. All results are expressed as a percentage of baseline vein size. The furosemide-induced venodilation was determined during the last 3 minutes of each furosemide infusion.
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Systemic Effects
Forearm volume averaged 984±32 mL. During the arterial vasoactivity experiments, blood pressure, heart rate, and FBF in the noninfused arm did not change significantly after intrabrachial infusion of furosemide. During local administration of furosemide in the venous vasoactivity experiments, blood pressure increased over
1 hour from 113±2/62±1 to 116±2/66±2 mm Hg
(for systolic and diastolic blood pressures,
P=.03 and P=.001, respectively, ANOVA with
repeated measures). There was no change in heart rate (61±2 to 61±2
bpm, P=NS). More relevantly, blood pressure increased within 5 minutes after systemic administration of 40 mg of furosemide from 118±1/68±2 to 121±2/71±2 mm Hg (P=.01 and P<.0001, respectively, Student's t test). Heart rate remained unchanged (63±2 to 65±1 bpm).
Direct Effects on FBF
Ratios of infused to control FBF and ipsilateral venous plasma
concentrations of furosemide are shown in Fig 1
(top). During five increasing dosages of
furosemide, there was no significant effect on FBF compared with the
placebo infusion. In 6 subjects, we infused furosemide 1000 µg
· min-1 ·
dL-1 for 6 minutes, leading to local
furosemide plasma concentrations of 234±40 µg/mL. In these
subjects, furosemide increased FBF in the infused arm slightly, by
23±9.7% (P<.05), but without a significant effect on the
FBF ratio of the infused and noninfused arms (P=.08).
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Intra-arterial bumetanide infusions led to local plasma concentrations ranging from 39±11 to 1748±327 ng/mL and also failed to alter FBF (data not shown).
Effect of furosemide on norepinephrine-induced
vasoconstriction. As shown in Fig 1
(bottom), local infusion of
norepinephrine into the brachial artery led to a
dose-dependent decrease in FBF (P<.001), with no
significant effect on systemic blood pressure. This vasoconstriction
was not inhibited by local infusion of furosemide
(P=NS).
Direct Effects on Dorsal Hand Vein Distensibility
Vein diameter of the participants was 0.74±0.05 mm. On
average, infusion of norepinephrine constricted the vein of
investigation to 31±2% of the control size.
Fig 2 demonstrates that continuous local
infusion of furosemide results in a dose-dependent attenuation of the
constrictor effect of norepinephrine (P<.001).
Post hoc t tests (with Bonferroni correction) revealed a
dose-dependent venodilation between doses of 0, 1, 10, and 100
µg/min. This direct venodilating effect of furosemide was
rapid in onset. After the last furosemide infusion was replaced with
NaCl 0.9% infusion, venodilation waned within a few minutes.
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Involvement of vascular prostaglandin synthesis
in the direct venous vasoactivity of furosemide. In 8 subjects,
furosemide-induced venorelaxation was assessed in the absence and
presence of local indomethacin administration. Fig 3
(left) shows that
indomethacin inhibits furosemide-induced venodilation,
because in this subgroup, furosemide dilated the vein by 54±17% and
furosemide in combination with indomethacin, by
14±17% (P=.025).
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Control experiments showed that indomethacin itself had no constrictor effect on basal vein tone. When baseline vein distensibility is taken as 100%, indomethacin 12.5 and 125 µg/min led to vein distensibilities of 101.4±0.5% and 100.2±1.2%, respectively (n=4, P=NS).
Involvement of vascular NO synthesis in the direct venous
vasoactivity of furosemide. Fig 3 (right) shows that
furosemide-induced venorelaxation was not inhibited by local L-NMMA
administration. In this subgroup, venorelaxation was 60±11% before
and 53±14% after placebo was replaced by L-NMMA (n=8,
P=NS).
