(Circulation. 1997;95:1308-1313.)
© 1997 American Heart Association, Inc.
Articles |
Persistent Inhibition of Platelets During Continuous Nitroglycerin Therapy Despite Hemodynamic Tolerance
the Department of Medicine, Montreal Heart Institute, University of Montreal Medical School, Canada.
Correspondence to Jules Y.T. Lam, MD, Thrombosis and Atherosclerosis Laboratory, Montreal Heart Institute, 5000 Belanger St E, Montreal, Quebec H1T 1C8, Canada.
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Abstract |
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Background Nitroglycerin has been shown to possess antiplatelet properties in both animals and humans. Tolerance to the hemodynamic effects of nitroglycerin develops with continuous therapy, but it is unclear whether there is tolerance to its antiplatelet effect.
Methods and Results Tolerance to nitroglycerin was studied by exposing porcine aortic media to flowing arterial blood from control pigs (n=9) or pigs treated with continuous nitroglycerin patches (Nitro-dur, 0.8 mg/h; n=11) at a shear rate of 3397 s-1 for 3 minutes. Relative to baseline, mean arterial pressure fell by 
10% at 3 and 24 hours (P<.05) but returned to baseline at 48 hours of continuous nitroglycerin treatment, whereas no significant changes were observed in control animals. Autologous 51Cr-labeled platelet deposition (x106/cm2) on the aortic media at baseline and 3, 24, and 48 hours remained stable in control animals, with mean values of 94.8±5.9, 89.4±8.3, 89.3±8.8, and 84.3±5.7, respectively. However, in pigs treated continuously with nitroglycerin for 48 hours, platelet deposition was reduced significantly at 3 (65.9±4.8), 24 (63.8±6.4), and 48 hours (56.5±7.3) of nitroglycerin treatment compared with baseline (93.1±3.6). Platelet aggregation induced by thrombin also decreased at 3 (12.4±1.3), 24 (12.6±1.7), and 48 hours (10.8±1.6) of nitroglycerin treatment compared with baseline (16.3±1.4) but remained unchanged in the control group. Also, nitroglycerin treatment increased intraplatelet cGMP at 3, 24, and 48 hours compared with baseline.
Conclusions This study demonstrates the persistent inhibition of platelet function and platelet deposition on an injured arterial wall by continuous nitroglycerin therapy despite hemodynamic tolerance.
Key Words: nitroglycerin • platelets • hemodynamics • vasodilation • thrombosis
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Introduction |
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Nitroglycerin, a potent vasodilator of both the coronary and peripheral vascular beds, has been used effectively for more than 100 years to treat coronary heart disease.1 2 3 Its biological effect is mediated by NO formation, which is also produced endogenously by the vascular endothelium.4 5 6
Recently, nitroglycerin has been shown to also inhibit platelet function. We demonstrated that the intravenous infusion of nitroglycerin at clinically relevant doses causes a reduction in platelet deposition onto aortic media in ex vivo superfusion chambers,7 as well as a reduction in platelet deposition in vivo at the site of arterial injury caused by balloon angioplasty in pigs,8 an effect that is also seen with aspirin.9 This is consistent with in vitro aggregation studies showing the platelet-inhibitory effect of nitroglycerin.10 11 12 Other studies have also demonstrated that cyclic blood flow responses caused by platelet aggregation and dislodgment can be inhibited by nitroglycerin or endogenous NO.13 14 These acute studies suggested that nitroglycerin may inhibit platelet/arterial wall interaction, probably through the formation of NO or S-nitrosothiols. The vasodilatory and antiplatelet effects of nitrosothiols or NO are mediated by an increase in cGMP level through activation of the guanylate cyclase enzyme.15 16 Furthermore, the antiplatelet efficacy of nitroglycerin can be prevented by the guanylate cyclase inhibitor methylene blue.7
However, the results of current studies suggest that the development of tolerance may limit its clinical efficacy. The development of hemodynamic tolerance is rapid and occurs within 48 hours of continuous nitroglycerin therapy.17 18 19 20 21 Although hemodynamic tolerance is well described, it is uncertain whether nitroglycerin still exerts an important antiplatelet effect with long-term therapy. In this regard, it is of note that a dissociation between hemodynamic tolerance and coronary arterial tolerance has been described.22 In this study, we investigated the influence on platelet function of 48-hour continuous nitroglycerin therapy, as assessed with impedance platelet aggregometry and ex vivo superfusion flow chambers measuring platelet deposition and accretion on an arterial media exposed to flowing blood.
