(Circulation. 1997;96:1647-1653.)
© 1997 American Heart Association, Inc.
Articles |
Human Platelet Ca2+ Mobilization, Glycoprotein IIb/IIIa Activation, and Experimental Coronary Thrombosis In Vivo in Dogs Are All Inhibited by the Inotropic Agent Amrinone
From the Department of Anesthesiology, Mayo Clinic, Rochester, Minn (J.C.S., B.B., I.B., C.U.); the Department of Anesthesiology, Medical College of Ohio, Toledo (M.N.); and the Cardiology Section, University of Wisconsin Medical School, Madison (J.F.)
Correspondence to J.C. Sill, MD, Department of Anesthesiology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905. E-mail sill.john{at}mayo.edu
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Abstract |
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Background Inotropic drugs are often used to treat acute, severe heart failure resulting from acute myocardial infarction and other unstable coronary artery syndromes. However, catecholamine inotropic agents may potentiate coronary thrombosis via a platelet
2-adrenergic mechanism, thus exacerbating the original
problem. The present studies were designed to determine whether the
nonadrenergic inotropic and vasodilator drug amrinone,
which elevates platelet cAMP levels, would both inhibit human
platelet Ca2+ mobilization and adhesion molecule
expression ex vivo and protect against experimental coronary
thrombosis in vivo in dogs. Methods and Results Human platelets in suspension were preincubated with amrinone 2.5 to 15 µg/mL; stimulated with the agonists thrombin 0.1 U/mL, ADP 10-6 mol/L, or arginine vasopressin 10-7 mol/L; and studied for Ca2+ mobilization, glycoprotein IIb/IIIa activation, and P-selectin expression by fluorescent flow cytometry methods. Experimental coronary thrombosis in vivo was studied in an open-chest dog model with critical coronary artery stenosis and deep vessel wall injury. Results showed that at the cellular level, amrinone inhibited agonist-induced Ca2+ mobilization and had modest inhibitory effects on adhesion molecule expression. In vivo in dogs, intravenous amrinone 2 mg/kg plus infusion at 20 µg·kg-1·min-1 completely abolished coronary thrombosis.
Conclusions The fact that amrinone inhibited human platelet activation at the cellular level and protected against experimental coronary thrombosis in vivo in dogs suggests a potentially advantageous antithrombotic action for this inotropic and vasodilator drug.
Key Words: inotropic agents • platelets • thrombosis
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Introduction |
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Acute myocardial infarction and other unstable coronary artery syndromes can cause acute cardiac failure, sometimes with a severity such that inotropic agents are indicated. For example, the GUSTO-1 investigators report that as many as a quarter of patients admitted to the hospital for acute myocardial infarction receive intravenous inotropic drugs at some time during their hospital course.1 A quandary arises when catecholamine agents are used in this setting, because those with
2-adrenergic activity may potentiate coronary
thrombosis via platelet 2-adrenergic receptor
mechanisms.2 3 4 5 6 In contrast to the
catecholamines, the inotropic and vasodilator agent
amrinone7 lacks 2-adrenergic activity.
