Circulation. 1998;98:1431-1437
(Circulation. 1998;98:1431-1437.)
© 1998 American Heart Association, Inc.
Effect of Platelet Activation on Coronary Collateral Blood Flow
James W. Kinn, MD;
; Robert J. Bache, MD
From the Division of Cardiology, Department of Internal Medicine,
University of Minnesota Medical School, Minneapolis, Minn.
Correspondence to Robert J. Bache, MD, Division of Cardiology, Department of Internal Medicine, University of Minnesota Medical School, Box 508 UMHC, 420 Delaware St SE, Minneapolis, MN 55455. E-mail bache001{at}maroon.tc.umn.edu
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Abstract
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Background—The platelet
products thromboxane A2 and
serotonin have been shown to cause constriction of
well-developed coronary collateral vessels. This study was
performed to determine whether intravascular platelet activation
produced with platelet activating factor (PAF) can cause a decrease
in coronary collateral blood flow.
Methods and Results—Collateral vessel growth was induced by
embolization of a hollow stainless steel plug into the left anterior
descending coronary artery (LAD) of adult dogs. The animals
were returned to the laboratory 3 to 6 weeks later for surgical
instrumentation and measurement of collateral blood flow. Collateral
flow was assessed by measuring retrograde blood flow from the
cannulated collateral-dependent artery. PAF (10 nmol) was injected into
the left main coronary artery to allow products of
platelet activation to reach collateral vessels arising from the
left coronary system. PAF caused a vasoconstrictor response,
which became maximal 3 minutes after injection and resulted in a
40.3±7.4% decrease in retrograde blood flow (32.1±2.1 to 19.6±3.2
mL/min; P<0.05). By 15 minutes after the PAF injection,
both retrograde blood flow and transcollateral resistance had returned
to normal. After pretreatment with the thromboxane
A2 receptor antagonist SQ30,741, the
vasoconstrictor response to PAF was abolished and, in contrast to the
decrease in retrograde blood flow from PAF alone, a weak vasodilator
effect was unmasked.
Conclusions—PAF caused a decrease in coronary collateral
blood flow. This vasoconstrictor response required the participation of
thromboxane A2.
Key Words: blood flow • collateral circulation • platelets • thromboxane
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Introduction
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In response to arterial occlusion,
native intercoronary collateral anastomoses undergo remarkable
growth and development to provide an alternate blood supply to the
dependent myocardium. During this process, the thin walled,
veinlike intercoronary anastomoses are transformed into vessels
which appear similar to small arteries. However, these collateral
vessels demonstrate histological abnormalities
including perivascular inflammation, endothelial
proliferation, and adherence of monocytes, neutrophils, and
platelets to the
endothelium.1 2 Each of these
adherent cell types is capable of producing the biologically active
phospholipid, platelet activating factor
(PAF).3 4 To what extent or by what stimulus
these cells produce PAF is unclear, but spontaneous platelet
activation can occur in narrowed coronary arteries, and this is
associated with PAF accumulation at the site of
endothelial injury.5
Well-developed canine coronary collateral vessels have
been shown to undergo vasoconstriction in response to the
thromboxane A2 analogue
U46619.6 Because thromboxane
A2 is liberated during platelet
degranulation,7 it is possible that activation of
platelets within or upstream from collateral vessels could cause
collateral vasoconstriction and decrease blood flow to the dependent
myocardium. PAF has the potential to activate
platelets adherent to the collateral vessels and to induce
aggregation of circulating platelets.8 No
studies of the effect of PAF on coronary collateral vessels are
currently available. Infusion of PAF into the normal coronary
circulation typically yields a biphasic response, with initial
vasodilation followed by vasoconstriction.9 10 11
Houston et al12 observed that exposure of
isolated coronary artery rings to aggregating platelets
resulted in relaxation, but after removal of the
endothelium, exposure to aggregating platelets
caused contraction. Inhibition of thromboxane
A2 production using a
thromboxane synthase blocker (dazoxiben) or a
thromboxane A2 receptor
antagonist (SQ29,548) attenuated contraction of the denuded
coronary artery rings in response to aggregating
platelets.12 These results indicate that
thromboxane A2 is an important
mediator of platelet-induced coronary artery constriction,
whereas an intact endothelium is necessary for the
relaxation of coronary artery segments in response to
platelet aggregation. The purpose of this study was to determine
the effects of intravascular platelet activation on
coronary collateral blood flow by measuring the response to PAF
in an in vivo canine model. This study also examined the importance of
thromboxane A2 in this response using
the receptor antagonist SQ30,741. This agent was used
because previous studies have demonstrated that SQ30,741 is a potent
antagonist of thromboxane
A2 mediated vasoconstriction that does not alter
the response to serotonin.13 14
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Methods
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All studies were conducted in accordance with the "Position of
the American Heart Association on Research Animal Use" and were
approved by the Animal Care Committee of the University of
Minnesota.