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Methods |
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Experimental Procedure
Normal Yorkshire pigs weighing
18 kg were sedated by an intramuscular injection of a mixture of 225 mg of ketamine (Rogarsetic, Rogar/STB Inc) and 125 mg of azaperone (Stresnil, Janssen Pharmaceutical). The pigs were intubated and maintained on anesthesia by mechanical ventilation with 0.5% halothane (Fluothane, Ayerst) in room air. The femoral artery was then cannulated, and femoral arterial blood was drawn into superfusion flow chambers to interact with an aortic media strip by means of a peristaltic pump placed distal to the flow chambers. A 3-minute superfusion was performed at a constant blood flow of 20 mL/min through the chamber at a shear rate of 3397 s-1 at 37°C,7 23 after which the aortic media was removed and the amount of radioactively labeled platelets interacting with the media was measured with a gamma counter. The same superfusion experiment was repeated 3, 24, and 48 hours later in control and nitroglycerin-treated animals. Arterial blood pressure was monitored during the superfusion experiment, and the experiments were performed in accordance with the Canadian Council on Animal Care. Twenty pigs were studied; 11 received continuous transdermal nitroglycerin treatment in the form of nitroglycerin patches, and the other 9 served as control animals. Nitroglycerin patches (Nitro-Dur, 0.8 mg/h; Key Pharmaceuticals, Schering) were placed on the neck area and changed every 24 hours for a period of 48 hours.
Documentation of Hemodynamic Tolerance
Additional experiments (n=9) were performed to determine whether nitrate tolerance toward its hemodynamic effect was achieved. A 7F introducer was placed in the femoral vein for administration of increasing concentrations of intravenous nitroglycerin, whereas mean arterial pressure was recorded. At baseline, before placement of the transdermal patch on the pigs, they were administered a bolus of 1, 2, and 5 µg/kg nitroglycerin, as well as 5% dextrose vehicle control. Decrease in mean arterial pressure was expressed as a percentage of baseline. Caution was taken to ensure return to basal hemodynamic values before administration of a new dose of nitroglycerin. After the completion of these studies, the transdermal patches were applied, and the same protocol was repeated at 3, 24, and 48 hours after patch application.
Radioactive Labeling of Platelets
On day 1, just before the superfusion experiment, 96 mL of blood was collected in 14 mL of anticoagulant citrate dextrose solution from each pig by venipuncture. After differential centrifugation, the platelet pellet was isolated and labeled with 400 µCi of 51Cr (Frosst, Merck Frosst) and then reinjected intravenously into the pig. The superfusion experiment was performed 2 hours after the injection.
Badimon Superfusion Chamber
The superfusion chamber was designed by Dr L. Badimon to mimic the tubelike shape of the vascular system. It is made of Plexiglas and consists of an upper lid and a lower block; the lower block has a small cylindrical hole of 1-mm diameter to allow the flow of blood. The upper lid of this cylindrical tube was removed, resulting in a window that permits direct exposure of flowing blood to a piece of exposed arterial media held in place by the pressure of the upper lid and secured by a surrounding chamber holder.7 23 24
Aortic Media
Aortas harvested from normal pigs were cleansed through removal of the excess adjacent adventitia. The intima and subjacent media were then removed by being peeled off of one corner of the longitudinally opened aorta and discarded. The remaining injured vessel wall provided a thrombogenic media that was exposed to circulating blood as 15x35-mm sections in the superfusion flow chamber experiments.
