Download The effect of cyclooxygenase inhibition on vasomotion

LABORATORY INVESTIGATION
VASOSPASM
The effect of cyclooxygenase inhibition on vasomotion
of proximal coronary arteries with endothelial
damage
GARY E. LANE, M.D.,
AND
ALFRED A. BOVE, M. D., PH. D.
ABSTRACT Vasomotion of the proximal branches of the left coronary artery was studied in an intact
anesthetized canine preparation after injury to the endothelium of the left anterior descending branch of
the left coronary artery (LAD) with a balloon angioplasty catheter. The dimensions of the left coronary
artery were examined by quantitative angiography and LAD flow was measured by determining
intracoronary 133Xe washout. Thirty minutes after endothelial damage alone dimensions of the LAD
remained unchanged. In five dogs continued observation for a total of 120 min revealed no significant
change in dimensions of the LAD. In another group of five dogs, after the administration of 5 mg/kg
indomethacin there was a progressive reduction in cross-sectional area of the LAD by 60. 90, and 105
min (37%, 42%, and 50%, respectively, p < .05). No significant change in the dimensions of the
undamaged left circumflex artery was noted after the administration of indomethacin. The effect of
another cyclooxygenase inhibitor (4 mg/kg meclofenamate) on endothelial damage to the LAD in an
additional four dogs was also examined. Again significant reduction of the cross-sectional area of the
LAD was seen at 60 and 120 min (40% and 44%, respectively, p < .05). Heart rate and blood pressure
were unchanged throughout the experiment in control and indomethacin-treated dogs. Mean blood
pressure rose slightly after administration of meclofenamate (from 80 + 5 to 98 + 7 at 120 min, p <
.05). These data indicate that the combination of endothelial injury and cyclooxygenase inhibition with
indomethacin or meclofenamate results in proximal coronary artery vasoconstriction. This phenomenon may have important implications regarding the complications of coronary angioplasty and in focal
spasm of diseased coronary arteries.
Circulation 72, No. 2, 389-396, 1985.
THE ENDOTHELIUM has been demonstrated in vitro
to have an important role in mediating relaxation of
vascular smooth muscle.' Recently, we used an intact
canine preparation to demonstrate an enhanced response to vasoconstrictor agents of proximal coronary
arteries with endothelial damage,2 but factors influencing these phenomena have not been specifically defined. The products of arachidonic acid metabolism
may play a role in modulating the vasomotor response,
considering the potent effects that such metabolites
have been shown to exert on the coronary circulation.,
Isolated coronary arteries have been demonstrated
to contract in response to disruption of arachidonic
acid metabolism by cyclooxygenase inhibition.4 In
From the Cardiovascular Division. Mayo Clinic, Rocheter, MN.
Supported in part by a grant from the PepsiCo Foundation.
Dr. Lane is a postdoctoral fellow supported by NIH trainine grant
NO. HL07111.
Address for correspondence: Alfred A. Bove. M.D., Ph.D., Cardiovascular Division, Mayo Clinic, Rochester, MN 55905.
Received Oct. 4, 1984; revision accepted May 9. 1985.
addition, balloon catheter-induced damage of canine
carotid arteries resulted in a reduction in vasodilator
metabolites prostaglandin (PG) 1I and PGE2, while vasoconstrictor metabolites of the lipoxygenase pathway
were increased.8
The clinical importance of these concepts may be
reflected in the complications of balloon coronary angioplasty and the spontaneous vasomotion (spasm) of
atherosclerotic coronary arteries. In this study we hypothesized that endothelial damage in the setting of
cyclooxygenase blockade would result in significant
vasoconstriction of proximal coronary arteries.
