© 1997 American Heart Association, Inc.
Articles |
Early Administration of Intravenous Magnesium Inhibits Arterial Thrombus Formation
From the Department of Medicine and Cardiology, Aarhus Amtssygehus, Aarhus University Hospital (H.B.R., K.T., S.E.H.); the Department of Cardiology, Skejby Sygehus, Aarhus University Hospital (S.D.K.); and the Institute of Experimental Clinical Research, Aarhus University (H.B.R., V.E.H.), Aarhus Denmark.
Correspondence to Hanne B. Ravn, MD, PhD, Institute of Experimental Clinical Research, Skejby Sygehus, Aarhus University Hospital, DK-8200 Aarhus N, Denmark. E-mail hbr{at}iekf.aau.dk
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Abstract |
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Abstract An antiplatelet effect of magnesium has been demonstrated in vitro and ex vivo, and this effect may be advantageous in patients with acute myocardial infarction to inhibit reocclusion after coronary angioplasty or thrombolysis. We investigated the antithrombotic in vivo effect of intravenous magnesium in a placebo-controlled, blinded study in 46 male Wistar rats. Thrombus formation was induced by standardized arteriotomy of the femoral artery and partial inversion of the vessel wall to produce a thrombogenic area. The vessel was transilluminated and visualized dynamically by in vivo microscopy. Thrombus area was measured every minute for 30 minutes after removal of the vessel clamp by image analysis techniques, and the number of visible emboli was registered. Animals were randomized into three groups: groups 1 and 2 received saline (control group, n=15) or MgSO4 (Mg-early group, n=15), respectively, during the entire infusion period. In group 3 intravenous saline was given during preparation of the arteriotomy followed by infusion of MgSO4 (Mg-late group, n=16) from 10 minutes after removal of the vessel clamp. Thrombus area was significantly reduced by 75% in the Mg-early group (P<.005) but not in the Mg-late group compared with the control group. Mean number of emboli was reduced during magnesium infusion. The serum magnesium level increased to 2.2 (2.1 to 2.5) and 3.5 (3.0 to 4.2) mmol/L after infusion in the Mg-late and the Mg-early group, respectively. In the present study, intravenous infusion of MgSO4 significantly reduced thrombus formation in vivo but only when it was given before reperfusion. The antithrombotic effect of magnesium may be utilized in patients with acute myocardial infarction to reduce the rate of reocclusion. Magnesium infusion may also be of value in elective arterial angioplasty, but this option has not been investigated in clinical trials. However, correct timing of magnesium administration is critical to obtain an efficient antithrombotic effect.
Key Words: magnesium • pharmacology • animal models • thrombosis drug therapy
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Introduction |
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Adjunctive therapy with antiplatelet and antithrombotic agents is important to maintain or improve coronary patency after thrombolytic therapy or acute coronary angioplasty in patients with MI.1 2 A paradoxical phenomenon after treatment with both streptokinase and TPA is the increase in local thrombin generation and platelet activation.3 4 5 6 The safety and efficacy of conventional antiplatelet therapy with low-dose ASA have been proved in several clinical trials.7 However, rethrombosis still occurs in a high proportion of patients with MI, thus necessitating the development and evaluation of new anticoagulant and antiplatelet drugs.
Intravenous magnesium therapy has been shown to reduce mortality in patients with MI in a meta-analysis of seven randomized trials8 and in the LIMIT-2 study comprising >2000 patients.9 However, results from a megatrial with >58 000 patients (ISIS-4)10 did not confirm the beneficial effect of intravenous magnesium in patients with MI. The cause of the discrepancy between ISIS-4 and the other randomized trials remains an open question, but a difference in protocol design has been suggested as a possible explanation.11 12 13 The difference in time interval between thrombolysis and the initiation of magnesium infusion has gained much particular attention. Experimental studies suggest that a myocardial protective effect can be obtained by magnesium infusion but only when its extracellular level is increased before or very early during reperfusion.14 15 16
A beneficial outcome of intravenous magnesium therapy in patients with MI may also originate from reduced thrombogenicity due to platelet inhibition. An antiplatelet effect of magnesium has been demonstrated in vitro17 18 19 20 21 and ex vivo.20 22 23 However, in most of these studies, platelets were investigated by aggregometry, which may be different from the in vivo situation with ongoing arterial thrombosis. Only a few studies on experimental thrombosis have been performed until now, but a marked reduction in thrombus formation has been observed after topical application24 and after bolus injection25 26 of magnesium. In the present study we investigated the antithrombotic effect of magnesium in a dynamic, in vivo model of experimental arterial thrombosis and evaluated whether a potential antithrombotic effect was time dependent.
