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(Circulation. 1996;94:3109-3114.)
© 1996 American Heart Association, Inc.
Articles |
Long-term Smoking Impairs Platelet-Derived Nitric Oxide Release
the Third Department of Internal Medicine, Kurume University School of Medicine, Kurume, Japan.
Correspondence to Dr Hisao Ikeda, Third Department of Internal Medicine, Kurume University School of Medicine, 67 Asahi-machi, Kurume 830, Japan.
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Abstract |
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Background Long-term smoking impairs endothelium-dependent vasodilation, which is mediated by nitric oxide (NO). However, it is unknown whether long-term smoking impairs the platelet-derived NO release, which regulates platelet aggregation.
Methods and Results Platelet-derived electrical current induced by collagen was measured with an NO-selective electrode in 12 smokers and 11 nonsmokers. Collagen-induced intraplatelet cGMP and platelet aggregation was measured in smokers and nonsmokers. S-nitroso-N-acetyl-dl-penicillamine, a direct NO donor, dose dependently increased in electrical current (r=.99). Collagen induced platelet aggregation and dose dependently increased electrical current (r=.94). Collagen-induced electrical current and cGMP were significantly augmented by L-arginine, a precursor of NO, and attenuated by NG-monomethyl-L-arginine, an inhibitor of NO synthesis. Significant correlation was found between collagen-induced electrical current and cGMP (r=.73). These findings indicate that the change in electrical current reflects the NO release through the L-arginine–NO pathway in platelets. Collagen-induced electrical current (6.7 versus 13.8 pA; P<.001) and cGMP (1.2 versus 3.0 pmol/109 platelets; P<.005) were significantly lower in smokers than in nonsmokers. Although L-arginine increased cGMP levels in both smokers and nonsmokers, the level was still lower in smokers than in nonsmokers. The inhibitory effect of L-arginine on collagen-induced platelet aggregation was significantly lower in smokers than in nonsmokers (P<.05).
Conclusions These findings provide evidence that platelet-derived NO release is significantly impaired in long-term smokers, resulting in the augmentation of platelet aggregability.
Key Words: smoking • risk factors • platelets • platelet-derived factors • collagen
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Introduction |
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Nitric oxide, which accounts for the biological properties of the endothelium-derived relaxing factor,1 2 is synthesized from L-arginine through NO synthase.3 4 NO inhibits platelet adhesion and aggregation by increasing the intracellular level of cGMP through the activation of soluble guanylate cyclase.5 6 7 Agonists such as collagen that induce platelet aggregation cause an increase in intraplatelet cGMP levels.8 The collagen-induced platelet aggregation is inhibited by L-arginine, a precursor of NO, and potentiated by L-NMMA, an inhibitor of NO synthesis, indicating the existence of an L-arginine–NO pathway through constitutive NO synthase in platelets during aggregation.8 9 10 This modulation of platelet aggregation by the L-arginine–NO pathway is recognized as a negative-feedback mechanism to inhibit aggregation.11 12
Epidemiological studies have demonstrated that cigarette smoking is a powerful risk factor for the development of atherosclerosis and thrombosis13 14 15 and that discontinuance of smoking is associated with a reduction in the risk of cardiovascular disease.14 16 Although overwhelming epidemiological data link smoking and adverse cardiovascular effects, the underlying mechanisms by which smoking increases the risk of cardiovascular disease have not been fully described. Recently, clinical studies have shown the impairment of endothelium-dependent coronary vasodilation17 18 and forearm vasodilation19 20 in long-term smokers. These findings of smoking-induced vascular endothelial dysfunction suggest the reduced NO release through the L-arginine–NO pathway and may provide important clinical implications for the effect of cigarette smoking on the development of atherosclerosis and thrombosis.
Previous studies have shown the augmented platelet aggregability and the alterations in the clotting cascade in long-term smokers and suggested the exaggerated risk of coronary thrombosis leading to coronary artery disease.21 22 23 It is plausible that in long-term smokers, NO release from platelets may be reduced. Recently, the development of highly selective electrodes24 25 26 for NO measurement has enabled us to measure the real-time release of NO from endothelial cells25 26 27 and platelets.28 29 We therefore investigated with an NO-selective electrode whether long-term smoking impairs platelet-derived NO release, which regulates platelet aggregation.
