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Vol. 83, Issue 6, 1933-1940, December 1997
Division of Cardiology, Vanderbilt University Medical Center, Nashville, Tennessee 37232-6300; and Clinical Research Center, University of Pennsylvania, Philadelphia, Pennsylvania 19104
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
ACKNOWLEDGEMENTS
FOOTNOTES
REFERENCES
ABSTRACT 
Lang, Chim C., Don B. Chomsky, Javed Butler, Shiv Kapoor,
and John R. Wilson. Prostaglandin production contributes to
exercise-induced vasodilation in heart failure. J. Appl. Physiol. 83(6): 1933-1940, 1997.
Endothelial release of prostaglandins may contribute to
exercise-induced skeletal muscle arteriolar vasodilation in patients
with heart failure. To test this hypothesis, we examined the effect of
indomethacin on leg circulation and metabolism in eight chronic heart
failure patients, aged 55 ± 4 yr. Central hemodynamics and leg
blood flow, determined by thermodilution, and leg metabolic parameters
were measured during maximum treadmill exercise before and 2 h after
oral administration of indomethacin (75 mg). Leg release of
6-ketoprostaglandin F1
was also
measured. During control exercise, leg blood flow increased from 0.34 ± 0.03 to 1.99 ± 0.19 l/min
(P < 0.001), leg
O2 consumption from 13.6 ± 1.8 to 164.5 ± 16.2 ml/min (P < 0.001), and leg prostanoid release from 54.1 ± 8.5 to
267.4 ± 35.8 pg/min (P < 0.001).
Indomethacin suppressed release of prostaglandin
F1
(P < 0.001) throughout exercise and
decreased leg blood flow during exercise
(P < 0.05). This was associated with
a corresponding decrease in leg O2 consumption (P < 0.05) and a higher level of
femoral venous lactate at peak exercise
(P < 0.01). These data suggest that
release of vasodilatory prostaglandins contributes to skeletal muscle
arteriolar vasodilation in patients with heart failure.
congestive heart failure; indomethacin; regional blood flow
INTRODUCTION BLOOD FLOW to working skeletal muscle is frequently
reduced during exertion in patients with heart failure (35, 40). This reduced perfusion of muscle is thought to be responsible, at least in
part, for one of the major clinical symptoms experienced by such
patients: exertional fatigue (35, 36). The mechanism responsible for
the reduction in skeletal muscle blood flow in heart failure remains
unclear, and a number of factors have been postulated. The role played
by various neurohormones, particularly the vasoconstrictive
neurohormones such as catecholamines and angiotensin II, have received
the most attention (8, 37, 38). However, a host of local factors and
mechanisms of "autoregulation" may also be important in
adjustment of skeletal muscle vascular resistance and blood flow. Some
of these factors include thromboxane, prostacyclin, various
prostaglandins, endothelin, endothelium-derived relaxation factor,
tissue and vascular renin-angiotensin, intrinsic myocyte tone and
myogenic responses, and metabolic factors; the role, relevance, and
relative importance of each remain to be determined in heart failure
(8, 10, 22, 43).
The vascular endothelium is the most prominent source of prostaglandin
formation in the circulation (3, 7), and several lines of evidence
suggest that local synthesis and release of vasodilatory prostaglandins
may contribute to vasodilation in skeletal muscle during exercise. In
animal experimental models, an increase in blood flow velocity and
shear stress has been shown to release prostaglandins from the skeletal
muscle microcirculation (20) and from cultured endothelial cells (13,
15). Young and Sparks (41) observed that exercise of the dog skeletal
muscle increased release of prostaglandin (PG) E. We and others (19, 39) have shown that physical exercise increases circulating levels of
vasodilatory prostaglandins in normal subjects and that administration
of cyclooxygenase inhibitors, which inhibit the production of these
prostaglandins, reduces blood flow to working muscle during exercise
(39) and attenuates the active hyperemia that occurs after ischemia and
exercise (5, 19, 42). The role of vasodilatory prostaglandin release
during exercise in heart failure has never been defined. Vasodilatory
prostaglandins may be important in maintaining blood flow under such
conditions of severe flow impairment. Alternatively, impaired release
of vasodilatory prostaglandins may contribute to the flow abnormality in heart failure.