Furthermore, amrinone is a phosphodiesterase III
inhibitor.8 9 Phosphodiesterase III
inhibitors increase cellular levels of the second messenger
3',5'-cAMP not only in cardiac myocytes but also in
platelets.10 11 12 13 14 15 16 Although cAMP serves to increase
contractility in cardiac myocytes, in platelets
cAMP opposes cellular activation and evokes platelet
quiescence.2 13 Previous studies concerning the
platelet effects of amrinone have largely been restricted to
platelet aggregation experiments using light transmittance
aggregometry methods.14 15 The purpose of the present
study was to determine whether amrinone would inhibit both human
platelet activation at the cellular level and experimental
coronary thrombosis in vivo in dogs. The first specific aim was to determine whether amrinone would inhibit agonist-induced Ca2+ mobilization in human platelets ex vivo. Within platelets, Ca2+ mobilization serves as an initial signaling step whereby external agonists such as thrombin and ADP activate platelets.2 17 Inhibition of the Ca2+ signal results in inhibition of platelet activation. The second aim, again at the cellular level, ex vivo, was to determine whether amrinone would inhibit agonist-induced adhesion molecule expression. Platelet adhesion molecules, when activated, provide the means whereby platelets become adhesive, a step essential to aggregation and thrombus formation.18 19 20 21 22 23 Two receptors, P-selectin and GP IIb/IIIa, were studied. P-selectin is released from platelet granules to the surface membrane during platelet activation, where it permits platelet binding to white blood cells and to the endothelium.23 GP IIb/IIIa is constitutively expressed on the platelet surface membrane and, when activated, serves as an anchoring site for soluble fibrinogen20 and von Willebrand factor.21 Pharmacological manipulation of this receptor has recognized relevance to the treatment of unstable coronary artery syndromes.18 19
The third specific aim was to test amrinone in vivo in a
well-characterized dog model in which critical coronary artery
stenosis plus intimal and medial damage generates
platelet-mediated periodic thrombosis followed by distal
embolizations.3 4 5 24 25 26 27 28 29 30 31 This model has been used to
examine the role of -adrenergic and serotonergic receptors, ADP and
platelet-activating factor agonists, prostacyclin, GP IIb/IIIa
receptor antagonists, tissue factor, and von
Willebrand GP Ib binding in in vivo thrombosis in several
species.3 4 5 24 25 26 27 28 29 30 31
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Methods |
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Preparation of Platelets for Ca2+ Studies
After approval from the Institutional Human Studies Review Board, 30-mL blood samples were obtained from healthy volunteers free of platelet-active drugs, and the blood was immediately anticoagulated with 1:7 vol/vol acid citrate dextrose. Samples were centrifuged (190g for 15 minutes), platelet-rich plasma was collected, EDTA 5 mmol/L was added, and the sample was centrifuged (900g for 10 minutes) to obtain a platelet pellet. The pellet was washed, repelleted, suspended in room-temperature Tyrode's buffer, and warmed to 37°C, and the platelets were loaded with the Ca2+-sensitive indicator indo 1, 10 µmol/L, for 30 minutes in the cell-permeant acetoxy-methyl ester form. Platelets were washed to remove excess indo 1 and resuspended in Tyrode's buffer with 0.4% BSA and 1.4 mmol/L CaCl2.
Estimation of Apparent Platelet
[Ca2+]i
Platelet suspension was incubated with and without 2.5 or 10
µg/mL amrinone for 10 minutes at 37°C. Samples (0.5 mL) were placed
in the reservoir chamber of a FACStar Plus flow cytometer (Becton
Dickinson), and platelets, 
800 per second, were propelled
through an argon ion laser beam tuned to the 351- to 364-nm band.
Fluorescent light emitted by each platelet was captured at
490 to 500 nm and 385 to 395 nm, emission wavelengths corresponding
approximately to the intensity maximal for Ca2+-free and
Ca2+-bound indo 1. Platelets were identified by light
scatter. Indo 1 signal ratios were collected from quiescent
platelets, a Ca2+-mobilizing agonist was added, and
indo 1 signals were monitored in the ensuing 3 minutes. Agonists
were thrombin 0.1 U/mL, ADP 10-6 mol/L, and
AVP 10-7 mol/L (approximately ED50
in this setting). Eight to 10 donors were studied for each agonist.
Indo 1 signal ratios were converted to approximate values for apparent
[Ca2+]i by standard
methods.32
Preparation of Whole Blood for Platelet Adhesion Receptor
Studies
After Human Studies Review Board approval, free-flowing venous
blood was collected from each of 12 healthy, medication-free
volunteers, the first 2 mL was discarded, and a 100-µL blood sample
was immediately ultradiluted 1:5000 vol/vol in room-temperature Hanks'
balanced salt solution (with HEPES 25 mmol/L, BSA 2%, and
CaCl2 1.4 mmol/L). Ultradilution permits avoidance of
anticoagulants, centrifugation, and washing steps and
protects against platelet-induced platelet activation and
against aggregate formation.