Methods
Experimental preparation. Ten adult mongrel dogs were
anesthetized with Innovar-vet (0.2 ml/kg im) and ventilated
with 70% nitrous oxide in oxygen via a Harvard respirator
(model 807). This form of anesthesia produces minimal effects
on the coronary circulation.9 1)
A No. 6F Lehman catheter and a No. SF bipolar pacing
catheter were advanced under fluoroscopic monitoring through
branches of the right external jugular vein into the coronary
sinus for blood sampling and pacing. Blood samples for Po,,
Vol. 72. No. 2, August 1985
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389
LANE aniid BOVE
oxygen saturation, and hemoglobin were obtained throughout
the experimental period.
A coronary guide catheter was advanced under fluoroscopy
retrograde through the left carotid artery to the ascending aorta.
After engagement of the ostium of the left coronary artery, as
determined by test injections of radiopaque contrast medium
(meglumine diatrizoate [Renografin-761). a G20-20 or 20-25S
balloon dilatation catheter (USCI) was advanced into the proximal portion of the left anterior descending branch of the left
coronary artery (LAD). Statham P23DG prcssure transducers
were balanced and calibrated for monitoring pressure from the
coronary guide catheter, balloon dilatation catheter, and a cannula inserted in the left femoral artery. The pressures and dlectrocardiogram were monitored continuously and recorded during each stage of the experiment.
Data analysis. Coronary blood flow was determined by injection of 0.25 mCi of '-5AXe through a No. 4F infusion catheter
positioned subselectively in the proximal LAD. Radioisotope
washout was monitored with a single crystal detector positioned
over the left chest at the midventricular level. Count data were
processed by a PDP 1 1/34 computer (Digital Equipment Corp.)
and the first 60 sec of the washout curve was used to determine
the slope (K) by a monoexponential log-linear least squares
calculation. Coronary blood flow was calculated as
Flow (ml/min.g) = 0.72 K/1.05
where 0.72 = myocardium-blood partition coefficient: 1.(5
density of the myocardium.
Coronary vascular resistance (mm Hg ml gmin) was calculated from the ratio
Mean arterial pressure
LAD flow
coronary
artery were quantitated with a
left
the
of
Dimensions
computerized angiographic analysis system.` Angiographic
examination was performed by injection of 4 to 5 ml of meglumine diatrizoate through the guide catheter into the left main
coronary artery. Spot x-ray films were obtained at 85 kV for 35
msec during mid-diastole with an electrocardiographic trigger
system. Angiograms were acquired in a constant right anterior
oblique projection in each animal. The opacified luminal edges
of the coronary artery were manually traced and digitized with a
quantitative angiography programii in a PDP 11 134 conmputer
(Digital Equipment Corp.). The program calculated luminal
diameter and cross-sectional area at mm intervals along the
artery measured. A representative 5 mim section of each scanned
artery was used to evaluate the results. ihe method of analysis
has been previously tested and described.
Arteriovenous oxygen differences (ml dl) were calculated by
takine the difference between arterial and coronary sinus blood
oxygen content. Oxygen content was calculated as (hemroglobin
g/l00 ml) x 1.35 ml O g x oxygen saturation.
Experimental procedure. After positioning of the catheters.
the baseline heart rate, blood pressure. and coronary blood flow
were measured and recorded. Subsequently, an angiogram of
the left coronarv artery was obtained. After the control measurements, balloon endotheli.ll damage was performed. The balloon
dilatation catheter was advanced under fluoroscopic and pressure monitoring to the midportion of the LAD. The balloon was
then inflated with a 50% contrast solution under low pressure.
While inflated the catheter was withdrawn to the proximal portion of the artery. This procedure was repeated tour to five
times, during which the lluoroscopic image was recorded on
videotape to localizc the region of ballloon endothelial dama(ee.
This nmethod has previously been shown to reliably induce endothelial damage as identified by scanning electron microscopy.~
Microscopic evalucation of arteries damniaged in these experi-
ments revealed findings similar to those of our previous studies.
A 2.0 mm balloon was selected for use in arteries with luminal
diameters of between 2.0 and 3.0 mm to avoid a myogenic
response or possible media] damage.