Induction of Collaterals
Collateral vessel development in adult mongrel dogs was induced
by catheter embolization of the left anterior descending
coronary artery (LAD) with a hollow plug as previously
described.6 Animals were anesthetized
with sodium pentobarbital (25 to 30 mg/kg IV), intubated, and
ventilated with a respirator. Under sterile conditions, an 8F Judkins
right coronary catheter was introduced into the right carotid
artery and advanced into the left coronary ostium. A 0.014-in
guidewire was passed through the catheter into the distal LAD.
Nitroglycerin (100 µg IC) was given and the
coronary artery diameter was assessed with a subsequent
contrast injection. The coronary catheter was then removed
while the guidewire position was carefully maintained. An appropriately
sized (2.3 to 3.0 mm OD, 1.1 mm
ID, 4.0 mm length) hollow stainless steel plug was
pushed along the guidewire with a length of flanged PE90 tubing and
wedged in the proximal or mid- portion of the LAD. Placement and
patency of the plug was confirmed with a second contrast injection. The
catheter and sheath were removed and the incision repaired. In pilot
studies, the intra-arterial plugs have been found to
undergo thrombotic occlusion within 48 to 72 hours.
Surgical Preparation
The animals were returned to the laboratory 3 to 6 weeks after
coronary embolization. They were premedicated with morphine
sulfate (1 mg/kg SC), anesthetized with 
-chloralose (100
mg/kg IV followed by 10 mg/kg per hour), intubated, and ventilated with
a respirator. Supplemental oxygen was given to maintain
arterial PO2 in the
physiological range. Two 6F NIH catheters were
introduced into the femoral arteries and positioned in the ascending
aorta for blood sampling and pressure monitoring. A similar catheter
was introduced into the left carotid artery and advanced into the left
ventricle. A left thoracotomy was performed in the fifth intercostal
space. The heart was suspended in a pericardial cradle, and a PVC
catheter (3.0 mm OD) was introduced into the left
atrium through the appendage. The occluding plug was located by
palpation of the LAD, and 1.5 cm of the artery was dissected free
proximally. The dog was heparinized (5000 U IV), the artery occluded
proximally, and a longitudinal arteriotomy performed between the plug
and the ligation. The plug was removed and the artery allowed to bleed
retrogradely to remove any residual thrombus. The occluding plug was
carefully inspected, and in each case the lumen was found to be totally
occluded by white thrombus. The artery was then cannulated with a
thin-wall stainless steel cannula (4.0 mm OD). Pressure at the
cannula tip was measured with a 23-gauge tube incorporated into
the wall of the cannula. A PE50 catheter was introduced into the
proximal LAD and advanced in a retrograde direction until the tip could
be palpated in the left main coronary artery to allow
intracoronary infusions. Aortic, left ventricular,
and coronary cannula pressures were measured with Statham P23ID
pressure transducers. Left ventricular pressure was
recorded at normal and high gain for measurement of
end-diastolic pressure. An electronic differentiator was
used to obtain left ventricular dP/dt. Data were
recorded on an 8-channel direct writing recorder.
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Drugs
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PAF was purchased from Sigma Chemical Co. PAF was stored at
-20°C in chloroform solution. After evaporation, the PAF was
suspended in a 0.2% solution of BSA in normal saline. SQ30,741 was
obtained from Squibb Pharmaceutical Co, stored at -20°C in 100%
ethanol, and diluted in normal saline.
Experimental Protocols
Two groups of animals were studied. Group 1 consisted of 5
animals used to determine the collateral flow response to platelet
activation produced by PAF. Group 2 consisted of 7 animals used to
determine the role of thromboxane A2
in the collateral response to PAF.