The purpose of this study was to clarify whether vasodilatory
prostaglandins contribute to exercise-induced arteriolar vasodilation in patients with heart failure. Accordingly, the effects of
prostaglandin synthesis inhibition with indomethacin on leg blood flow
responses to exercise were examined in patients with heart failure.
METHODS
O2) levels below the normal range for their ages; the average (range) peak exercise O2 was 11.5 ± 1.1 ml · min
1 · kg1
(range: 5.5-16.5
ml · min1 · kg1).
All patients had exertional breathlessness or fatigue, or both, despite
therapy with angiotensin-converting enzyme inhibitors, digoxin, and
diuretic drugs, and all were classified in New York Heart Association
functional class II-III. None had peripheral edema, ascites, angina
pectoris, intermittent claudication, or reduced pulses in his or her
legs at the time of the study. Before enrollment in the study, all
patients were optimally diuresed, with no evidence of fluid retention.
Left ventricular dysfunction was attributable to coronary artery
disease in six patients and to idiopathic dilated cardiomyopathy in two
patients. No patient was on a nonsteroidal anti-inflammatory drug or
aspirin, and none had received any vasodilator therapy for at least 48 h. The protocol was approved by the Institutional Review Board of
Vanderbilt University. Written informed consent was obtained from all
subjects.
(6-keto-PGF1), a stable metabolite of prostacyclin, the predominant vasodilatory prostaglandin released from the endothelium.
Patients then stood up on the treadmill, and, after a 5-min
equilibration period, standing measurements of central and leg hemodynamics were recorded. Gas-exchange analysis was performed with
the patient breathing into a disposable pneumotac, with his or her nose
clamped, by using a Medgraphics Cardio
O2 combined O2/electrocardiographic
exercise system (Medical Graphics, St. Paul, MN). The patient's left
index finger was also attached to a pulse oximeter to continuously
monitor arterial hemoglobin O2 saturation.
The patient then commenced exercise on the treadmill by using a
Naughton protocol. The patient was asked to rate the level of dyspnea
and leg fatigue by using the Borg Scale (1). This scale rates the level
of perceived symptoms by using a scale of 6 (none) to 20 (severe). All
patients continued exercising until symptoms of dyspnea or fatigue, or
both, forced them to stop. Respiratory gas and hemodynamic measurements
were made continuously. During each 3-min exercise stage, leg blood
flow was measured starting at 45 s, with a total of at least three
measurements. The average of these measurements was then taken as the
mean flow for the exercise stage. Central hemodynamic measurements were recorded simultaneously. Blood sampling from both pulmonary artery and
femoral vein was performed during the last 45 s of the stage. Immediately after exercise was terminated, 75 mg indomethacin were
administered orally; indomethacin is rapidly absorbed, reaching peak
concentrations within 1-2 h after oral administration (16). After
subjects rested semirecumbent for 2 h, the exercise protocol was
repeated. Hemodynamic and metabolic measurements were made at identical
exercise times as during control exercise. If a patient exercised
longer after drug administration, measurements were also made at the
new maximum exercise level.
Normal subjects.
For comparison, five normal subjects (aged 49 ± 2 yr; 4 men and 1 woman) also underwent exercise testing before and after indomethacin
administration. Studies were performed as noted above, with one
exception: pulmonary artery catheters were not inserted.
Leg blood flow measurements.
Leg blood flow was determined by the thermodilution method described by
Jorfeldt et al. (18). In brief, femoral vein flow was measured with a
50-cm 5-F thermodilution catheter with the thermistor at 2 cm and
injection port 12 cm from the tip. Flow was determined by rapid
injection of a 3-ml iced dextrose bolus, with the aid of a commercially
available thermodilution computer (Baxter Vigilance Monitor, Baxter
Healthcare, Irvine, CA). Output curves were displayed on a screen to
ensure exponential decay curve. Jorfeldt et al. have demonstrated that
femoral venous flow measured by this technique agrees closely with leg
flow determined by injection of indocyanine green into the femoral
artery with sampling from the femoral vein.
Measured variables.