After endothelial injury, a 30-min period was allowed to
eliminate any transient responses. At the end of ths 30 minperiod, the heart rate, pressures, LAD coronary blood flow, and
angiographic dimensions were obtained. All animals in the experimental groups sustained endothelial damage as described.
In the control group (n = 5), after the stabilization period, serial
recording of pressures. heart rate, and coronary dimensions
were obtained every 15 min for 90 min. Coronary blood flow
measurements were taken at 30 min intervals. In one treated
group (n = 5) 5 mg/kg is indomethacin was administered and
pressure, coronary blood flow, and coronary angiographic measurements were recorded as described. In the other treated group
(n = 4). 4 mg/kg iv meclofenamate was administered and the
same measurements were obtained.
Statistical analysis. Results are reported as mean + SEM.
Data were analyzed with Student's t test for paired variables and
by two-way analysis of variance.
Results
Hemodynamic parameters. The arterial pressure and
heart rate did not change significantly throughout the
study in the control animals (table 1). The indomethacin-treated animals demonstrated a slight, but nonsignificant, increase in arterial pressure and heart rate
after the administration of indomethacin (table 2). In
the meclofenamate-treated animals there was a significant increase in arterial pressure from the 30 min measurement until the end of the experiment, and heart rate
was unchanged (table 3).
Coronary blood flow and resistance. In the control animals (endothelial damage only) there was a significant
decrease in coronary blood flow ( 21% at 90 min,
p < .05). However, the calculated coronary vascular
resistance revealed only a slight, statistically nonsignificant, increase (table 1).
In the indomethacin-treated animals there was a decrease in coronary blood flow and an increase in coronary vascular resistance to values that were not significantly different from initial control values (table 2).
A small but significant rise in coronary blood flow
was seen after the endothelial damage procedure was
performed in the meclofenamate group (+ 34% after
endothelial damage, p < .05). The coronary vascular
resistance decreased slightly at this point, and increased significantly (H+ 19%, p < .05) at 90 min after
the administration of meclofenamate.
Hemoglobin levels were 9.3 + 1.6 g!dl in the control group, 10.6 ± 1.4 g/dl in the indomethacin group,
and 11. 1 + 3 g/dl in the meclofenamate group. There
were no significant changes in myocardial arteriovenous oxygen difference throughout the experimental
period in either group of animals. Arterial oxygen saturation was 95% to 96% throughout the experiment.
CIRCULATION
390
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LABORATORY INVESTIGATION-VASOSPASM
TABLE 1
Hemodynamic parameters in control animals with endothelial damage only
Heart
rate
(bpm)
Control
15 min
30 min
45 min
60 min
75 min
90 min
105 min
120 min
78±7
73+7
77±6
74+7
77+6
76 5
Mean
arterial
pressure
(mm Hg)
LAD
coronary
blood flow
(ml/min.g)
LAD
coronary
vascular
resistance
(mm Hgml/g-min)
Myocardial
arteriovenous
oxygen
difference
(ml 0,/dl)
82+5
82+7
82+4
1.66+0.09
50+5
5.98+0.70
1.40+0.08
59+4
6.37+0.84
1.66+0.26
57+ 11
5.84+0.62
1.31 0.08A
62+5
6.59+0.80
1.38 0.07A
58+4
5.69+0.57
82+5
80+5
84 7
81 +6
82+ 7
83+7
75+7
76 + 7
77±7
Data are mean + SEM.
Ap < .05
vs control.
Dimensions of the left coronary artery. Figure 1 illustrates a typical coronary angiogram of the dog left
coronary artery after endothelial injury and indometha-
cin. The midportion of the LAD is narrowed compared
with control.
In dogs from the control group (endothelial damage
only) the portion of the LAD that sustained endothelial damage did not change significantly in diameter
or cross-sectional area for 120 min after the injury
(figure 2).