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Group 1: Effects of PAF on Collateral Vasomotor Tone
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Animals were allowed to stabilize for 20 to 30 minutes after
completion of the surgical preparation. Collateral flow was then
assessed by collecting retrograde blood from the coronary
cannula into a graduated cylinder over 20 seconds while the tip of the
cannula was maintained at the level of the heart. Collections were
repeated until stable values were achieved. After completion of
baseline measurements, the PAF vehicle (3 mL of 0.2% BSA in normal
saline) was injected into the left main coronary artery over 5
seconds. Retrograde blood flow was measured at 1, 3, 5, 10, and 15
minutes after vehicle administration. Next, PAF was injected into the
left main coronary artery in increasing doses of 0.1, 1.0, and
10 nmol. These doses were chosen because similar doses have produced
vasoactive effects in other coronary
segments.9 10 11 An intracoronary route of
drug administration was used to minimize systemic effects of PAF.
Hemodynamic responses to each dose were recorded
over a 15-minute interval. Baseline measurements of retrograde blood
flow were made 1 minute before injection, and then at 1, 3, 5, 10, and
15 minutes after each PAF injection. In each case,
hemodynamic and retrograde flow measurements had
returned to control values before the subsequent dose of PAF was
administered.
Group 2: Contribution of Thromboxane A2 to the
Collateral Response to PAF
Because PAF was observed to cause a decrease in collateral blood
flow in Group 1, animals in Group 2 were used to determine the role of
thromboxane A2 in this response.
Collateral blood flow was assessed by measuring retrograde flow as
previously described. The responses of collateral blood flow to vehicle
and then to high-dose PAF (10 nmol injected over 5 seconds) were each
assessed over a 15-minute interval by measuring retrograde flow 1
minute before and 1, 3, 5, 10, and 15 minutes after
intracoronary injection. Next, the selective
thromboxane A2 receptor
antagonist SQ30,741 (100 µg/kg) was infused into the left
main coronary artery over 30
minutes.10 15 Retrograde blood flow was measured
during the initial 15 minutes after beginning the SQ30,741 infusion
using the same time points described above. After 15 minutes of
SQ30,741 infusion, PAF (10 nmol) was again injected into the left main
coronary artery and the response to PAF was measured over the
final 15 minutes of the SQ30,741 infusion. The effects of SQ30,741 were
then allowed to subside over a period of 1 hour. After this recovery
period, a third dose of 10 nmol of PAF was injected into the left main
coronary artery to confirm that the vasoconstrictor response
was still intact.
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Data Analysis
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Heart rate, aortic and left ventricular pressures,
and left ventricular dP/dt were measured from the strip
chart recordings. Hemodynamic data were
analyzed using ANOVA for repeated measures. A value of
P<0.05 was required for statistical significance. If
significant, data were further compared using the Wilcoxon
signed rank test.
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Results
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Group 1: Effects of PAF
In all animals, the coronary artery was found to be
totally occluded. Hemodynamic data and retrograde blood
flow measurements were obtained at baseline and 1, 3, 5, 10, and 15
minutes after the start of each intervention. The peak response
generally occurred at 3 minutes after PAF administration and subsided
by the end of the 15-minute observation period. Measurements obtained 1
minute before and 3 minutes after the start of each intervention are
reported in Table 1
. At baseline,
mean aortic blood pressure was 79±5.0 mm Hg, whereas pressure
measured in the LAD with the cannula closed was 62±5.1 mm Hg.
The transcollateral pressure gradient, calculated as the difference
between mean aortic pressure and mean LAD coronary pressure
while the coronary cannula was closed, was 15.8±2.6
mm Hg. When the cannula was opened, baseline retrograde blood flow was
30.4±1.8 mL/min and transcollateral resistance was 2.65±0.29
mm Hg · mL-1 ·
min-1. PAF vehicle injected into the left main
coronary artery produced no significant change in systemic
hemodynamics (Table 1). Three minutes after injection
of vehicle there was an 8.1±2.3% increase in retrograde blood flow
(30.4±1.8 versus 32.8±1.7 mL/min; P<0.05), as seen Fiure
1.