Hemoglobin concentration was measured by using a Coulter counter;
hemoglobin O2 saturation was
measured with a CO-oximeter precalibrated with human blood. Blood
O2 content was calculated as the
product of hemoglobin 1.34 ml O2/g
hemoglobin and percent O2
saturation. O2 extraction was
calculated as the ratio of the arteriovenous
O2 difference to arterial
O2 content.
Cardiac output was calculated from the Fick principle as systemic
O2 uptake divided by systemic
arteriovenous O2 difference. Systemic vascular resistance was calculated as the mean arterial pressure divided by cardiac output. Leg vascular resistance was calculated as (arterial pressure 
femoral vein pressure) divided by
leg flow. Leg O2 was
calculated as the product of femoral flow and the arteriovenous
O2 difference across the leg. Leg
PGF1 release was calculated as
femoral venous PGF1
concentration leg flow rate.
Reproducibility studies.
The period between exercise tests was 2 h. To ensure that exercise
results are reproducible when repeated at this interval, reproducibility measurements were made in another group of patients with heart failure (1 woman and 4 men; aged 53 ± 4 yr; left
ventricular ejection fraction: 24 ± 2%). At peak exercise, the
following key measurements were found to be reproducible: exercise
duration (13.8 ± 1.2 vs. 14.2 ± 1.4 min, first vs. second
exercise); systemic maximum
O2 (13.8 ± 1.0 vs. 13.3 ± 0.9 ml · min1 · kg1);
mean arterial pressure (93 ± 2 vs. 95 ± 1 mmHg); cardiac output (6.8 ± 0.7 vs. 7.3 ± 0.7 l/min); leg blood flow (2.24 ± 0.44 vs. 2.14 ± 0.31 l/min); femoral venous lactate (35.7 ± 8.8 vs. 32.7 ± 12.0 mg/dl); and leg
O2 (376 ± 62 vs. 366 ± 27 ml/min).
Blood assays.
Blood samples for measurement of blood
6-keto-PGF1 were collected in
prechilled polypropylene test tubes containing 4.5 mM EDTA and a
prostaglandin-synthesis inhibitor, meprobamate. The plasma fraction was
separated from whole blood and immediately stored at 70°C
until assayed. Measurements of blood
6-keto-PGF1 were made by using
commercially available radioimmunoassay kits (New England Nuclear,
Boston, MA) as previously described (39). In brief, the prostaglandins
were first extracted from the plasma fraction by acidifying to a pH of
3.0 with 2 M citric acid. A known amount of radiolabeled standard was
added to each sample to assess recovery. Extraction, concentration, and
partial purification of prostaglandins were carried out by using Bond
Elut C18 columns (Analyt Chem
International, Harbor City, CA). Further purification was carried out
by using Bond Elut S-1 columns (Analyt Chem International). Elution
with a solvent mixture (benzene-ethyl acetate-methanol) of increasing
polarity was used to separate prostaglandins from other more or less
polar substances. The extract was dried under nitrogen gas and
reconstituted to the desired volume with an assay buffer. Recoveries
ranged from 75 to 95%. If the recovery was <65%, samples were
extracted. Results were corrected for recovery and were expressed in
picograms per milliliter. The coefficient of variation for
PGF1 was <5%. The
sensitivity of the system was ~2.5 pg/assay tube for
PGF1.
Statistical analysis.
Values are presented as means ± SE. During exercise, variables were
compared at the highest identical peak exercise time achieved by both
tests. Submaximal exercise variables were also determined and were
defined as variables at 50% of the peak exercise. Statistical analysis
was performed by using analysis of variance and the paired t-test (SPSS for Windows, version 6, SPSS, Chicago, IL). A P < 0.05 was considered as statistically significant.
RESULTS
O2 levels of 24.9 ± 4.2 ml · min1 · kg1.
The effect of indomethacin on leg blood flow,
O2, and prostaglandin release
is summarized in Table 1. There was no
significant effect of indomethacin on peak exercise
O2 or any leg hemodynamic or metabolic parameter.
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concentration than did the normal subjects (134 ± 11 vs. 70 ± 7 pg/ml) (P < 0.001), although leg
PGF1 release was similar.