In the dogs in the indomethacin-treated group, there
were no significant changes in diameter of cross-sec-
of the undamaged left circumflex coronary
or after drug. In addition, after
endothelial damage of the LAD no change in luminal
dimensions occurred for 30 min. However, the administration of indomethacin produced a significant reduction in the luminal diameter of the LAD at 60, 90, and
105 min (21%, p < .02; 25%, p < .01; and 30%,
p < .01, respectively) vs initial baseline diameter (figure 3). Cross-sectional area was concurrently reduced
at 60, 90, and 105 min (37%, p < .02; 42%, p < .02;
and 50%, p < .02, respectively) vs initial baseline area
(figure 4).
tional
area
artery either before
TABLE 2
Hemodynamic parameters in animals with endothelial damage receiving indomethacin
LAD
coronary
vascular
resistance
Myocardial
arteriovenous
rate
Mean
arterial
pressure
LAD
coronary
blood flow
(bpm)
(mm Hg)
(ml/min.g)
Control
Endothelial damage
73+8
86+8
2.12+0.59
48+8
6.07+0.28
15 min
30 min
Indomethacin
15 min
30 min
45 min
60 min
75 min
90 min
105 min
65+5
73+8
85+5
85+7
1.81+0.18
49+5
7.15+0.40
1.90+0.17
48+5
7.0+0.52
1.63+0.2
55+4
6.99+0.57
1.69+0.24
59+8
7.5+0.60
Heart
70+5
70+4
70+6
74+6
78+6
78+7
76+6
(mm
Hg/ml/gmin)
oxygen
difference
(ml 0A/dl)
87+6
90+5
94+4
89+5
94+3
91+3
96+4
Data are mean + SEM.
Vol. 72, No. 2, August 1985
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391
LANE and BOVE
TABLE 3
Hemodynamic parameters in animals with endothelial damage receiving meclofenamate
Control
Endothelial damage
30 min
Meclofenamate
15min
30 min
60 min
90 min
120 min
NTG
Heart
rate
(bpm)
Mean
arterial
pressure
(mm Hg)
LAD
coronary
blood flow
(ml/minng)
LAD
coronary
vascular
resistance
(mm Hg/mlUgmin)
Myocardial
arteriovenous
oxygen
difference
(ml O dl)
72 I5
80+5
2.03 0.43
48 14
6.76+0.49
80 14
916
2.73 0.47A
35 5
6.86 0.64
72+13
71 +0
71+8
74+ 11
71 10
72 9
94+3
92 3A
94+5A
96+5A
98 +7A
2.09 0.56
2.07 0.46
2.27 0.47
51+11
5lill
47+9
57+ 5A
55 17
7.35 0.26
7.12 0.33
7.44+0.69
7.14+0.30
7.90 0.51 A
7.76 0.39
2.04+0.50
2.18 0.49
96Q6A
Data are mean + SEM.
NTG = nitroglycerin.
Ap
<
.05.
Analysis of the dimensions of the LAD in the group
treated with meclofenamate (n = 4) also revealed a
significant reduction in diameter at 60, 90, and 120
min (21%, 18%, and 27%, respectively, all p < .05).
Cross-sectional area (figure 5) was concurrently reduced at 60 and 120 min (40% and 49%, respectively,
p < .05). After the administration of 200 gg of intracoronary nitroglycerin the dimensions of the LAD re-
turned to baseline in both the indomethacin and meclofenamate groups.
Discussion
We have demonstrated significant vasoconstriction
of endothelial-damaged proximal LADs in the setting
of cyclooxygenase inhibition. Indomethacin did not
affect the dimensions of the undamaged left circumflex
coronary artery, and control animals with endothelial
damage alone did not have significant constriction.
Significant vasoconstriction of damaged LADs was
also seen in a group of meclofenamate-treated dogs.
