Download Influence of Indomethacin on the Systemic and

Clinical Science and Molecular Medicine, (1978)54,141-145
Influence of indomethacin on the systemic and pulmonary
vascular resistance in man
A. WENNMALM
Department of Clinical Physiology, Karolinska Institute at the Serafimer Hospital, Stockholm, Sweden
(Received 25 February 1977; accepted 2 August 1977)
Summary
Introduction
1. Indomethacin, an inhibitor of the cyclooxygenase system that converts arachidonic acid
into prostaglandins and related substances, was
infused intravenously in 12 healthy volunteer
subjects.
2. Systemic systolic and diastolic blood pres­
sures and heart rate were recorded in all subjects,
and in most of them also the systemic arteriovenous oxygen difference, the total oxygen uptake
and the pulmonary arterial and wedge pressures.
3. The infusion of indomethacin was followed
by a decreased cardiac output (from 7-3 ± 0-3 to
6·3 ± 0-3 litres/min) and an increased mean
systemic blood pressure (from 92 + 1 to 102 + 1
mmHg), indicating an elevation of the total
systemic vascular resistance (from 98 ± 4 to 124 ±
5 kPa l _l s) by indomethacin. The ventilation and
the pulmonary vascular resistance did not change
after the infusion of indomethacin.
4. The results suggest that products formed by
the cyclo-oxygenase system at rest exert a relaxing
effect in certain parts of the systemic vascular bed,
thereby lowering the systemic vascular resistance.
Prostaglandins are vasoactive in many species
(Karim, 1972). In man, infusion of prostaglandin
E, has been reported to increase heart rate and
stroke volume, and decrease both arteriovenous 0 2
difference and peripheral resistance (Carlson,
Ekelund & Orö, 1969,1970). In rabbits, infusion of
the prostaglandin E2 precursor, arachidonic acid,
causes hypotension, provided that the endogenous
synthesis of prostaglandins is not inhibited
(Änggärd & Larsson, 1973). Prostaglandins have
frequently been proposed to play a role in the
regulation of blood pressure (Lee, 1976), in both
normotensive and hypertensive subjects. This
hypothesis has been supported by the observation
that acute administration of indomethacin, an
inhibitor of the cyclo-oxygenase that converts
arachidonic acid into prostaglandins and
prostaglandin-related substances (endoperoxides,
thromboxane, prostacyclin) (Vane, 1971), leads to
hypertension (Lonigro et al., 1973; Lee, 1976).
Such hypertension implies that the peripheral
vascular tone is subject to a continuous relaxing
influence from endogenous vasodilating prostaglan­
dins or prostaglandin-related substances. In this
study we present data to support the role for these
endogenous vasodilating substances in the
regulation of the systemic vascular resistance in
man.
Key words: cardiac output, heart rate, stroke
volume, right atrial blood pressure, oxygen
uptake, prostaglandin synthesis inhibition,
pulmonary blood pressure, pulmonary wedge
pressure, systemic blood pressure.
Correspondence: Or Ake Wennmalm, Department of
Clinical Physiology, Huddinge Hospital, S-141 86 Huddinge,
Sweden.
Methods
The study was performed with the permission of
the Ethical Committee at the Karolinska Institute.
Healthy male volunteer subjects, aged 23-51 years
141
142
Ä. Wennmalm
and weighing 65-89 kg, participated. They were all
informed of the nature, possible risks and purpose
of the investigation before giving their voluntary
consent to participate. A Swan-Ganz catheter (no.
5 or no. 7) was inserted percutaneously into a
medial cubital vein and passed under fluoroscopic
control to the pulmonary artery. A short Teflon
catheter was introduced into a brachial artery.
Pressure recording was performed via a pressure
transducer
(Elema,
EMT
35)
on
a
photokymograph (Abem Ultralette). The midthoracic height was used as zero-pressure level.
Expired air was collected in Douglas bags and
analysed by the Scholander microtechnique. Blood
samples from the brachial artery and pulmonary
artery were drawn for determination of oxygen
content (Holmgren & Pernow, 1959). Pressure
recordings were performed with the catheter in the
pulmonary wedge position, in the pulmonary and
brachial artery, and in the right atrium. The cardiac
output was determined by the Fick principle. All
pressures, as well as cardiac output, were deter­
mined 0-10 min before and immediately after the
infusion of indomethacin. In two subjects, blood
pressure and cardiac output was also measured 20,
50 and 80 min after the end of the drug infusion.