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concentration and leg
PGF1 release, although femoral
venous PGF1 concentration was
still significantly higher than in normal subjects. Resting supine
cardiac output, mean arterial pressure, and systemic vascular
resistance were not altered by indomethacin. However, pulmonary
arterial pressure and pulmonary capillary wedge pressure were
significantly higher after indomethacin. Supine leg blood flow, leg
O2, and femoral
venous lactate were not altered by indomethacin.
Patients with heart failure: Exercise measurements.
During control exercise, patients exercised for 10.9 ± 1.8 min and
were limited by progressive dyspnea and fatigue, at reduced maximum
O2 levels of 11.5 ± 1.1 ml · min1 · kg1,
the normal maximum O2 being
>20-25
ml · min1 · kg1.
Exercise was associated with an impaired cardiac output response to
exercise and markedly elevated intracardiac pressures (Figs. 1 and 2).
In all patients, treadmill exercise increased leg blood flow (Fig. 3). Leg vascular resistance decreased from 192.9 ± 22.7 to 14.5 ± 2.8 U (P < 0.001). There was also a graded increase in leg release of PGF1
(Fig. 4). At peak exercise,
leg O2 was 165 ± 16 ml/min, similar to levels noted after load
1 in the normal subjects (189 ± 44 ml/min,
P = not significant vs. patients with
heart failure). When the normal subjects and patients with heart
failure were compared at these similar work levels, patients with heart
failure exhibited significantly higher femoral venous PGF1 concentration (142 ± 12 vs. 67 ± 6 pg/ml) and significantly higher leg
PGF1 release (267 ± 36 vs.
97 ± 14 pg/min) (both P < 0.01).
O2,
O2 consumption.
* P < 0.05;
** P < 0.01, indomethacin vs.
control.
In the patients with heart failure, treatment with indomethacin markedly suppressed leg PGF1
throughout the entire period of exercise (Fig. 4). In seven of eight
patients, indomethacin blunted the increase in leg blood flow with
exercise (Fig. 3, P < 0.05). The
exercise-induced decrease in leg vascular resistance was blunted to
24.3 ± 4.6 U (P < 0.01). This
was accompanied by a decrease in leg
O2
(P < 0.05) (Fig. 3). The increase in
femoral venous lactate during exercise was also higher after
indomethacin (P < 0.01) (Fig. 3).
Indomethacin had no effect on the cardiac output response to exercise
(Fig. 1). Mean arterial pressure and systemic vascular resistance
tended to be higher after indomethacin, although this effect did not
reach statistical significance. The increase in right atrial and
pulmonary pressures during exercise was also not altered by
indomethacin treatment (Fig. 2). Total exercise duration was unchanged
(10.9 ± 1.8 vs. 10.9 ± 1.9 min, control vs. indomethacin) as
was the symptomatology, according to the Borg Scale (results not
shown). In this acute study, indomethacin administration did not alter
either the maximal systemic
O2 (from 11.6 ± 3.3 to
11.7 ± 1.6 ml · min1 · kg1,
control vs. indomethacin) or the systemic arteriovenous
O2 difference at peak exercise
(from 14.6 ± 0.9 to 15.1 ± 0.7 mg/dl, control vs.
indomethacin).
DISCUSSION
The vascular endothelium is the most prominent source of prostaglandin formation in the circulation (3, 7), and it has been suggested that vasodilatory prostaglandins, such as PGE2 and PGI2, collectively may play an important role in circulatory homeostasis (10). Experimental studies have demonstrated that these vasodilatory prostaglandins are released by the kidney and the coronary circulation during hypoperfusion of these vascular beds (14, 27). The stimuli for the local production of these prostaglandins include tissue ischemia as well as the direct influence of vasoactive substances such as angiotensin II, norepinephrine, and vasopressin (25, 30, 45). In addition to its vasodilatory effects, PGE2 also increases sodium excretion and attenuates the activation of vasopressin on renal tubular permeability to water (23, 44). PGE2 and PGI2 also influence renal renin release (6). Thus it has been suggested that in vasoconstrictive states such as heart failure, these prostaglandins, together with atrial natriuretic factor, dopamine, and kinins, serve as counterregulatory mechanisms to the potent vasoconstrictor sodium-retentive hormones such as renin-angiotensin and sympathetic nervous system and vasopressin (11).