The similar effect of indomethacin and meclofenamate
4.0
-
E
E
3.0
-
a)
2.0 -
E
-D
1.0 -
4 60 5 9 1 120
15
30 45 60 75 90 105 120
C
minutes
ED
FIGURE 2. Diameter of mid portion of LAD measuLred by quiantitative
coronary angIography over a 1 20 min period after endothelial damage
(ED). Data expressed as imiean + SEM.
f1
FIGURE 1. Right anterior obliquLe left coironary angiogram fromi an
intact dog betore (top) and after co m bincd indlomiiiethacin a nd endothelial
injUly (bottom)i). There is a focally narrowed aiea in the niid portion of
the LAD (arrow).
392
1
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CIRCULATION
LABORATORY INVESTIGATION-VASOSPASM
3.6
6.0
-
-
3.4
I LCX
3.2 3.0
-
E
E 2.8 2.6 E 2.4 0t
5.0
l
CM
I
I LAD
i0
(u
I
4.0 -
a)
CO
2.2 -
3.0 -
2.0
1.8
E
E
*
-
*
C
15 30 15 30 45 60 75 90 105 NTG
IND
minutes
ED
2.0
`
(5 mg/kg)
FIGURE 3. Diameter of mid portion of LAD and circumflex (LCX)
coronary arteries measured by quantitative angiography over 105 min
after endothelial damage (ED) to the LAD and intravenous indomethacin (IND). The LAD showed a progressive focal narrowing in the
endothelial-damaged segment. NTG = nitroglycerin. Data expressed
as mean ± SEM.
on the damaged LAD would support a shared mechanism of action such as cyclooxygenase inhibition.
The reduction in the dimensions of the damaged
coronary arteries in the group treated with indomethacin or meclofenamate could not be explained by a
10.0 -
9.0 8.0
7.0 CTC
E
E
0
CA
T LCX
-
6.0
-
5.0
-
I
I
I LAD
a)
4.0
-
3.0
-
C 30 1 5 30 60 90 1 20 NTG
ED MEC
minutes
(4mglkg)
FIGURE 5. Cross-sectional area of the LAD after endothelial damage
(ED) and meclofenamate (MEC). NTG = nitroglycerin. Data are expressed as mean + SEM.
decrease in myocardial metabolic demands,'3 since the
heart rate and blood pressure actually increased slightly during the experiment.
There was also no significant alteration of coronary
blood flow or coronary vascular resistance in the group
treated with indomethacin. A small but significant increase in coronary vascular resistance was noted 90
min after the administration of meclofenamate. These
measurements were made in dogs in the resting state
and no attempt was made to determine the coronary
flow reserve during the vasoconstriction. It is probable
that the degree of vasoconstriction seen in this experiment would result in a serious limitation to nutrient
flow through a coronary arterial lumen previously
compromised to a moderate degree by an atheroscle-
rotic stenosis.
,. rT
,1
.,
.
.
1
.
,
.
C 15 30 15 30 45 60 75
minutes
ED
IND
90 105
NTG
(5 mg/kg)
FIGURE 4. Cross-sectional area of LAD. and circumflex (LCX) coronary arteries after endothelial damage (ED) to the LAD and indomethanitroglycerin. Data expressed as mean + SEM.
cin (IND). NTG
=
Intravenous indomethacin has been shown to slightly decrease resting coronary blood flow4 14 and in some
experiments to diminish the reactive hyperemic response in open-chest or isolated heart canine preparations.5 However, in other anesthetized animal preparations a significant alteration of resting coronary
blood flow or coronary vascular resistance has not
been observed.'6'5 Indomethacin causes contraction of
isolated coronary artery strips in vitro.4 6 7 In addition,
isolated balloon-dilated canine carotid arterial segments exhibit an enhanced contractile response to norepinephrine after the addition of indomethacin.'6 The
Vol. 72, No. 2, August 1985
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393
LANE anid BOVE
principal action of indomethacin is to inhibit the enzyme cyclooxygenase.>' Another cyclooxygenase inhibitor. acetylsalicylic acid, has also been shown to
contract isolated coronary arterial preparations. 7 In
inan, Freidman et al].1 have demonstrated a substantial
fall in coronary blood flow ( 181 to 1 1 1 ml/min) and a
rise in coronary vascular resistance (+ 73%) in response to the administration of intravenous indomethacin (0.5 mg/kg) to patients with coronary artery disease. The exact mechanism underlying this response
has not been elucidated. In particular, it is unknown
whether this elevation of coronary resistance occurs
because of vasoconstriction within the distal resistance
vasculature or at the level of proximal conductance in
coronary arteries with significant stenoses.