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Table 1. Hemodynamic Data From 5 Dogs in Group 1 During
Control Conditions and 3 Minutes After Administration of
PAF
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The smallest dose of PAF (10-10 mol)
administered into the left main coronary artery produced no
significant systemic hemodynamic effects (Table 1
) but
prevented the increase in collateral flow produced by vehicle alone
(Figure 1). Injection of PAF at a dose of 10-9
mol tended to decrease mean aortic pressure and distal coronary
pressure with the cannula closed, but the transcollateral pressure
gradient was not significantly altered (17.5±3.4 versus 18.2±2.9
mm Hg; P=NS). Heart rate tended to increase with this dose
of PAF, but this was not statistically significant. Retrograde blood
flow tended to decrease with this dose of PAF, but this did not achieve
statistical significance (Figure 1). After injection of the highest
dose of PAF (10-8 mol), inflation of the aortic
occluder was generally required to maintain proximal aortic pressure.
Peak systemic hemodynamic changes and coronary
collateral flow effects occurred approximately 3 minutes after
administration of PAF and returned to control values before the end of
the 15-minute observation period. This dose of PAF decreased mean
aortic pressure and tended to increase heart rate (Table 1). Distal LAD
coronary pressure with the cannula closed also decreased
(55±6.6 versus 43±3.4 mm Hg; P<0.05), and the
transcollateral pressure gradient tended to increase, although this was
not statistically significant (21.0±5.8 versus 26.0±6.3 mm Hg).
Three minutes after high-dose PAF injection, retrograde flow was
decreased 40.2±7.4% (32.1±2.7 versus 19.6±3.2 mL/min;
P<0.05). This corresponded to a 70.1±25.0% increase in
transcollateral resistance (2.48±0.24 versus 4.40±0.92
mm Hg · mL-1 ·
min-1; P<0.05). By the end of the
15-minute time interval, retrograde flows had returned to baseline.
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Figure 1. Retrograde blood flow from the cannulated
collateral-dependent LAD in response to PAF in doses of 0.1, 1.0, and
10 nmol, as well as vehicle control in 5 animals in group 1.
*P<0.05 vs baseline.  P<0.05 vs
vehicle control at the same time point.
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Group 2: Effects of SQ30,741 on the Collateral Response to
PAF
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After the vasoconstrictor response to PAF
(10-8 mol intracoronary) had been
established (Figure 2), the contribution
of thromboxane A2 was evaluated with
the thromboxane A2 receptor
antagonist SQ30,741. Infusion of SQ30,741 into the left
main coronary artery produced no systemic
hemodynamic effects (Table 2) and no change in retrograde blood flow
in comparison with baseline measurements (32.8±5.0 mL/min at baseline
versus 34.5±3.2 mL/min at 3 minutes; P=NS), or in
comparison to matched vehicle time points (32.8±1.7 versus 34.5±3.2
mL/min at 3 minutes; P=NS). Similarly, there were no
significant changes in transcollateral resistance.
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Figure 2. Response of retrograde blood flow from the
cannulated collateral dependent LAD to PAF (10-8mol IC)
during baseline conditions and during thromboxane
A2 receptor blockage produced by infusion of SQ30,741 in 7
animals in group 2. *P<0.05 vs vehicle.
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During the final 15 minutes of the SQ30,741 infusion, PAF
(10-8 mol) was again injected into the left main
coronary artery. In comparison to the previous injection, the
tendency toward decreased aortic pressure was attenuated (Table 2). As
shown in Figure 2, SQ30,741 abolished the collateral vasoconstrictor
effect of PAF so that 3 minutes after PAF injection retrograde flow was
37.0±3.0 mL/min as compared with 19.6±3.2 mL/min 3 minutes after PAF
injection before SQ30,741 (P<0.05). At this time, the
transcollateral resistance was 2.11±0.21 mm Hg ·
mL-1 · min-1 as
compared to 4.40±0.92 mm Hg ·
mL-1 · min-1 with
PAF alone (P<0.05). Furthermore, SQ30,741 unmasked a weak
collateral vasodilator response; analysis of variance testing
demonstrated increased retrograde flow when PAF was administered during
SQ30,741 infusion (P<0.05). However, this response was
small so that no significant difference was found between vehicle and
PAF after SQ30,741 for any of the individual time points. In comparison
with vehicle control measurements, transcollateral resistance was
significantly decreased relative to the corresponding 3-minute
vehicle value (2.11±0.21 versus 2.51±0.26
mm Hg · mL-1 · min-1;
P<0.05). Figure 2 demonstrates that the vasodilator effect
of PAF unmasked by SQ30,741 was somewhat delayed, occurring 3 to 5
minutes after injection of PAF, whereas the vasoconstrictor effect of
PAF occurred predominantly 1 to 3 minutes after PAF injection.