Effect of systemic administration of furosemide on dorsal hand
vein distensibility. As shown in Fig 2 (right), parenteral
administration (contralateral antecubital vein) of 40 mg furosemide led
to increases in vein diameter of 18±8%, 26±11%, and 45±11% at 2,
4, and 8 minutes, respectively (P<.01). Post hoc tests
(Bonferroni) revealed that venodilation was significantly different
from baseline at t=4 minutes (P=.028) and 8 minutes
(P=.001).
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Discussion |
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It is generally accepted that the reduction in venous return as a result of a nondiuretic vascular effect by furosemide is therapeutically important in achieving rapid symptomatic relief for patients with left ventricular heart failure. The mechanism of this action is unclear. Because of the absence of data on the direct vasoactivity of furosemide in vivo, we examined the vascular effects of local furosemide administration on arterial and venous vessels in humans. Our data strongly suggest that furosemide does not exert any direct arterial vasodilator or antivasoconstrictor activity in the human forearm but does have a direct venodilator effect, which is associated with vascular prostaglandin synthesis.
Direct Effects on FBF
Our results demonstrate the absence of a direct effect of
loop-active diuretics on FBF during intra-arterial
infusions, which results in clinically relevant plasma concentrations
in the infused forearm. The absence of vasoactivity in this
concentration range is consistent with most previous
experiments on isolated arteries.7 8 In these in vitro
experiments, direct vasodilator properties of furosemide were observed
only at concentrations >10-4 mol/L,
whereas in our first series of experiments, the furosemide
concentration at the highest infusion rate reached 47±10
µg/mL, equivalent to 1.4x10-4
mol/L. To examine the direct arterial effects of
furosemide at very high concentrations in vivo, we infused furosemide
1000 µg · min-1 ·
dL-1 into the brachial artery, leading to a
local concentration of 234±40 µg/mL
(0.71x10-3 mol/L). Even at these
supratherapeutic concentrations, only a negligible increase in FBF was
observed.
In the rat, furosemide did not change baseline mesenteric blood flow, but systemic administration did inhibit the decrease in blood flow produced by angiotensin II and norepinephrine.14 In contrast, we observed no effect of local furosemide on norepinephrine-induced attenuation of FBF. From our studies, we conclude that furosemide does not exert any direct arterial vasodilator or antivasoconstrictor activity in the human forearm. As such, the previously reported decrease in FBF after systemic administration of furosemide3 4 22 is probably due to an indirect effect of the drug, in particular a stimulation of the renin-angiotensin system.5 Of course, our experiments do not allow us to exclude direct arterial vasoactivity of furosemide in other vascular beds, eg, the lung or kidney.
Direct Effects on Dorsal Hand Vein Distensibility
The present investigation shows that furosemide exerts a
direct vasodilator effect on preconstricted dorsal hand veins.
Time-control experiments demonstrated that this effect of furosemide
cannot be explained by a spontaneous reduction in
norepinephrine-induced constriction over time. The local
concentration of furosemide cannot be estimated precisely because the
venous flow was not measured in these studies. However, if the flow in
the dorsal hand vein is assumed to be 1 mL/min (5% of
arterial FBF),23 furosemide plasma
concentrations can be estimated to range from 0.2 to 20 µg/mL
during our dose-response studies. Systemic administration of 40 mg
furosemide leads to a plasma concentration of 3.8±0.3 µg/mL
in the first 15 minutes in normal subjects,24 which is
within the range of the estimated plasma concentrations. This, as well
as the observation of a similar venodilator effect after systemic
administration of 40 mg furosemide, suggests that the increase of
venous compliance observed after systemic administration of furosemide
may be the result of direct effects on the venous circulation. Compared
with other substances such as nitroprusside25 and
substance P,26 which exert venodilatory properties at an
infusion rate of nanograms per minute, furosemide is much less potent.
However, its effect does have clinical relevance, especially in the
first few minutes after parenteral administration.
Mechanism of Action
Two hypotheses concerning the direct vascular effects of
furosemide emerge from the literature. The first hypothesis focuses on
furosemide-induced inhibition of vascular Na-K–2 Cl cotransport,
whereas the second is directed to the role of
prostaglandins in the vascular activity of furosemide.