Recently, extensive investigation in vitro has documnented the importance of the endothelium in the
regulation of vasomotion.' The responses (especially
relaxation) of vascular sinooth imuscle to many neurohumoral mediators are enclothelium-dependent. The
endothelium is susceptible to miany toxic or mechanical injury processes. For example. coronary transluimiinal balloon angioplasty causes a loss of endothelium
and platelet adhesion to the denuded arterial wall.`
Also, endothelial damage has beeni postulated to be an
imnportant feature in the evolution of an atherosclerotic
stenosi's.2- These examples illustrate how endothelialdamnaged vessels may potentilate abnormial vasoconstrictor responses of proximiial coroniary arteries.
Derivatives of airachidonic acid have been dlemonstrated to produce imnpressive effects on the coronary
circulation. Prostacyc lin plays an impor-tant role in
controlling platelet agLgregation on vascular endotheliUm]. In addition, it is a potent coronary vasodilator.
Infusion of thromboxane A, into coronary arteries will
result in vasoconstriction.` Recently. products of the
alternative pathway of arachidonic acid imetabolism
(via lipoxygenase) have also been deinonstrated to ex~
ert impressive etfects on the coronarv circulationi.'-7,
Leukotrienes C4. D4. and E, (originally described as
slow-reacting substance of analphylaxis or SRS-A )
have been shown to provoke potenit coronary vasoconstriction resulting in significant ischemiiia in several
animal preparations.?
Trauma induced by the angioplasty balloon catheter
does result in an alteration of arachidonic acid mcetabolism, which in turn results in a decrease in vasodilator
PGs stuch as prostacyclin and an increase in lipoxvgen
ase products.8 Coronary arteries that sustained endothelial damage alone in our experinlents did not miianifest vasoconstriction. Intervention into the imetabolic
pathwayi of arachidonic acid bv inhibition of the en
zyme cyclooxygenase with indomethacin did result in
significant vasoconstriction. Experimental evidence
has demonstrated enhanced release of anaphylatic
mediators (SRS-A) from lung. enhancemnent of antigen-induced tracheal contraction. and increased production of chemotatic factors in the presence of cyclooxygenase inhibitors. 4 These findings suggest that
inhibition of cyclooxygenase may result in preferential
metabolisimi of arachidonic acid via the lipoxygenase
pathway with the production of vasoconstrictor leukotrienes.-8 This shift in metabolism may accentuate the
production of lipoxygenase products as previously described in balloon catheter-traumatized canine carotid
arteries.' Alternatively, a reduction in the amount of
prostacyclin present in the arterial wall caused by a
combination of traumiiia and cyclooxygenase inhibition
could result in vasoconstriction. The precise alteration
in arachidonic acid imetabolismii responsible for the results cannot be specifiel with the available data.
A direct vasoconstrictor action of indomethacin on
endothel ial-damaged arteries could be postulated.
However, the temporal course of the vasoconstrictor
would suggest an action requiring tiimie foI alteration of
a biosynthetic pathway. Further experimentation
should allow foir a more accurate explanation of the
vasoconsitrictol response. Kalsner' has delmlonstrated
contriaction of coronary artery preparations in vitro by
aspirin and indomiiethaciln. Addition of one inhibitor
followedl by the other did not potentialte the vasoconstriction., suggesting a similar nmechanisml of action for
the two agents in these experimiients in vitro. In addition. vasoconstriction iniduced by meclofenamuate in
the present study would also sLupport the iiimportance of
cyclooxygenase inhibition in miiediating the vasoconstrictor response.