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Methods |
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Forty-six male Wistar rats weighing 265 to 310 g were used in the present study. Before the experiment, the animals were kept at a constant temperature (20°C) with an artificial light/dark cycle of 12 hours:12 hours and had free access to water and a standard pellet diet. Induction of anesthesia was obtained with pentobarbital (50 mg/kg body weight IP) and midazolam (2 mg/kg body weight SC) subcutaneously. Anesthesia was maintained with repeated doses of subcutaneous pentobarbital. A tracheotomy was performed to ensure airway patency throughout the experiment. The left carotid artery was cannulated for continuous monitoring of blood pressure and withdrawal of blood samples at the end of the experiment. Blood pressure was measured as end pressure with a sampling frequency of 20 Hz and a personal computer equipped with an amplifier and recording software (Super-Mingo V2.10, NBA-Electronic Gatehouse). An indwelling cannula was placed in the left femoral vein for administration of test drugs. Body temperature was registered with a rectal probe and maintained between 36.5°C and 37.5°C by use of an adjustable heat lamp. Animals were euthanized by an intravenous overdose of pentobarbital. The animals were treated according to the principles stated in Danish law on animal experiments.
Thrombosis Model
A thrombogenic lesion was induced in the femoral artery by
performing an arteriotomy and inversion of the arterial
wall so that deteriorated endothelium and
subendothelial tissue would protrude into the vessel
lumen after closure. Distal to the inguinal ligament, 10 to 15 mm
of the right femoral artery was carefully dissected free and placed in
a double microvascular clamp (Acland double approximator clamp 3V). An
arteriotomy including approximately one third of the vessel
circumference was performed. For closure, four sutures (10-0 nylon on a
100-µm needle; B. Braun-SSCAG, Neuhausen am Rheinfall, Schwitzerland;
a gift from Leo, Løvens Kemiske Fabrik, Denmark) were equally
distributed along the arteriotomy, with the two middle stitches
ensuring inversion of the proximal vessel wall (Fig 1
). After release of the vessel clamp and
after hemostasis was assured, the vessel was prepared for videotape
recording. In case bleeding occurred, a piece of gauze soaked
in isotonic saline was placed to cover the anastomotic site for 30
seconds without compression; if necessary, this procedure was
repeated.
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To visualize thrombus formation, the vessel was transilluminated by
using a fiber-optic and prism–based light device (patent No.
PCT/EP96/03249) designed for this purpose. The vessel was placed in the
transilluminator, and light intensity was adjusted to the actual vessel
size. A homogeneous light beam was projected through
the artery. Whereas erythrocytes absorb light, platelets and
aggregates comprising platelets allow light to pass through them,
resulting in a bright white area. Thrombus formation was registered
dynamically by using in vivo microscopy and a built-in video camera
(Sony CCD-iris; SSC-N370CE, Brock & Michelsen) for tape
recording (Super VHS; Panasonic NV-FS88EC, Matsushita, Electric
Industrial Co), with the images displayed on a monitor (Fig 2). Subsequently the tape
recordings were analyzed off-line by using a personal
computer equipped with a digitizing board (Matrox-MVP-AT, Matrox
Electronic Systems Ltd) and software (4.0 Bioscan; Optimas, Perimeter).