Quantification of Platelet Deposition
The extent of platelet deposition (x106/cm2) onto aortic media segments was quantified through assessment of the amount of 51Cr-labeled platelets that interact with the media. This was obtained by measuring the radioactivity in counts per minute (cpm) in each segment of aortic media. The radioactivity per milliliter of blood was also determined at the time of the experiment as well as the whole blood platelet count (Coulter counter) obtained from the femoral artery. The number of platelets deposited on the media was calculated with the following equation, as previously described7 24 : No. of Platelets on Aortic Media=[(51Cr cpm on Aortic Media)x(No. of Platelets/mL of Blood)]/(51Cr cpm/mL of Blood).
Platelet Aggregation Studies
Platelet aggregation was tested at 37°C on citrated whole blood diluted 1:1 in sterile physiological saline, using an impedance aggregometer (Chronolog Corp). The tests were performed in close proximity to the animal and within the first minute after blood sampling. The tests were initiated by the addition of a concentration of 0.075 U/mL thrombin (Hoechst Behring). Platelet aggregation was quantified in terms of maximum amplitude (
) obtained 3 minutes after the addition of thrombin,10 11 and results were obtained with the use of AGGRO/LINK software (Chronolog).
Cyclic Nucleotide Levels
Blood samples were withdrawn during the experiment, and isobutyl methyl xanthine was added to prevent cGMP degradation by phosphodiesterases. Intraplatelet cGMP was measured with a commercially available radioimmunoassay kit (Amersham International) after extraction with 10% trichloroacetic acid. Trichloroacetic acid was removed by ether extraction, and samples were dried under a stream of nitrogen at 60°C. The extract was dissolved in 500 µL of assay buffer before analysis.
Statistical Analysis
All values are expressed as mean±SEM. Repeated ANOVAs were used for multigroup comparison, and when significant, an intergroup comparison was performed with a Fisher's multiple-comparison test; values of P<.05 were considered significant.
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Results |
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Mean Arterial Pressure
Control pigs (n=9) had relatively stable mean arterial pressure during 48 hours as described in the Table
, with average values of 53.1 mm Hg at baseline and 52.7 mm Hg at 48 hours. In a second group of 11 pigs that were treated with continuous nitroglycerin patches for 48 hours, mean arterial pressure significantly fell by 10% at 3 (50.0±2.4 mm Hg) and 24 (49.4±3.3 mm Hg) hours after patch application compared with a baseline value of 55.9±3.0 mm Hg. At 48 hours, mean arterial pressure returned to a near-baseline value of 57.2±3.0 mm Hg (Table).
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The documentation of hemodynamic tolerance to the continuous administration of nitroglycerin is shown in Fig 1, which demonstrates the dose-dependent decrease in blood pressure obtained after nitroglycerin infusion in animals in the basal state (time 0) before continuous nitroglycerin patch application. However, the ability of intravenous doses of nitroglycerin to vasodilate and decrease blood pressure diminishes with time after continuous nitroglycerin treatment, such that after 48 hours of continuous nitroglycerin therapy, there was a significantly decreased lowering of blood pressure (63% [1.0±0.4% versus 2.7±0.6%, P<.05] and 40% [3.1±0.6% versus 5.2±0.6%, P<.05]) compared with the initial basal decrease induced by intravenous nitroglycerin at doses of 1 and 2 µg/kg, respectively. However, the blood pressure decrease with the higher dose of 5 µg/kg intravenously administered nitroglycerin was not significantly attenuated, being only 15% less (8.8±0.8% versus 10.3±1.0%) at 48 hours of continuous nitroglycerin treatment compared with its initial baseline value. This suggests that the vascular tolerance was partially overcome by the higher dose of nitroglycerin. Administration of the 5% dextrose vehicle at the beginning or at the end of the experiment did not alter mean arterial pressure. In control untreated animals, the administration of intravenous nitroglycerin produced a consistent decrease in blood pressure, with no diminution of the vasodilator effect with time.