Fluorescent Immunostaining of Platelet
Adhesion Receptors
Samples (200 µL) of ultradilute whole blood suspension were
preincubated for 10 minutes at room temperature with 0, 5, or 15
µg/mL amrinone and activated with thrombin 0.1 U/mL or ADP
10-6 mol/L. Immunostaining for
activated GP IIb/IIIa was done with saturating concentrations
of PAC-1, a FITC-conjugated mouse anti-human IgM monoclonal antibody
directed against the fibrinogen binding site on activated GP
IIb/IIIa.33 34 PAC-1 does not bind to
inactivated GP IIb/IIIa on quiescent platelets. After
20 minutes, samples were fixed for 2 hours with 1 mL 1%
paraformaldehyde plus 0.1% azide in 0.9% saline,
washed, and resuspended in a solution of the same composition at 4°C.
Samples were stored in the dark and analyzed within 24 hours.
Immunostaining for P-selectin was done in a similar
manner with saturating concentrations of a PE-conjugated mouse
anti-human IgG monoclonal antibody with immunostaining
after 1% paraformaldehyde fixation. In all studies,
two color methods were used in which platelets labeled with PAC-1
were colabeled with a PE-conjugated monoclonal antibody against CD41,
this second marker serving solely as a platelet-identifying
label.33 34 Platelets labeled for P-selectin were
colabeled with a FITC-conjugated monoclonal antibody against
pan-platelet marker CD61.
Platelet GP IIb/IIIa (Activated) and P-Selectin Assay
by Flow Cytometry
A flow cytometer (FACScan, Becton Dickinson) was used to measure
immunostain fluorescence with excitation via argon
laser light at 488 nm, and emissions were collected at 530 nm for FITC
and at 585 nm for PE. Threshold and electronic gatings were set by use
of both light scatter and fluorescence from the
pan-platelet label. Positivity threshold was set by use of
fluorescence intensity from the pan-platelet label along
with appropriate isotype controls. Data (10 000 events per sample)
were displayed in dot plot format, dots representing
simultaneous signals from both the label of interest and
the pan-platelet marker. Results are expressed as percent of events
designated positive for the marker of interest.33 34
Preparation of Dogs for Experimental Coronary
Thrombosis Studies
The model has been described previously.35 After
approval by the Institutional Animal Care Committee, eight mongrel dogs
(25 to 35 kg) were anesthetized with sodium pentobarbital (35
mg/kg IV), intubated, and mechanically ventilated with oxygen/air. A
catheter was placed in a femoral artery for blood pressure monitoring
and a thermodilution catheter placed in the pulmonary artery
via a femoral vein for measuring cardiac output and for drug infusions.
After a left thoracotomy, the heart was exposed, a 2- to 3-cm segment
of proximal left circumflex coronary artery dissected free, and
an EMF probe (Spectra Med) placed around the artery. Distal to the flow
probe, the artery was damaged by squeezing with cushioned forceps,
producing intimal and medial damage as previously
described.31 Reduction in vessel diameter by 70% was
produced by a constricting plastic cylinder placed around the outside
of the artery.31 35 (Critical stenosis was
confirmed by documenting absence of hyperemic response to
temporary 20-second snare occlusion of the vessel.) The lesion
generates platelet-rich thrombus, with a resultant decrease in
circumflex blood flow. At the nadir of the decrease in blood flow, the
thrombus either spontaneously breaks loose and embolizes
distally or can be made to break loose by gentle shaking of the plastic
constrictor. The cycle then repeats. CFR frequency and magnitude serve
as a semiquantitative measure of thrombus formation.