Planimetry of the thrombus area was performed every minute for the
first 30 minutes after removal of the vessel clamp (Fig 3). For each experiment, a curve
displaying thrombus area vs time was produced and the AUC was
calculated. An increase in two-dimensional area was defined as thrombus
growth, whereas a decrease represented dispersion and/or
embolization. The number of emboli was counted from the videotape
recordings. An embolus was defined as a visible fragment that
had become detached from the thrombus.
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Study Design
Forty-six rats were randomized into three groups. In each group,
infusion of test drug 1 was initiated immediately after application of
the approximator clamp and continued while the arteriotomy was
performed (30 minutes), and for the first 10 minutes after removal of
the vessel clamp. At that time, infusion of test drug 2 was started and
infused for the remaining 20 minutes of the observation period. All
drugs were administered intravenously (1 mL/h). Group 1,
the placebo (control) group, received saline throughout the entire
infusion period; in Group 2, 0.6 mmol/mL MgSO4 was
infused during both periods (Mg-early group). In the last group, Group
3, saline was infused until 10 minutes after removal of the vessel
clamp, and afterward MgSO4 (0.6 mmol/ml) was given for
the remaining 20 minutes (Mg-late group).
Blood samples were drawn from the arterial catheter (the first 0.5 mL of blood was discarded) into dry Monovette tubes. Samples for S-Mg analysis were centrifuged at 1800g for 10 minutes at room temperature and stored at -20°C. At the end of the 30-minute observation period, the vessel clamp was reapplied to the artery. A 15- to 20-mm specimen of the artery including the arteriotomy was cut out and placed in formaldehyde/sodium phosphate, 4% wt/vol. Vessel specimens were processed for light microscopy examination and stained with Picro-Mallory's stain for identification of platelets.
Statistics
All values are given as median and interquartile range (25% to
75%). Comparison of two groups was done using the Mann-Whitney
U test. One-way ANOVA (Kruskal-Wallis) was used when more
than two groups were compared. Bivariate analysis was performed
using Spearman's 
to explore the relationship between (1) thrombus
size and S-Mg and (2) thrombus size and number of emboli. A value of
P<.05 was considered significant.
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Results |
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In the Mg-early group, a significant reduction of 75% in median AUC was observed [22.1x103 µm2 (0 to 75.5x103 µm2), (P<.005)] compared with the control group, in which the median AUC was 85.5x103 µm2 (51.9 to 219.5x103 µm2). In the Mg-early group, 5 of the 15 animals had no thrombus material in the vessel lumen after removal of the vessel clamp or at any time during the observation period. In the control and Mg-late groups, all of the animals had ongoing thrombus formation at certain times during the observation period. In the Mg-late group, in which magnesium infusion was initiated 10 minutes after removal of the vessel clamp, the median AUC was 97.1x103 µm2 (22.7 to 117.0x103 µm2), which was not significantly different from that in the placebo group. Comparison of thrombus areas within 10 minutes after removal of the vessel clamp did not reveal any significant difference between the control group and the Mg-late group, suggesting that the initial thrombus area in the two groups was similar (results not shown).
Median thrombus areas versus time in the three treatment groups are
shown in fig 4. Not only total area but
also initial and maximal areas were significantly smaller in the
Mg-early group (P<.005), whereas no significant difference
was observed between the Mg-late and control groups. Vessels containing
thrombus material at the end of the observation period were harvested
and prepared for light microscopy. Histological
examination revealed that the thrombus consisted mainly of
platelets and contained only a few erythrocytes and fibrin strands
(Fig 5).
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The median number of visible emboli during the 30-minute observation
period was largest in the control group [40 (23 to 69); Table 1], whereas in the Mg-early group a
significantly lower number was observed, with a median value of 5 (0 to
23; P<.001). In the Mg-late group, the total number of
emboli [18 (12 to 43)] was not significantly different from that of
the control group. However, a significant (P<.01) decrease
in the median number of emboli was registered during the last 20
minutes when magnesium was infused (Table 1), whereas the number of
emboli during saline infusion was indistinguishable from that in the
first 10 minutes in the control group (NS). A positive, significant
correlation was found between the AUC and the number of emboli in each
animal (=.76, P<.0001), suggesting that the frequency of
embolization is partly related to thrombus size.