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Influence of Nitroglycerin on Platelet Deposition
No significant changes were observed in control pigs with regard to platelet deposition (x106/cm2) onto aortic media in comparison of baseline values with those at 3, 24, and 48 hours. As demonstrated in Fig 2, platelet deposition on the aortic media at baseline was 94.8±5.9 in control animals and 93.1±3.6 (P=NS) in pigs assigned to nitroglycerin. Platelet deposition on the aortic media was significantly reduced when pigs were treated with continuous nitroglycerin patches for 48 hours. There was a significant 29% reduction in platelet deposition after only 3 hours (65.9±4.8) (P<.05) of nitroglycerin therapy. Platelet deposition was decreased after 24 hours (63.8±6.4) compared with baseline and remained decreased at 48 hours with a mean of 56.5±7.3x106/cm2, representing a decrease of 39.3% compared with baseline and of 33% compared with control animals. These results were statistically significant (P<.05) compared with baseline and the control group (Fig 2).
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Efficacy of Nitroglycerin on Platelet Aggregation
Although platelet aggregation from control pigs remained relatively stable, with mean values ranging from 15.0±1.7 at baseline to 14.2±1.3 at 48 hours (Fig 3), platelet aggregation induced by thrombin decreased when pigs were treated with continuous nitroglycerin patches for 48 hours. A significant 24% reduction is observed within the first 3 hours alone (12.4±1.3 ) (P<.05) compared with a baseline value of 16.3±1.4 . Platelet aggregation remained decreased at 24 hours with a mean of 12.6±1.7 and was further reduced at 48 hours with a mean of 10.8±1.6 (Fig 3).
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cGMP Levels in Platelets
In the control group, seven pigs in which intraplatelet cGMP levels were measured showed no significant changes between baseline (mean, 0.30±0.03 pmol/108 platelets) and 48 hours (mean, 0.30±0.04 pmol/108 platelets). In the nitroglycerin-treated pigs, a significant increase in intraplatelet cGMP levels to a mean of 0.90±0.16 pmol/108 platelets (P<.01) was observed at 3 hours relative to a baseline level of 0.52±0.05 pmol/108 platelets, as demonstrated in Fig 4. The level of cGMP at 24 and 48 hours (0.73±0.05 and 0.75±0.07 pmol/108 platelets, respectively) was still significantly increased compared with baseline (both P<.05); however, there were no significant differences among the 3-, 24-, and 48-hour cGMP levels.
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P<.01, *P<.05 vs baseline. No significant differences are observed among values at 3, 24, and 48 hours. |
Discussion |
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In this study, we showed that continuous administration of transdermal nitroglycerin significantly decreased platelet aggregation and platelet deposition on an exposed arterial media. These antiplatelet effects were observed after 3 hours of nitroglycerin treatment and remained decreased after 48 hours of continuous therapy, when mean arterial blood pressure returned to baseline values and attenuated the ability of intravenous doses of nitroglycerin to vasodilate and decrease arterial pressure, suggesting the presence of hemodynamic tolerance. Thus, this study demonstrates the persistent antiplatelet property of transdermal nitroglycerin despite the development of tolerance to its hemodynamic effects or a dissociation between hemodynamic tolerance and persistent platelet inhibition.
It is known that nitroglycerin is a potent vasodilator when given acutely, and we and others have also shown that nitroglycerin possesses antiplatelet and antithrombotic properties7 8 10 11 12 13 14 that may be as great as or even greater than those achieved with aspirin under similar experimental conditions.8 9 This platelet-inhibitory effect has been demonstrated in animal models of cyclic flow variations associated with coronary stenosis and thrombosis,13 in a porcine model of deep arterial injury and thrombus formation,7 8 25 and in patients with coronary disease.10 11 12 However, these studies were performed after acute intravenous or transdermal nitroglycerin therapy. Although it is known that tolerance to the hemodynamic effects of nitroglycerin may develop with continued use,17 18 19 20 21 it is unclear whether tolerance to the antiplatelet effect occurs. In this study, the development of tolerance was supported by the return of mean arterial pressure to baseline after chronic transdermal nitroglycerin administration and by challenge of the hemodynamically tolerant animals with increasing concentrations of intravenous nitroglycerin. The blood pressure–lowering effects of the smaller doses of intravenous nitroglycerin (1 and 2 µg/kg) were substantially attenuated, confirming that hemodynamic tolerance was achieved in the animals previously treated with continuous transdermal nitroglycerin. As expected, this hemodynamic tolerance was partially overcome by the use of the higher dose of 5 µg/kg, which is in agreement with other observations26 27 that during nitrate tolerance, increasing doses of nitrates had to be administered to induce effects previously obtained with a lower dose. Thus, similar to the observation that coronary arterial tolerance can be dissociated from hemodynamic tolerance,22 we were able to show a dissociation between hemodynamic tolerance and persistent platelet-inhibitory effects with continued use, as demonstrated by a persistent decrease in platelet aggregation and platelet-thrombus formation with a simultaneous increase in platelet cGMP levels. In addition, there is even a slight tendency for platelets to be more inhibited at 48 hours rather than a diminution in or a loss of this effect.