Indomethacin (Merck, Sharp and Dohme), 70
μπιοΐ (25 mg), was dissolved in 5 ml of ethanol and
diluted to 2-3 mmol/1 with phosphate buffer (0-1
mmol/1), pH 7-5, and infused at a rate of 4-7-6-4
μπιοΐ (1-7-2-3 mg)/min via the Swan-Ganz
catheter, to a total dose of 0-91 ± 0-02 μιηοΐ (0-32
± 0-01 mg)/kg body weight. Systemic blood
pressure was recorded continuously during the
infusion. In some experiments, solvent only (5 ml
of ethanol in 25 ml of phosphate buffer, 0-1
mmol/1) was infused.
Values are given as mean ± SE. Standard
statistical methods were employed, with the paired
r-test.
Results
Before the infusion of indomethacin the circulation
was normokinetic in all subjects and the systemic
and pulmonary systolic and diastolic blood pres­
sures were well within the normal limits.
Within 2-3 min after the start of the infusion of
indomethacin at a rate of 4-7-6-4 /<mol (1-7-2-3
mg)/min, the systemic systolic and diastolic blood
pressures increased, reaching a maximal value
within 10 min. After the end of the infusion of
indomethacin the blood pressure slowly returned
towards the basal value, but the diastolic pressure
remained raised by about 8% in the two subjects in
whom the arterial blood pressure was followed 80
min after the infusion had been stopped. Im­
mediately after the end of the indomethacin
infusion, the mean systemic blood pressure was
102 ± 1 mmHg, significantly higher (P < 0-001)
than before the infusion (92 ± 1 mmHg) (Fig. 1).
The increase in blood pressure after indomethacin
was due to a rise in both systolic (from 123 ± 2 to
129 ± 3 mmHg) and diastolic (from 72 ± 1 to 82
± 2 mmHg) blood pressure (Fig. 1).
The cardiac output fell significantly (P < 0-01),
from 7-3 + 0-3 before to 6-3 ± 0-3 litres/min
immediately after, the infusion of indomethacin.
The fall was due to a reduction in heart rate, from
67 ± 3 to 59 ± 2 beats/min (Fig. 2). The systemic
vascular resistance, estimated from the mean
arterial — right atrial blood pressure difference and
the cardiac output, increased significantly {P <
0-01) after indomethacin, from 98 ± 4 before to
124 + 5 kPa l - 1 s immediately after the infusion
(Fig. 1). In the two subjects in whom the postinfusion period of haemodynamic measurements
was prolonged the vascular resistance 80 min after
the infusion of drug was still elevated by 9%
compared with before the infusion.
The pulmonary systolic, diastolic and wedge
pressures were not significantly affected by the
infusion of indomethacin (Fig. 1 and Fig. 2). The
pulmonary vascular resistance, estimated from the
mean pulmonary arterial — wedge pressure dif­
ference and the cardiac output, changed in­
significantly after the infusion (Fig. 1). The mean
oxygen uptake of the subjects was 330 ml/min
before indomethacin, exceeding their estimated
basal oxygen consumption by 28% (range 2-50%),
but this was unaffected by indomethacin. The
respiratory frequency (13-4 ± 0-7/min before and
14-8 ± 1-3/min after the drug infusion), the tidal
volume (0-70 + 0-08 litre before and 0-67 ± 0-04
litre after the drug infusion) and the arterial oxygen
saturation (97-9 ± 0-4% before and 97-9 ± 0-3%
after the drug infusion) were also unchanged. No
side-effects of the drug were observed. In the
control experiments, where solvent was infused
alone, the mean systemic blood pressure was 92 ±
2 mmHg before and 93 ± 3 mmHg after the
infusion, and the cardiac output was 7-3 ± 0-5
litres/min before and 7-2 ± 0-7 litres/min after the
infusion. There was thus no evidence that the
solvent possessed any circulatory effects.
Indomethacin and vascular tone
143
Systemic circulation
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FIG. 1. Blood pressure and vascular resistance in the systemic and pulmonary circulation in man before (B) and after
(A) infusion of 70 μτηοΐ (25 mg) of indomethacin. The smaller symbols indicate the individual observations, and the
larger symbols indicate mean values ± SE of these observations. Significance of differences from the corresponding
figure before indomethacin (Student's f-test): *P < 0-05; **P < 0-01; **·/» < 0-001.