Protocol for Coronary Thrombosis Studies
The experiment was done during four study periods. (1)
Spontaneous CFRs were assessed during an initial 30-minute baseline
control period. (2) Thrombosis was augmented by infusion of
epinephrine, a prothrombotic agonist, at 0.2
µg·kg-1·min-1
IV for 20 minutes, a dose known to restore CFRs in dogs previously
inhibited with aspirin. The preparation was allowed to rest for 10
minutes to permit return to baseline. (3) Amrinone was infused during
10 minutes as repeated 10-mg IV doses to a total of 2 mg/kg and
continued at 20
µg·kg-1·min-1
IV for 30 minutes. (This dose schedule was based on results from a
previous limited experiment in two dogs. No attempt was made to
determine an ED50 for amrinone but rather to determine an
effective amrinone dose regimen.) (4) In four of the eight dogs,
amrinone infusion was continued. Epinephrine was reintroduced
at 0.2
µg·kg-1·min-1
IV for 20 minutes. In the other four of the eight dogs,
intravenous amrinone was discontinued and
recurrence of CFRs was recorded for 30 minutes.
Statistical Methods
All data are reported as mean±SEM. Statistical analysis
was done with repeated-measures ANOVA, with
multivariate analysis, and by paired Student's
t test. Values of P<.05 were considered
significant.
Materials
Amrinone was obtained from Sanofi Winthrop Pharmaceuticals. Indo
1 was from Molecular Probes. PAC-1 was obtained with the help of Dr S.
J. Shattil, from the University of Pennsylvania Cell Center. Other
monoclonal antibodies were from commercial sources. Anti-CD41 clone P2
was from Immunotech. Anti–P-selectin clone AC 1.2 and anti-CD61 clone
RUU-PL7FI2 were from Becton Dickinson. Other agonists and chemicals
were from Sigma Chemical Co.
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Results |
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Platelet Ca2+ Mobilization
The aim was to determine whether amrinone would inhibit agonist-induced Ca2+ mobilization in human platelets. Baseline [Ca2+]i was stable in unstimulated, quiescent platelets. Preincubation with amrinone 2.5 µg/mL and with amrinone 10 µg/mL had no effect on baseline [Ca2+]i in quiescent platelets. The agonists thrombin 0.1 U/mL, ADP 10-6 mol/L, and AVP 10-7 mol/L each evoked a vigorous and typical increase in platelet [Ca2+]i. Amrinone at the two concentrations tested attenuated Ca2+ mobilization evoked by the agonists. Results from an individual experiment are shown in Fig 1
, in which indo 1
fluorescence emission ratios are plotted against time. Results
are summarized in Table 1, in which peak indo 1
fluorescence emission ratios have been converted to approximate
apparent [Ca2+]i by standard transformation
methods.32
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Platelet Adhesion Molecule Expression
Platelet GP IIb/IIIa activation. The aim was to
determine whether amrinone would inhibit agonist-induced expression of
activated GP IIb/IIIa recognized by monoclonal antibody PAC-1.
Results show that 1% of unstimulated, quiescent platelets
expressed activated GP IIb/IIIa. Amrinone 5 µg/mL and
amrinone 15 µg/mL had no effect on activated GP IIb/IIIa
expressed by unstimulated platelets. Both thrombin 0.1 U/mL and ADP
10-6 mol/L evoked modest increases in PAC-1
binding, ie, expression of activated GP IIb/IIIa. Amrinone at
both concentrations tested attenuated expression of activated
GP IIb/IIIa. An example of an individual experiment is shown in Fig 2. Dots in this figure represent dual
fluorescence, both from FITC-conjugated PAC-1, which labels
conformationally active GP IIb/IIIa, and from a PE-conjugated
monoclonal antibody against CD41, which served as a pan-platelet
marker. Data are summarized in Table 2.
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Platelet P-selectin expression. The purpose was to
determine whether amrinone would inhibit agonist-induced platelet
P-selectin expression. Approximately 1% of quiescent, unstimulated
platelets expressed P-selectin. Preincubation with amrinone 5
µg/mL or 10 µg/mL had no effect on P-selectin expression by
quiescent platelets. Thrombin 0.1 U/mL and ADP
10-6 mol/L each evoked typical increases in
percentage of platelets expressing P-selectin, with the response to
thrombin being vigorous. Amrinone had a modest inhibitory
effect on agonist-induced P-selectin expression. Results are shown in
Fig 3 and Table 3.