Previous studies on prostaglandins in patients with heart failure. There have only been a few studies that have investigated the role of prostaglandins in patients with heart failure. Two general approaches have been employed. First, plasma levels of prostaglandins and their metabolites have been measured. Dzau and coworkers (12) have reported that plasma levels of PGF1 and
of PGM, an immunoreactive metabolite of
PGE2, were 3-10 times higher
in patients with heart failure than in normal subjects. The stimuli for
the increased prostaglandin synthesis and release in patients with
heart failure are not known, but the relationship observed between
circulating levels of prostaglandin metabolites and the
vasoconstrictive hormones in these studies suggests a stimulatory
effect of these vasoactive substances on prostaglandin synthesis.
The second approach used to study prostaglandins in heart failure has
been the administration of cyclooxygenase inhibitors, agents that
inhibit the synthesis of prostaglandins. Because the kidneys are known
to release PGE2 in a
low-cardiac-output state (26), most early studies have focused on the
renal effects of cyclooxygenase inhibitor. These studies demonstrated
deterioration in renal hemodynamics, with reported cases of acute renal
insufficiency (34). The more systemic effects of nonsteroidal
anti-inflammatory drugs in heart failure were studied by Dzau and
colleagues (12), who found that when indomethacin was administered to
hyponatremic patients with elevated vasodilatory and vasoconstrictive
hormones, there was a significant increase in pulmonary wedge pressure, mean arterial pressure, and systemic vascular resistance. In contrast, in normonatremic patients with normal concentrations of catecholamines, plasma renin activity, and prostaglandin metabolites showed no significant hemodynamic changes after administration of indomethacin. The authors concluded that both vasoconstrictors and vasodilatory prostaglandins are operative to an increased extent in patients with
heart failure complicated by hyponatremia and that nonsteroidal anti-inflammatory drugs may induce hemodynamic deterioration in this
setting.
Effect of indomethacin at rest.
In the present study, all of the patients were optimally diuresed, and
none of the patients had evidence of fluid retention or serum sodium
levels <135 mmol/l. Nevertheless, femoral venous levels of
PGF1 were about twice the
levels found in the normal subjects. Cardiac outputs were significantly
decreased, whereas pulmonary wedge pressures increased.
In patients with heart failure at rest, indomethacin reduced femoral
venous PGF1 levels by ~25%,
although PGF1
concentrations still remained higher than in the normal subjects. No
significant change in resting mean arterial pressure or systemic
vascular resistance was noted. However, pulmonary wedge pressure
pressures increased substantially, indicating that indomethacin can
adversely affect central hemodynamic parameters even in patients with
normal sodium levels.
Prostaglandins and peripheral arteriolar vasodilatation during
exercise.
Over the last two decades, observations both in humans and in
experimental animals suggest that exercise induces the release of
prostaglandins from skeletal muscle, which may contribute to the
vasodilation of skeletal vascular bed during exercise (17, 19, 37, 39).
To date, all the observations made in humans have been in normal
subjects. The role played by the release of these vasodilatory
prostaglandins in patients with heart failure is not
known. To the best of our knowledge, this is the first study to examine
the role of vasodilatory prostaglandins during exercise in patients
with heart failure.
To investigate the contribution of prostaglandin release to vascular
regulation, leg resistance and blood flow were used as indexes of
skeletal muscle resistance and flow, respectively; flow to nonmuscular
tissue makes up only a small portion of leg blood flow during exercise
(29). Systemic and leg O2 and
femoral venous lactate were used as indexes of the adequacy of
O2 delivery to working muscle (2,
33). To evaluate changes during exercise, variables were compared at
identical work times. Exercise level influences muscle blood flow and
metabolism. Therefore, comparison of data at different work times would
leave uncertain whether any change observed is due to indomethacin or
differences in workload.
During control exercise, femoral venous
PGF1 concentrations and leg
PGF1 were significantly higher
in the patients with heart failure than in the normal control subjects,
suggesting increased prostaglandin release from skeletal muscle. In
addition, all patients developed metabolic changes, suggesting impaired blood flow to working muscle. Specifically, patients were limited by
fatigue at reduced maximum
O2. The leg
O2 and femoral
venous lactate accumulated at maximum exercise were markedly increased above levels observed in normal subjects at comparable workloads (28).