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The antithrombotic effect of magnesium was not accompanied by a significant increase in bleeding tendency. Bleeding complications were registered, and we found that 6 of 15 animals in the control group, 4 of 15 in the Mg-early, and 6 of 16 in the Mg-late group had one or more bleeding episodes after hemostasis had been obtained (NS). No excessive bleeding was observed.
At the end of the observation period, S-Mg was measured. The median
S-Mg level in the control group was 0.8 mmol/L (0.7 to 0.9
mmol/L). After Mg infusion the median S-Mg was 2.2 mmol/L (2.1 to
2.5 mmol/L) in the Mg-late group (P<.001) and 3.5
mmol/L (3.0 to 4.2 mmol/L) in the Mg-early group
(P<.0001). There was no statistically significant
difference between S-Mg levels in the two Mg treated groups. The
relationship between S-Mg level and AUC for each animal was explored,
but no statistically significant correlation was found (=-.29;
p=.07).
Blood pressure was not significantly different among the three groups
before infusion of test drug 1 (baseline). However, in the Mg-late and
Mg-early groups, a significant (P<.01) decrease in blood
pressure was observed, from 128 to 110 mm Hg and 125 to 90
mm Hg, respectively, during the observation period. In the control
group blood pressure remained stable (Table 2).
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Discussion |
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An antithrombotic effect of magnesium was demonstrated in the present study. The effect was obtained without introducing an increased bleeding tendency or impairment of the cardiovascular system. However, the timing of magnesium administration seemed to be important, as the antithrombotic effect was present only when magnesium was given before reperfusion of the artery. In the Mg-late group, a tendency toward reduced thrombogenicity was observed, but the difference was not significant. S-Mg was somewhat higher, though not statistically significantly higher, in the Mg-early group than in the Mg-late group. A nonsignificant correlation between S-Mg and AUC in individual animals was observed, suggesting that the difference in antithrombotic effect of Mg cannot be solely explained by a dose-dependent effect. Magnesium infusion did not impair circulation, although a minor decrease in blood pressure was observed in both magnesium treatment groups. In humans, toxic effects of magnesium are usually not seen when the S-Mg is <4 mmol/L.27
Platelets are intimately involved in thrombus formation at the site of coronary occlusion, even after successful thrombolysis, the underlying stimulus for platelet-initiated rethrombosis persists for many hours or longer.1 Mg is able to inhibit adhesion as well as aggregation of human platelets.20 21 The reason why magnesium was so effective in reducing thrombus formation when given before but not after reperfusion is not known. One explanation may be that platelet aggregation is more easily inhibited when platelets are treated before exposure to thrombogenic stimuli. Platelet aggregation involves a reaction cascade, wherein the initial reaction between a single platelet and the subendothelial thrombogenic substance leads to exponential activation of other platelets by means of several pathways. Reducing the initial platelet–vessel wall interaction would dampen the whole reaction cascade. Another possible explanation is that the platelet–vessel wall interaction, compared with the platelet-platelet interaction, can be reduced more significantly with lower magnesium concentrations. In one study, adhesion of washed platelets to immobilized fibrinogen was inhibited dose-dependently, with a half-maximal effect of magnesium at a concentration of 2 mmol/L.20 Similarly, dose-dependent inhibition of platelet aggregation has also been described, with a half-maximal effect of magnesium in the concentration range of 2.4 to 7 mmol/L after thrombin-induced aggregation in washed platelets.19 20 21 Theoretically in the present study, the antiadhesive effect may be dominant over the antiaggregatory effect at the actual S-Mg level.
A consistent inhibitory effect of magnesium on
platelet aggregation after stimulation with different agonists
(collagen, ADP, thrombin, etc) has been observed,21
indicating that inhibition is due to blockage of a common pathway.