The phenomenon of tolerance is a state in which despite continuing plasma levels of nitrates, there is a diminution in clinical effectiveness. Tolerance to the blood pressure and heart rate changes induced by nitroglycerin occurs rapidly and has been more thoroughly demonstrated and investigated through the use of repeated exercise testing during the continuous administration of oral and transdermal nitroglycerin.1 17 18 The exact cellular mechanism of tolerance is unknown. Depletion of sulfhydryl groups, neuroendocrine activation, or increase in intravascular volume has been implicated.1 17 18 19 20 21 Other studies show no depletion in vascular cysteine during hemodynamic tolerance,28 and the prevention of tolerance by the concomitant administration of sulfhydryl donors such as N-acetylcysteine,21 29 30 converting enzyme inhibitors,31 or diuretics32 has been inconclusive and does not suggest that tolerance can be prevented by one of these pharmacological means. Fung et al33 suggested that at least part of the tolerance may occur at a local level in the vasculature. However, even in the vascular tree, the development and extent of tolerance may vary according to the type and location of the vascular tree.34 The current study reports the absence of tolerance only for platelets, which differ from other tissues in many ways, including a limited life span in circulation and lack of DNA material and transcriptional control. Clearly, further mechanistic studies are required at the cellular level to differentiate between hemodynamic and vascular tolerance and the absence of nitrate tolerance in platelets during hemodynamic tolerance.
Because early and rapid analysis of blood may be critically important in detection of the effects of labile blood factors and drugs with short half-lives such as nitroglycerin or NO, the use of the whole blood aggregometer in this study provided certain advantages, such as the avoidance of platelet manipulation, time-consuming centrifugation steps, and the loss of platelet-active blood factors. However, a good correlation has been reported between the results obtained with the whole blood platelet aggregation and optical platelet-rich plasma platelet aggregation,35 with a higher sensitivity of the former to detect the effects of some aggregating and antiplatelet agents.36 37 Indeed, in contrast to the optical aggregometer, the whole blood aggregometer allows studies in the presence of all blood elements, including red cells and neutrophils, which may affect platelet function. Nevertheless, studies that focus mainly on platelet aggregatory responses to selected agonists may not accurately reflect thrombotic conditions in the intact circulation, in the presence of flowing blood and shear forces and vessel wall component, which may be better explored through the superfusion chamber experiments. The consistent and concordant responses to nitroglycerin in showing inhibition of platelet aggregation, inhibition of platelet deposition on the vessel wall, and enhanced cGMP formation even after 48 hours of continuous treatment lend support to a persistent effect of nitroglycerin on platelet function.
The clinical significance of the antiplatelet effect of nitroglycerin and the lack of tolerance of the platelet effect on prolonged nitroglycerin therapy is unknown. It has been suggested that the antiplatelet effect may be responsible for at least part of the clinical benefit seen with nitroglycerin in unstable angina. Absence of tolerance to the antiplatelet efficacy of nitroglycerin would likely be of benefit in this clinical setting, in which nitroglycerin is usually administered continuously rather than intermittently, and at doses that may not induce hemodynamic changes or long after tolerance to the hemodynamic effects of nitroglycerin has developed. The reduction in the incidence of myocardial infarction with the use of intravenous nitroglycerin and N-acetylcysteine in patients with unstable angina, a syndrome associated with coronary thrombosis, is also compatible with an antiplatelet effect for nitroglycerin therapy.38 Considering the importance of platelet/vessel wall interactions in terms of initiation and propagation of mural thrombosis, it is reasonable to hypothesize that the observed decrease in platelet deposition and platelet aggregation as documented in this study may have clinical implications.