Methodologic considerations. The procedure of balloon catheter-incducd endothelial injury used in these
experiments has been previously shown to reliably result in extensive endothelial loss with platelet aggrecation.' The technique described was used after consideration of several factors, including the signif-icance
of endothelial damage in modulating vasomnotor responses. The importance of avoiding a myogenic
response. and possibly overdistending the artery resulting in paralysis of the imiuscular media was considered. .' Although possibly not completely analogous to
clinical coronary angioplasty, this preparation does reproduce the commnlon occurrence of endothelial injury.
In addition, it is unlikely that extensive medial damage
OCCLr.S often during clinical coronary angioplasty. in
view of the relatively commrnion occurrence of spasmi in
this setting.-"
394
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LABORATORY INVESTIGATION-VASOSPASM
Isolated artery preparations have been described to
undergo indomethacin-induced vasoconstriction even
when no procedures are performed to induce endothelial injury.)7 It is possible that inadvertent endothelial
injury occurred in these preparations or that the dose of
indomethacin responsible for the effects seen was not
analogous to the dose used in our experiments. Use of
acetylcholine as a spasmogen in some of these experimentS6' 37 would support the former possibility. Also,
interaction between blood and the vessel wall is not
allowed for in the experiments in vitro.
The doses of indomethacin and meclofenamate used
in our experiments were selected because they have
been shown to be effective in inducing cyclooxygenase
inhibition in the canine coronary circulation.4 It
should also be noted that neither indomethacin or meclofenamate prevented a proximal coronary artery vasodilator response to intracoronary nitroglycerin.
Clinical importance of findings. Percutaneous transluminal coronary angioplasty results in extensive endothelial damage.22 Coronary artery spasm occurs in 4%
to 5% of the coronary angioplasty procedures.8 One
third of these episodes of spasm are associated with
major complications such as myocardial infarction,
emergency coronary artery bypass surgery, or death.
There are data to suggest that coronary artery spasm
plays a major role in the development of acute occlusion after percutaneous coronary angioplasty.`9 Many
patients undergoing this procedure receive cyclooxygenase inhibitors for their antiplatelet effects. Our
work suggests that the interaction of endothelial injury
and cyclooxyenase inhibition may lead to a propensity
for vasoconstriction of the proximal coronary artery.
However, the dose of cyclooxygenase inhibitor used in
our study was equivalent to doses used for treatment of
inflammatory disorders and platelet-inhibitory doses
are generally lower.
As mentioned previously, the study of Freidman et
al.2' demonstrated a substantial elevation of coronary
vascular resistance by indomethacin in patients with
atherosclerotic coronary artery disease. The anatomic
site of this vasoconstrictor effect has not been localized. It is possible that the diseased proximal coronary
arteries of these patients provided a setting for the
vasoconstrictor action of indomethacin at the site of
atherosclerotic stenoses. This could explain the decrease in coronary blood flow noted in these patients.
In concluson, we have demonstrated an important
interaction of endothelial injury of normal coronary
arteries and cyclooxygenase inhibition that resulted in
a coronary vasoconstrictor response in an intact anesthesized canine preparation. Further study of this
phenomenon should allow for greater understanding of
the role of PGs and leukotrienes in the pathogenesis of
abnormal coronary vasomotion.
We thank Messers. J. Dewey, C. Grabau, and R. Owen for
technical assistance and Mrs. L. Schwieder for preparing the
manuscript.
References
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1980
5. Sakanashi M, Araki H. Furukawa T, Rokutanda M, Yonemua K: A
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CIRCULATION
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The effect of cyclooxygenase inhibition on vasomotion of proximal coronary arteries with
endothelial damage.
G E Lane and A A Bove
Circulation. 1985;72:389-396
doi: 10.1161/01.CIR.72.2.389
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