The limb vascular resistance noted at maximal exercise was also higher
than levels observed by us in patients with normal exercise capacity,
suggesting reduced limb vasodilation (35).
Indomethacin markedly attenuated leg
PGF1 release in the patients
with heart failure. This effect was associated with a decrease in leg
blood flow and leg O2 and an
increase in femoral venous lactate concentrations at peak exercise,
suggesting decreased skeletal muscle
O2 delivery and increased muscle
glycolysis.
Interestingly, peak O2 and
exercise duration remained unchanged despite the reduction in peak leg
O2. It is
conceivable that the O2 of
other tissues increased. For example, respiratory muscle
O2 could have increased.
Alternatively, the reduction in peak leg
O2 may have been spurious
because of the imprecision of leg flow measurements or the fact that
leg O2 extraction was not directly
measured.
It should be emphasized that the failure of peak
O2 to decrease acutely does
not predict the chronic effects of prostaglandin blockade. It is a
widely recognized phenomenon that the acute changes observed in blood
flow studies of this nature do not necessarily translate immediately to
changes in exercise duration. One example of this phenomenon is with
angiotensin-converting enzyme inhibitors. Such agents do not have an
acute effect on exercise duration but, when administered chronically,
are associated with improved exercise capacity (9). Clearly, further
studies are required to examine the more chronic effects of
indomethacin on exercise hemodynamics in heart failure.
Indomethacin had no significant effect on leg blood flow or
O2 in the normal subjects. In
a previous study, we noted that administration of indomethacin into the
brachial artery of normal subjects decreased forearm blood flow at rest
and during exercise (39). Therefore, the dose of indomethacin utilized
in the present study may have been insufficient to block prostaglandin
production. Alternatively, the degree of skeletal muscle prostaglandin
activation during control exercise may have been so small that
indomethacin had little measurable effect, a conclusion supported by
the low femoral venous levels of
PGF1 noted throughout exercise
in the normal subjects. In any event, the greater impact of
indomethacin in the patients with heart failure further suggests
increased vascular modulation by prostaglandins in heart failure.
Study limitations.
This study has a number of limitations. First, the use of skeletal
muscle glycolysis as a marker of blood flow to working muscle is
supported by prior observations that reducing muscle blood flow
augments glycolysis (2, 33). However, glycolysis also occurs normally
in well-oxygenated working muscle and is affected by pH and substrate
availability (4). We cannot totally exclude the possibility that
changes in these other variables may have affected our results. Second,
leg blood flow was determined by using volumetric flow measurements via
an indwelling thermodilution catheter. This technique does not provide
direct information about regional distribution of blood flow within
skeletal muscle. It is not able to distinguish flow to working muscles
from nonnutrient shunt flow. Nevertheless, the thermodilution method is
widely regarded as the optimal method for measuring volumetric blood flow to an exercising limb (21, 32). Finally, a cyclooxygenase inhibitor such as indomethacin will inhibit not only the synthesis of
vasodilatory prostaglandins but also vasoconstrictor prostaglandins such as thromboxane A2. One cannot
exclude the possibility that some of the effects noted in this study
resulted from changes in both vasoconstrictor and vasodilator
prostaglandins.
Conclusions.
The present study suggests that prostaglandin release plays an
important role in modulating exercise-induced vasodilation in patients
with heart failure. Interventions that enhance prostaglandin release
therefore may be beneficial in patients with heart failure. Conversely,
administration of agents that impair prostaglandin release to patients
with heart failure may have adverse affects on exercise performance.
Nonsteroidal agents have already been shown to adversely affect renal
function, ventricular performance, and hemodynamic function in heart
failure (12, 23, 33). Clinicians should avoid such agents in patients
with heart failure whenever possible.
ACKNOWLEDGEMENTS
This study was supported in part by RO-1 Grant HL-53059 from the National Institutes of Health and a Grant-in-Aid from the National American Heart Association. C. C. Lang is a recipient of a Merck International Fellowship in Clinical Pharmacology Award.
FOOTNOTES
Address for reprint requests: J. R. Wilson, Div. of Cardiology, 315 Medical Research Bldg. II, Vanderbilt Univ. Medical Center, Nashville, TN 37232-6300.
Received 20 March 1997; accepted in final form 4 August 1997.
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