Our results also show that platelet cGMP is significantly increased 48 hours after continuous transdermal nitroglycerin therapy. It has been demonstrated that organic nitrates and nitroglycerin, which release NO, inhibit platelet function by stimulating soluble guanylate cyclase and increasing platelet cGMP,17 18 and we have previously shown that methylene blue, an inhibitor of guanylate cyclase, can inhibit the antiplatelet effects of nitroglycerin.7 Increase in cGMP, by 44% in this study, appears to be sufficient to alter platelet function and, more importantly, suggests that tolerance may not be active at the platelet level because there is a persistent decrease in platelet deposition and aggregation associated with an increase in cGMP at 3, 24, and 48 hours of continuous nitroglycerin treatment compared with baseline values. There were no significant differences between the 3-, 24-, and 48-hour results. In contrast, vascular tolerance is associated with an impaired increase in cGMP in response to nitrovasodilators in vascular smooth muscle.39 40 These changes induced by continuous nitroglycerin therapy are not only persistent but also consistent within the three parameters of platelet function assessed. It is possible that the differences between hemodynamic tolerance and absence of tolerance in platelet function may be due to neurohormonal activation, which can reverse the hemodynamic effect of nitroglycerin without altering platelet function. This is supported by recent data from Munzel and Bassenge,41 who demonstrated the beneficial effectiveness of ACE inhibitors when used at a high dose in reducing nitrate tolerance. Alternatively, platelets and their responses to chronic nitrate therapy may be unique and different from vascular smooth muscle because of their known lack of DNA material and transcriptional regulation.
It may be argued that our findings obtained in pigs may not be applicable to patients with ischemic heart disease in whom there may be widespread endothelial dysfunction and decreased metabolism of nitroglycerin to NO. However, we have previously shown in both patients with chronic stable coronary disease and patients with unstable angina that intravenous or transdermal nitroglycerin delivery significantly inhibits platelet function and platelet thrombus formation.10 11 Thus, platelets from patients with coronary disease appear to respond to nitroglycerin. Nitroglycerin is used widely and continuously for many days, during treatment for the acute ischemic coronary syndromes in which platelet aggregation and platelet thrombosis play a major role. The persistent inhibition of platelets by nitroglycerin as documented in this study raises a plausible hypothesis to explain many of the beneficial effects observed when this drug is used in these situations. The administration of nitroglycerin in subjects with acute myocardial infarction decreases the need for analgesics,42 promotes patency of the infarct-related artery during fibrinolysis,43 and decreases infarct size in patients not treated with fibrinolytics.44 A continuous infusion during unstable angina controls episodes of chest pain without significant changes in mean arterial pressure and heart rate and without the apparent development of tolerance to the drug.45
In conclusion, data from this study strongly support an in vivo antiplatelet effect of nitroglycerin that appears to be persistent over the 48 hours of continuous treatment. However, the hemodynamic effects appear to become attenuated with time. These data suggest that the platelet-inhibitory effects of nitroglycerin may be of clinical relevance and may contribute to its benefits in the treatment of unstable angina. In addition, these data support the hypothesis that tolerance to the effect of nitroglycerin may be tissue specific and so allow us to rethink our views on the mechanisms of nitroglycerin-induced tolerance and possibly stimulate new directions in this field of research.
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Acknowledgments |
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Dr Lam was supported in part by the Medical Research Council of Canada, the Heart and Stroke Foundation of Canada-Quebec Affiliate, and the Fonds de la Recherche en Sante du Quebec. Dr Hebert was supported in part by an FES scholarship from the University of Montreal.
Received June 25, 1996; revision received October 16, 1996; accepted October 28, 1996.
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