After the effects of SQ30,741 had subsided, PAF was again injected to
insure that the vasoconstrictor effects of PAF were not attenuated by
repeated injection. This final injection of PAF resulted in decreases
in retrograde blood flow (27.7±1.4 versus 18.0±2.0 mL/min;
P<0.05) and increases in transcollateral resistance
(2.89±.30 versus 4.17±0.44 mm Hg ·
mL-1 · min-1;
P<0.05). As shown in Figure 3, the minimum retrograde blood flow
(19.6±3.2 versus 18.0±2.0 mL/min; P=NS) and peak
transcollateral resistance (4.40±0.92 versus 4.17±0.44
mm Hg · mL-1 · min-1;
P=NS) in response to PAF were similar before and 1 hour
after SQ30,741 infusion, respectively.
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Figure 3. Comparison of the effects of the first (#1) and
final (#3) doses of PAF on retrograde blood flow from the cannulated
collateral-dependent LAD for 7 dogs in group 2. *P<0.05
vs vehicle control.
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Discussion
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This study demonstrates that PAF can produce a marked decrease in
coronary collateral blood flow. This response was dependent on
the activity of thromboxane because thromboxane
A2 receptor blockade with SQ30,741 abolished the
PAF-induced decrease in collateral blood flow.
Methodological Considerations
In the present study, collateral flow was estimated by opening
the cannulated collateral-dependent coronary artery to
atmospheric pressure to allow measurement of retrograde blood flow. The
retrograde flow technique underestimates total collateral flow because
opening the coronary cannula does not completely abolish blood
flow into the collateral-dependent myocardium. Retrograde
flow is derived principally from epicardial collateral vessels, likely
with a small contribution from microvascular
collaterals.16 Microvascular collaterals enter
recipient vessels distal to a site of significant resistance so that
blood flowing through these channels tends not to be diverted in a
retrograde direction when the cannula is
opened.16 Changes in retrograde flow reflect
principally vasomotor activity of the epicardial collateral vessels and
the donor arteries. Collateral flow can also be influenced by changes
in vasomotor tone of microvascular collaterals as well as by the
resistance vessels in both the normal and collateral-dependent regions.
These latter effects were not assessed in the present study.
However, effects of PAF on microvascular collateral blood flow would
likely have a relatively small effect on total collateral flow;
we have previously observed, using this experimental model,
that continuing flow into the collateral-dependent region
represents only approximately 25% of total collateral flow,
whereas retrograde flow accounts for approximately 75% of total
collateral flow.17 PAF was infused into the left
main coronary artery. Although this excludes collateral
contributions from the right coronary artery, it allows
pharmacologic manipulation of collaterals arising from the left
circumflex, proximal LAD and septal arteries, which are the major
source of collaterals to the LAD in the dog.18
Studies were performed 3 to 6 weeks after coronary occlusion at
a time when collateral vessels are not fully developed. However,
prominent responses to both vasoconstrictor and vasodilator agonists
(including endothelium-dependent vasodilators) are
present in developing collateral vessels studied as early as 2
weeks after coronary occlusion.19
Nevertheless, it is possible that the responses observed in the
present study could change with further collateral maturation.
Another limitation of this study is related to the systemic effects of
PAF. PAF has powerful hemodynamic effects, the most
notable being systemic hypotension.9 10 11 For this
reason, PAF was administered by the intracoronary route to
allow use of relatively small doses to minimize systemic effects.