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Experimental Coronary Thrombosis in Dogs
This four-part study was designed to determine whether amrinone
would attenuate experimental coronary artery thrombus formation
in vivo in dogs. (1) Seven of eight dogs exhibited spontaneous CFRs
during an initial 30-minute baseline control period. (2)
Prothrombotic epinephrine was introduced at 0.2
µg·kg-1·min-1
IV, a dose known to restore CFRs previously inhibited by
aspirin.5 During epinephrine infusion, all eight
dogs exhibited CFRs with frequency increased from baseline.
Epinephrine was discontinued, and once again seven of eight
dogs demonstrated spontaneous CFRs. (3) Amrinone was administered as
repeated 10-mg IV bolus doses during 10 minutes to a total dose of 2
mg/kg, resulting in complete abolition of CFRs in all of the seven
animals exhibiting spontaneous CFRs. The amrinone effect was rapid,
with abolition of CFRs occurring within 1.1±0.4 minutes of the first
10-mg IV bolus of amrinone. Amrinone was continued at 20
µg·kg-1·min-1
IV for 30 minutes, with continued absence of CFRs. (Recordings
from a single dog are shown in Fig 4A.) (4) In a
subgroup of four of the eight dogs, amrinone infusion was continued,
but prothrombotic tendency was increased by reintroducing
epinephrine 0.2
µg·kg-1·min-1
IV. Despite epinephrine, CFRs remained absent in all four dogs
receiving simultaneous amrinone infusion (Fig 4B). In the
other four dogs, in which amrinone infusion was stopped, spontaneous
CFRs recurred in three of four animals. Results are summarized in Table 4. Results from an individual experiment are shown in
Fig 4A and 4B.
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Discussion |
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Phosphodiesterase III inhibitors, including amrinone, elevate platelet cAMP levels8 9 10 11 12 and inhibit platelet function, at least when assessed by light transmittance aggregometry methods.10 11 12 13 14 15 16 Some experimental phosphodiesterase III compounds also attenuate platelet Ca2+ signaling.10 12 The present results extend these previous findings by demonstrating that the clinically useful drug amrinone attenuates agonist-induced platelet Ca2+ mobilization, inhibits activation and expression of adhesion molecules of importance to coronary thrombosis, and abolishes experimental coronary thrombosis in dogs in vivo.
Ca2+ Mobilization
Amrinone inhibited Ca2+ mobilization evoked by ADP,
thrombin, and AVP. Both ADP and thrombin have immediate importance to
coronary thrombosis in humans, and thrombin in particular, as a
final product of tissue factor activity, initiates, amplifies, and
sustains coronary thrombosis. AVP evokes well-characterized
Ca2+ signaling responses in many types of animal cells,
including platelets.3 All three agonists mobilize
Ca2+ via a receptor–G protein–phospholipase
C–inositol trisphosphate signaling axis.2 17 Some steps,
in particular phospholipase C activity and the
Ca2+-releasing actions of inositol trisphosphate at
platelet Ca2+ stores, are sensitive to inhibition by
increased levels of platelet cAMP,17 one of the known
actions of amrinone.
Adhesion Receptors
With some caveats, the present results show that amrinone
inhibited agonist-induced adhesion molecule expression in human
platelets. Adhesion receptors provide a means whereby
activated platelets bind to one another, to white blood
cells, and to structures within the damaged vessel
wall.18 19 20 21 22 23 Amrinone at most only modestly inhibited
P-selectin expression. The other receptor studied, GP IIb/IIIa, has
considerable importance to coronary
thrombosis.18 19 20 When platelets are activated,
GP IIb/IIIa takes on a new three-dimensional conformational state and
in doing so reveals binding sites for fibrinogen.20 21 22
Platelet-rich thrombus is built on a core of activated
platelets linked together via fibrinogen bridges. Present
results show that amrinone inhibited GP IIb/IIIa activation, although
not with the same inhibitory vigor as seen in current
Ca2+ mobilization experiments. The mechanism of amrinone
action is unclear, although inhibition of Ca2+ mobilization
by amrinone, a result shown in the present experiments, would
inhibit GP IIb/IIIa activation to some degree.