Magnesium is believed to exert its platelet-inhibitory
effect by reducing calcium mobilization in platelets and reducing
fibrinogen binding to the platelet membrane.19 20 A
dose-dependent inhibition of 
-granule release and TxA2
synthesis has also been observed.21 However, -granule
release and TxA2 synthesis both have an
aggregation-dependent component. The reduction may therefore only
reflect surface-mediated inhibition of platelet aggregation.
Inhibition of platelets may also originate from an increased
release of prostacyclin from the vessel wall.28 In
comparison, ASA is known to inhibit the
cyclooxygenase enzyme, thus selectively resulting
in reduced formation of proaggregatory TxA2.29
Previous platelet studies have shown that ASA is able to inhibit
platelet aggregation significantly after stimulation with weak
agonists like ADP and arachidonic acid.30
These agonists are important mainly during recruitment of platelets
for stabilization of the initial thrombus. When stronger agonists like
collagen or thrombin are present, stimulation may be able to bypass
the arachidonic acid pathway, thereby leading to
platelet aggregation and an increased risk of occlusion, which may
explain why ASA is only partially effective in preventing thrombotic
events.30 In the LIMIT-2 Study, the beneficial effect of
magnesium was not modified by concomitant ASA therapy, suggesting that
magnesium exerts its effect independent of the antiplatelet effect
obtained with ASA.9 In our laboratory, we have previously
shown that magnesium also inhibits platelet aggregation after
pretreatment with ASA.21 Furthermore, a synergistic effect
has been observed during collagen-induced aggregation after concomitant
ASA and magnesium therapy.21 This finding may be explained
by inhibition of different pathways, thereby reducing platelet
aggregation more substantially. Further studies are needed to verify
that the synergism between Mg and ASA is also present in vivo.
Standard therapy in patients with MI now comprises a thrombolytic drug given in combination with antiplatelet and/or anticoagulant drugs. The importance of low-dose ASA as adjunctive therapy has been well documented in several clinical trials.7 One possible explanation for the benefit of antiplatelet therapy is the fact that platelet hyperreactivity is associated with increased mortality and cardiac events in survivors of MI.31 32 In high-risk patients undergoing coronary angioplasty, treatment with the potent glycoprotein IIb/IIIa inhibitor c7E3 significantly reduced the frequency of acute ischemic events.2 During angioplasty the endothelium is traumatized, with subsequent activation of platelets.33 This activation may be inhibited by pretreatment with intravenous magnesium, but clinical studies are needed to elucidate this.
To obtain an S-Mg concentration of twice or more the normal physiological concentration, the magnesium salt must be given intravenously. This is normally done by giving a bolus infusion to obtain an immediate rise in the extracellular concentration, followed by a low-dose infusion to maintain the magnesium level. Owing to its route of administration, magnesium is useful mainly during acute ischemic cardiac events or before elective arterial angioplasty/by-pass surgery in hospitalized patients.34
The importance of magnesium administration before reperfusion has been demonstrated recently in two experimental studies that evaluated the effect of magnesium therapy on infarct size.15 16 Both studies showed that the timing of magnesium therapy was crucial to obtain preservation of the myocardium. A >50% reduction in infarct size was observed in both studies when magnesium was given before reperfusion. This improved myocardial preservation is thought to originate from reduced reperfusion injury, because Mg inhibits intracellular calcium overload.35 Platelet inhibition23 and the antithrombotic effect shown by us may supply a complementary action to the myocardial protective effect of magnesium observed in these experimental studies.15 16
In summary, results from the present study suggest that infusion of MgSO4 can reduce thrombus formation in an experimental thrombosis model in rats. The timing of treatment is important, and a delay of even 10 minutes results in a tremendous reduction in effect. The importance of the proper timing of magnesium administration has now been demonstrated in two different areas in which Mg may exert its beneficial effect in MI. Knowledge of this time dependency should be implemented in the study design of future clinical trials.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This study was supported by grants from the Danish Heart Foundation (to H.B.R.), and the Danish Medical Research Council, the Family Hede Nielsen Fonden, the Villum Kann Rasmussen Fonden, and Nycomed DAK A/S (to V.E.H.).
Received January 3, 1997; accepted April 30, 1997.
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