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Methods |
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Study Subjects
The study groups consisted of 12 healthy men who smoked at least 15 cigarettes per day for >5 years and 11 healthy, age-matched men who never smoked. All subjects had no evidence of other major risk factors, including hypercholesterolemia, hypertension, and diabetes mellitus. Long-term smokers had abstained from smoking for
120 minutes before the start of the investigations to avoid the short-term effects of smoking on platelet function. Written informed consent was obtained from all subjects. The Table
lists the baseline characteristics of the two groups. The baseline characteristics of the nonsmoking and smoking groups were similar in terms of age and sex distribution. The two groups did not differ with respect to blood pressure; heart rate; total cholesterol, HDL, LDL, and fasting blood sugar levels; platelet count; fibrinogen level; prothrombin time; and plasma epinephrine and norepinephrine amounts. The plasma nicotine level was 6.8±1.5 ng/mL in smokers but was not detectable in nonsmokers.
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Preparation of Washed Platelets
Platelet suspensions were prepared according to the previously described method.30 Briefly, 20 mL blood from all subjects who were free of drugs for 2 weeks was collected by venepuncture into a plastic tube containing 3.15% trisodium citrate (1:9 vol/vol) and prostacyclin (2 µg/mL; Sigma Chemical Co) and then centrifuged at 250g for 20 minutes at 22°C. The obtained supernatant, platelet-rich plasma, was recentrifuged at 900g for 10 minutes at 22°C after the addition of prostacyclin (300 ng/mL). The platelet pellet was resuspended in 5 mL Ca2+- and Mg2+-free Tyrode's solution, pH 7.4, containing prostacyclin (300 ng/mL) and centrifuged at 800g for 10 minutes at 37°C. The platelet pellet was resuspended in 1.5 mL Tyrode's solution containing Ca2+ and Mg2+. The platelet concentration was then adjusted to the range of 1 to 2x105 platelets/µL in Tyrode's solution. Tyrode's solution consisted of the following compositions (mmol/L): NaCl 136, KCl 2.7, NaHCO3 12, NaH2PO4·2H2O 0.42, CaCl2 1.8, MgCl2·6H2O 1, glucose 5.5, and HEPES 5, pH 7.4.
Measurement of Electrical Current With an NO-Selective Electrode
The present study was performed with a commercially available NO meter (model NO-501, Inter Medical Co) that measures picoampere-order redox current between the working electrode and the counterelectrode. Briefly, the working electrode consisted of platinum-iridium alloy wire ( 0.2-mm diameter) coated with a three-layered membrane, including the KCl membrane, NO-selective resin, and normal silicone membrane. The counterelectrode was made of carbon fiber (0.5-mm diameter).26 The NO meter and electrodes were placed in an electromagnetic shield box to avoid the electrical perturbation on the electrodes. The two electrodes in the chamber were positioned within 5 mm of each other. The working electrode was supplied with +0.6 V for the electrochemical oxidation of NO diffusing through the membrane to keep the current from possible contaminants of oxygen because electrode responses to oxygen changes were observed at voltages lower than +0.4 V.24 26 The obtained electrical current was then recorded at the rate of 10 mm/min on a strip-chart recorder, and a change in electrical current was considered an index of NO release.
Experimental Protocols
Protocol 1: Effects of SNAP on Electrical Current
The electrodes were carefully put into a small chamber containing Tyrode's solution through a Teflon-coated tube connected to reservoirs placed above the chamber. A nonpulsatile constant perfusion in a Teflon-coated tube was maintained at a flow rate of 1.5 mL/min according to the method of a previous study.26 After the baseline current was stabilized with Tyrode's perfusate at 37°C, the perfusate was switched to that containing SNAP (Inter Medical Co), a direct NO donor. Seven different doses of SNAP from 10-5 to 10-3 mol/L were tested separately, and the electrical current was measured (each dose, n=6).
Protocol 2: Effects of Collagen on Platelet-Derived Electrical Current
The electrodes were placed in the chamber containing washed platelet suspensions obtained from six nonsmokers that were incubated at 37°C with a Teflon-coated stirring bar at 600 rpm. After the baseline current was stabilized, collagen (1, 3, and 5 µg/mL; Nycomed Arzneimittel Co) was added, and the electrical current was measured.