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FIG. 2. Haemodynamic variables and oxygen uptake in man before (B) and after (A) infusion of 70 /raiol (25 mg) of
indomethacin. For explanation of symbols see Fig. 1. a-v: Arteriovenous difference.
144
Ä. Wennmalm
Discussion
Infusion of indomethacin, but not of solvent,
caused a rise in systemic blood pressure which
started after infusion of 10-20//mol (3-6-7-2 mg),
and was fully developed after infusion of about 50
μτηοΐ. This rise was in parallel with a fall in cardiac
output, indicating that the underlying mechanism
was an increase in the systemic vascular resistance.
The
ventilation
and
the
pulmonary
haemodynamics were not affected significantly.
This seems to contrast with recent findings in dogs,
where indomethacin was reported to increase the
pulmonary vascular resistance (Kadowitz, Chapnick, Joiner & Hyman, 1975). However, that study
used a technique which cannot be applied in
humans and the possibility that discrete changes in
pulmonary resistance occurred also in the present
investigation cannot be ruled out.
The observed effect of indomethacin in raising
the peripheral vascular resistance may arise
centrally or peripherally. Although the possibility
of a central action cannot be excluded, there is an
attractive hypothesis for a peripheral effect. In­
domethacin is an inhibitor of the cyclo-oxygenase
that converts arachidonic acid into prostaglandins
and prostaglandin-related substances like endoperoxides, thromboxane and prostacyclin (Vane,
1971), of which some are potent vasodilators. If
production of vasodilating prostaglandins or
related substances occurs normally in the walls of
the systemic resistance vessels the observed effect
of indomethacin may have arisen from withdrawal
of these vasodilating substances. There is good
reason to assume that the cyclo-oxygenase system
really was inhibited: in humans indomethacin in an
oral dose of 140 μταόΐ (50 mg) x4 depresses the
urinary excretion of the main prostaglandin E
metabolite by 77-98% (Hamberg, 1972). Further­
more, intravenous administration of indomethacin
results in about twice the plasma concentration
obtained when the same dose is given orally
(Duggan, Hogans, Kwan & McMahon, 1972), and
consequently the 70 μτηοΐ (25 mg) that we gave
intravenously should have been adequate for
inhibition of synthesis. In addition, indomethacin
has recently been shown to inhibit synthesis of
prostaglandin in man at a plasma drug con­
centration of 0-28 μτηοΐ/ΐ (0-1 ^g/ml) (Rane et al.y
1977). Assuming a volume of distribution for
indomethacin of 50 litres in our subjects, a drug
concentration of 0-28 μταο\/\ would be reached
after 2-3 min of infusion. Thus, if the rise in
systemic blood pressure after indomethacin was
due to cyclo-oxygenase inhibition, this would
account for the rapid onset of the effect. However,
we cannot exclude the possibility that the observed
effect of indomethacin was to some extent indepen­
dent of inhibition of synthesis of prostaglandin and
related substances. Such a non-specific effect by
this drug on vasoconstrictor responses has been
proposed earlier (Janczewska & HerbaczynskaCedro, 1974; Manku & Horrobin, 1976).
We did not perform regional flow measurements
and so cannot identify the vascular bed or beds
affected by indomethacin. It has recently been
shown that the blood flow in the resting skeletal
muscle in humans is unaffected by indomethacin
(Kilbom & Wennmalm, 1976), suggesting that
muscular vasoconstrictioi^s not responsible for the
observed increase in res^rance. The renal blood
flow has been reported to fall upon the infusion of
indomethacin in dogs (Lonigro, Itskovitz,
Crowshaw & McGiff, 1973). Such an effect might
also account for our findings, but an isolated fall in
renal blood flow cannot by itself explain the
observed fall in cardiac output of about 1 litre/min.
An increased resistance elicited by the drug in other
regions too, e.g. the splanchnic vascular bed, may
also have contributed.
Our studies show that the cyclo-oxygenase
inhibitor indomethacin increases the systemic
vascular resistance in man. This observation may
indicate a resistance-regulatory role for endogenously formed prostaglandins or related
substances in the systemic vascular bed.
Acknowledgments
This investigation was supported by the Swedish
Medical Research Council, project 04X-4341.
Indomethacin was kindly put at our disposal by the
Merck, Sharp and Dohme Company.
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Indomethacin and vascular tone
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