Na-K–2 Cl Cotransport Inhibition
The presence of Na-K–2 Cl cotransport in
endothelial and vascular smooth muscle cells has been
established, but its role in the regulation of vascular tone is
unclear.27 28 29 In a recent report, furosemide relaxed
canine venous but not arterial vessels taken from a variety
of vascular beds.9 In the same vessels, Na-K–2 Cl
cotransport distribution was determined, and the magnitude of the
vasodilator effect was found to correlate with Na-K–2 Cl cotransport
distribution. The correlation between Na-K–2 Cl cotransport
distribution and vascular activity suggests a role for this
cotransporter in the vascular action of furosemide. However, inhibition
of renal Na-K–2 Cl cotransport occurs at 10-4
to 10-3 mol/L
furosemide,30 concentrations 10 to 50 times the local
concentration in the hand vein, and the importance of this action of
furosemide to its venodilator properties remains uncertain.
Augmented Prostaglandin Synthesis
The effect of systemic administration of furosemide on venous
capacitance has been compared between healthy subjects and anephric
patients. Venous capacitance increased in healthy volunteers but not in
anephric patients.3 This effect could be blocked by
pretreatment of the cyclooxygenase
inhibitor indomethacin, suggesting a role
for renal prostaglandin release in the vascular effects of
furosemide. Our results indicate that renal prostaglandin
synthesis is not necessarily important for the direct venous
vasodilation, because the release of renal prostaglandins
cannot have been stimulated after the local furosemide infusions. This
does not rule out the possibility that furosemide-induced
vasodilation is mediated by activation of vascular PGI2
synthesis. Lundergan et al,31 using an isolated canine
lung lobe perfused with autologous blood at constant flow, demonstrated
that furosemide-induced decreases in pulmonary artery perfusion
pressure were mediated by prostaglandins because they were
abolished by treatment of the lung with indomethacin.
Recently, it was shown in cultured bovine aortic
endothelial cells that furosemide stimulated the
production of prostacyclin and NO at clinically relevant
concentrations.18 In our study, the direct venodilator
effect of furosemide on veins was almost totally abolished by local
administration of indomethacin, indicating that this
direct vascular effect is dependent on local vascular
prostaglandin synthesis. It is unclear whether the
endothelial or the vascular smooth muscle cell is the
source of the prostaglandin production augmented by
furosemide. In vivo endothelial stripping with
distilled water32 seems a possibility to address this
question, but these experiments are quite invasive, and NSAID treatment
will be necessary to prevent blood clotting,32 which will
obscure the interpretation of the furosemide-induced venodilation. It
is unknown whether the furosemide-enhanced vascular PGI2
production18 is the consequence of a nonspecific
action of furosemide or of inhibition of the vascular Na-K–2 Cl
cotransporter. Furthermore, the effect of systemic treatment with
indomethacin or other NSAIDs on the furosemide-induced
venorelaxation and its clinical implications are unknown.
The venorelaxation persisted after addition of L-NMMA, so it appears that the effect is not mediated by endothelial NO release.
Conclusions
The present study provides the first evidence that furosemide
at therapeutic concentrations exerts no direct vasodilator or
antivasoconstrictor effect on arterial resistance vessels
in the human forearm but rather directly dilates veins in humans. The
direct venodilation was inhibited by local indomethacin
administration but not by blockade of NO synthesis, indicating that the
direct vascular venodilation is dependent on local
prostaglandin but not on NO production.
Hemodynamic changes observed directly after systemic
administration of furosemide are probably due to a direct venodilator
effect of the drug.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This study was supported by the Dutch Heart Foundation, grant 94.059.
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Footnotes |
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Reprint requests to Prof Dr P. Smits, MD, PhD, Department of Pharmacology (233), University of Nijmegen, PO Box 9101, 6500 HB Nijmegen, the Netherlands.
Received January 15, 1997; revision received April 24, 1997; accepted April 28, 1997.
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References |
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