Nevertheless, there was a trend toward a decrease in aortic blood
pressure that was statistically significant during the highest dose of
PAF. To account for the decrease in collateral driving pressure,
collateral resistance was calculated. This calculation demonstrated a
substantial vasoconstrictor response to PAF with a 70±25% increase in
collateral resistance in response to the highest dose of PAF. The
decrease in arterial pressure following PAF was associated
with a trend toward an increase in heart rate, suggesting reflex
sympathetic activation. Sympathetic activation would not be expected to
cause collateral constriction, however, because both in vitro studies
of isolated collateral vessels and in vivo studies of well-developed
collateral vessels have failed to demonstrate vasoconstriction in
response to -adrenergic agonists.20
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Effects of PAF
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PAF is a potent stimulus for platelet
aggregation.7 Aggregating platelets release
multiple vasoactive substances, including thromboxane
A2, serotonin, ADP, and
histamine.8 12 Houston et
al12 demonstrated that aggregating platelets
caused relaxation of preconstricted coronary artery rings. This
was an endothelium-dependent response, because
aggregating platelets resulted in vasoconstriction of denuded
coronary artery rings that could be blocked with selective
antagonists of thromboxane
A2 and serotonin. Both
thromboxane A2 and
serotonin have been demonstrated to exert vasoconstrictor
activity on canine coronary collateral vessels in
vivo.6 Our observation of collateral
vasoconstriction in response to PAF is consistent with these
previous findings. In contrast to the present results, Leong et
al21 demonstrated that the PAF receptor
antagonist WEB 2086 did not improve collateral flow or
limit myocardial infarct size in a dog model of acute coronary
occlusion. PAF acts on a variety of receptor subtypes, whereas
WEB 2086 antagonizes only a subset of these
receptors,22 so the negative results could have
been due in part to incomplete receptor blockade. More likely, however,
failure of WEB 2086 to alter collateral flow during acute myocardial
infarction was the result of the limited vasomotor capacity of the
rudimentary native collateral vasculature present at the time of
acute coronary occlusion.
In contrast to the strictly vasoconstrictor response of the collateral
system to PAF in the present study, other investigators have
observed a biphasic response to PAF in the normal coronary
circulation with transient initial vasodilation followed by
vasoconstriction.9 10 11 In the normal heart, the
initial coronary vasodilation generally lasts 15 to 30 seconds
and consequently might not have been detected in the present study,
in which the first flow measurement was made 1 minute after the PAF
injection. Alternatively, the lack of vasodilation could reflect
absence of receptors to platelet derived substances such as ADP or
serotonin on the collateral vessel
endothelium. Shimokawa et al23
demonstrated that 4 weeks after balloon denudation of normal
coronary arteries, vessel segments containing newly regenerated
endothelium have an impaired vasodilator response to
aggregating platelets. It is possible that newly developed
endothelium in immature collaterals might have a
similarly impaired vasodilator response to platelet
aggregation.
Direct effects of PAF on collateral vasomotor tone could have
contributed to the modest increase in retrograde flow observed after
thromboxane A2 blockade in this
study. Shimokawa et al23 reported that PAF caused
endothelium-dependent relaxation in isolated porcine
coronary arteries at concentrations several orders of magnitude
higher (IC50 10-4.5 mol)
than used in the present study. Hu and Man22
reported a weak biphasic response after PAF injection in an isolated
rat heart preparation perfused with Krebs-Henseleit buffer.
Consequently, it is possible that PAF exerted a direct vasodilator
effect on the collateral vasculature in the present study. Although
a weak PAF-induced collateral vasodilation cannot be excluded, it did
not play an important role in our study because vasoconstriction was
the predominant response. Furthermore, vasoconstriction was completely
abolished by the specific thromboxane receptor
antagonist SQ30,741. Similarly, Loots and
DeClerck24 demonstrated that platelet
aggregation induced by collagen fibrils caused vasoconstriction in a
cat hindlimb collateral model, suggesting that it was aggregation of
platelets that led to constriction of the collateral
vasculature.
Role of Thromboxane A2 in the Collateral
Response to PAF
Thromboxane A2 has previously been
demonstrated to cause vasoconstriction in both normal coronary
vasculature25 and in moderately well-developed
coronary collateral vessels.6 SQ30,741
completely abolished the vasoconstrictor response to PAF in the
present study, suggesting that thromboxane
A2 was the predominant agent responsible for
coronary collateral vasoconstriction. In accordance with our
observations, Forsterman et al25 found that when
isolated coronary artery rings were exposed to aggregating
platelets, thromboxane A2
liberated from platelets was the predominant vasoconstrictor. In
contrast to our findings, Loots and DeClerck24
found that in a cat hindlimb collateral vessel preparation,
serotonin had a greater role in collateral vasoconstriction
than thromboxane A2. This difference
may be due to differences in species or vascular bed. A possible role
for serotonin in the collateral vasoconstrictor response to
PAF was not examined in the present study. Although
thromboxane A2 appears to be the
predominant vasoconstrictor, it is possible that any vasoconstrictor
effect of serotonin was not powerful enough to override the
PAF-induced vasodilator activity which was unmasked during SQ30,741
infusion. Further studies are necessary to determine a potential
contribution of serotonin to this response.
Thromboxane A2 receptor blockade
with SQ30,741 unmasked a weak vasodilator response.