The magnitude of adhesion molecule expression evoked by thrombin and ADP in the present experiments was not particularly robust. Ultradilution methods may have been responsible, because at 1:5000 vol/vol dilution, spatial separation between cells would interrupt platelet-to-platelet paracrine signaling, with loss of platelet self-amplifying activation processes via messengers such as thromboxane A2. In addition, 2% albumin used in the Hanks' buffer, a relatively high concentration by cell culture standards but one that ensures good platelet integrity ex vivo, may decrease responses reported by the immunostains.
Limitations of Studies Done Ex Vivo in Human Platelets
The Ca2+ mobilization and adhesion receptor results
are encouraging. However, it is well recognized that the study of
platelets ex vivo is fraught with problems. For example, sample
isolation, centrifugation, platelet pellet
preparation, and washing procedures can all perturb platelet
responses. Attempts were made to lessen these influences in the
present adhesion receptor studies by use of ultradilution methods.
Nevertheless, the present results must be interpreted in the light
of limitations inevitably imposed by ex vivo conditions. In addition,
amrinone concentrations in the 2.5- to 15-µg/mL range were studied.
However, indications for amrinone use in terms of plasma levels have
not been well established in clinical practice.
Coronary Thrombus Formation In Vivo in Dogs
The sine qua non test for putative platelet-inhibiting drugs
is demonstration of platelet inhibition in vivo. Amrinone rapidly
abolished coronary thrombosis in vivo in dogs and protected
against thrombosis even when epinephrine was
infused.4 5 Of the inhibitory agents
previously studied in the CFR model, amrinone is one of the few that
both completely block CFRs and protect against CFR recurrence
when epinephrine is infused. Aspirin, for example, in this
model fails to protect against CFRs induced by
epinephrine.5 Protection comparable to that
currently observed with amrinone is also provided by nitric oxide
donors, by the GP IIb/IIIa antagonist antibody Rheopro, and
by the thienopyridines clopidrogrel and ticlopidine. This topic has
recently been reviewed.36 The mechanism of protection by
amrinone against experimental coronary thrombosis is not clear
but probably includes platelet inhibition, especially because CFRs
in this dog model are platelet-dependent. However, it would be
wrong to ascribe antithrombotic amrinone effects observed in vivo in
dogs entirely to the antiplatelet activity of amrinone that was
currently observed ex vivo in human platelets.
Limitations of the In Vivo Dog Model
This model, in various forms, has served in a number of milestone
studies concerning the roles of endogenous and other
agonists in coronary thrombosis, including demonstration of the
contributory roles of thromboxane
A2,24 serotonin,3
2-adrenergic agonism,3 ADP,25
and platelet-activating factor.26 The model lacks the
thrombogenic components present in ruptured atherosclerotic plaque
in humans. However, features of the model do mimic unstable
coronary disease in humans, notably critical stenosis,
high shear stress, turbulent blood flow, endothelial
damage, and deep vessel wall injury. Furthermore, a number of drugs
investigated for their antiplatelet effects in this dog model have
gone on to successful clinical trials.
Conclusions
Results of the present studies demonstrate that in human
platelets studied ex vivo, amrinone inhibited Ca2+
signaling and modestly inhibited P-selectin expression and GP IIb/IIIa
activation. In dogs, intravenous amrinone abolished
experimental coronary thrombosis, even when CFRs were
potentiated by epinephrine. Results raise the possibility that
the antithrombotic actions of amrinone may be useful in treatment of
acute refractory heart failure associated with unstable
coronary artery syndromes. However, how closely amrinone
actions observed under present experimental conditions can be
extrapolated to the human condition needs to be determined.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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Rita Nelson, Terry Halsey, and Richard Koenig are thanked for technical help, and Janet Beckman is acknowledged for secretarial assistance. The Mayo Foundation is thanked for a grant to pursue this study.
Received October 14, 1996; revision received March 6, 1997; accepted March 11, 1997.
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