Intracoronary infusion of SQ30,741 did not alter baseline
retrograde flow, indicating that the vasodilation from the combination
of SQ30,741 and PAF was not due to the effects of SQ30,741 alone. The
modest increase in collateral flow could have resulted from
vasodilators released by aggregating platelets including
ADP,11 histamine,26 and
prostacyclin or other prostanoids.27 PAF-induced
endothelium-dependent vasodilation could also have
contributed to the vasodilation from PAF during SQ30,741
infusion.28 A direct vasodilator effect on
coronary arterial vessels has been demonstrated at
PAF concentrations several orders of magnitude higher than those
achieved in the present study.23 27 Although
statistically significant, the magnitude of PAF-induced collateral
vasodilation during thromboxane A2
receptor blockade was small.
It can be argued that SQ30,741 might have decreased PAF-induced
platelet aggregation, thereby attenuating the release of vasoactive
platelet derived compounds. However, previous investigators have
reported that PAF can induce platelet aggregation independent of
thromboxane
A2.29 The mechanisms by
which PAF induces platelet aggregation likely include more than 1
pathway. Independent contributions of both the
cyclooxygenase and lipoxygenase
pathways have been demonstrated in PAF-induced platelet
aggregation.29 30 In addition, PAF appears to
exert effects via a "third pathway."13 29 30 31
Furthermore, although it is unknown whether SQ30,741 directly affects
PAF-induced platelet aggregation, the thromboxane
A2 receptor antagonist SQ29,548 does
not inhibit platelet aggregation in response to ADP in
vitro.12 In addition, Aprill et
al15 found that pretreatment with the
thromboxane synthase inhibitor UK38,485
abolished the increase of measured thromboxane
B2 generated in response to PAF but did not alter
PAF-induced platelet aggregation. Therefore, it is unlikely that
blockade of PAF-induced collateral constriction by SQ30,741 in the
present study resulted from inhibition of PAF-induced platelet
aggregation.
In designing this study, there was concern that tachyphylaxis might
develop during repeated injections of PAF. Thus, PAF-induced bronchial
smooth muscle contraction has been found to be attenuated after
multiple doses.32 To determine whether the
collateral vessel response to PAF remained stable, we injected a final
dose of PAF after the effects of SQ30,741 had subsided; the response of
collateral flow was not different from the initial injection. Likewise,
the absolute magnitude of the response of collateral flow was not
altered with serial doses of PAF. Therefore, in this experimental
model, serial doses of 10 nmol of PAF produced a reproducible response
in the collateral vessels. However, only 3 doses of PAF were used, each
separated by 45 to 60 minutes; it is possible that tachyphylaxis would
occur with a larger number of doses.
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Clinical Implications
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Ischemia is associated with rapid accumulation of
myocardial lysophospholipids.33 34 Lyso-PAF, the
precursor of PAF, can increase by as much as 50% within 20 minutes of
myocardial ischemia.35 Developing
collateral vessels may have even greater potential to produce PAF
because the monocytes, neutrophils, and platelets adherent to the
collateral endothelial surfaces are capable of
producing PAF.1 2 These findings suggest that
collateral dependent myocardial regions could be vulnerable to
vasoconstriction produced by PAF. Willerson and
associates15 36 37 38 have demonstrated that
cyclic flow variations resulting from platelet aggregation at the
site of a coronary artery stenosis are associated with
accumulation of PAF in the damaged vessel5 and
production of thromboxane A2
and serotonin in concentrations that are sufficient to
cause vasoconstriction. Increased thromboxane
A2 production has been demonstrated in
patients with myocardial ischemia.39
Platelet aggregation in diseased donor arteries from which
collateral vessels arise would have potential to decrease blood flow to
the dependent myocardial region. In addition, ischemia can
cause release of other mediators of vasoconstriction such as
neuropeptide Y40 or
endothelin41 which could contribute to impaired
perfusion of collateral-dependent myocardium.
|
Acknowledgments
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We wish to acknowledge the assistance of Melanie Crampton and
Todd Pavek for outstanding technical contributions to the care and
surgical preparation of the animals used in this study. This study was
supported by US Public Health Service grants HL-20598 and HL-58067 from
the National Heart, Lung, and Blood Institute. James Kinn was supported
by an Individual National Research Service Award (HL-08826).
Received February 9, 1998;
revision received April 16, 1998;
accepted April 20, 1998.
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Top
Abstract
Introduction