Protocol 3: Effects of L-Arginine or L-NMMA on Platelet-Derived Electrical Currents Induced by Collagen
The electrodes were placed in the chamber containing washed platelet suspensions obtained from six nonsmokers in the presence of L-arginine (100 µmol/L; Sigma Chemical Co) or L-NMMA (300 µmol/L; Wako Chemical Co) that were incubated at 37°C with a stirring bar at 600 rpm. Collagen (3 µg/mL) was added to initiate the reaction, and the electrical current was measured.
Protocol 4: Collagen-Induced Platelet-Derived Electrical Currents in Nonsmokers and Smokers
The electrodes were placed in the chamber containing washed platelet suspensions from 11 nonsmokers or 12 smokers that were incubated at 37°C with a stirring bar at 600 rpm. Collagen (3 µg/mL) was added to initiate the reaction, and the electrical current was measured.
Protocol 5: Measurements of Intraplatelet cGMP Levels in Nonsmokers and Smokers
Intraplatelet cGMP levels were measured in the presence of Tyrode's solution alone, Tyrode's solution plus L-arginine (100 µmol/L), or Tyrode's solution plus L-NMMA (300 µmol/L). Platelet aggregation was induced by collagen (3 µg/mL) and terminated after 5 minutes by the addition of HClO4 (final concentration, 6%). The washed platelet suspension was then sonicated twice for 5 seconds with a tip sonicator (model MS-50, Heat Systems-Ultrasonics Inc) and centrifuged at 12 000g for 2 minutes. Subsequently, the collected supernatant was neutralized with the addition of 200 µL of 60% KOH. After centrifugation (12 000g for 2 minutes), the sample was assayed for the cGMP content by a specific radioimmunoassay kit (Yamasa Shoyu Co). In the present study, the change in the intraplatelet cGMP level after stimulation by collagen (ie, collagen-induced intraplatelet cGMP) was expressed by subtracting the level in the absence of collagen from the level in the presence of collagen.
Protocol 6: Effects of L-Arginine or L-NMMA on Collagen-Induced Platelet Aggregation in Nonsmokers and Smokers
Collagen (3 µg/mL)-induced platelet aggregation was measured in the washed platelet suspension from seven nonsmokers and six smokers as described above. Platelet suspension was preincubated with L-arginine (10, 100, or 300 µmol/L) or L-NMMA (300 µmol/L) for 5 minutes before the addition of collagen. Subsequently, collagen (3 µg/mL) was added, and light transmission was monitored continuously for 5 minutes with a platelet aggregometer (model PAT-4M, MC Medical Co). The extent of aggregation was expressed as the percent change in light transmission, considering the transmission of Tyrode's solution as 100% and that of washed platelet suspension as zero.
Statistical Analysis
Data are expressed as mean±SD. The Mann-Whitney U test was used for comparison of unpaired data. Repeated measures ANOVA with the Scheffe test was applied for multiple comparisons. A linear correlation analysis was used to test dose-response effects. Differences were considered statistically significant when P<.05.
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Results |
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Measurements of Electrical Current With NO-Selective Electrode
Fig 1A
shows the relation between the concentration of SNAP and the change in electrical current. Although Tyrode's solution alone did not produce any electrical current, SNAP caused dose-dependent changes in the electrical current from 4.0±1.2 to 366±37.8 pA. Electrical current exhibited an excellent correlation with the SNAP concentration (r=.99, P<.001). Fig 1B shows the relation between the concentration of collagen and the change in electrical current in six nonsmokers. The addition of collagen induced platelet aggregation and dose dependently increased electrical current from 6.4±1.2 to 23.7±2.7 pA. Electrical current exhibited a high correlation with collagen concentration (r=.94, P<.001). Fig 2A shows representative recordings of the electrical current in washed platelet suspensions induced by collagen in the presence of Tyrode's solution alone, Tyrode's solution plus L-arginine, or Tyrode's solution plus L-NMMA. Fig 2B summarizes the effect of L-arginine or L-NMMA on the collagen-induced platelet-derived electrical current in nonsmokers. The addition of L-arginine significantly augmented electrical current (P<.05), and the addition of L-NMMA significantly attenuated the electrical current (P<.05).
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P<.05 vs L-arginine.
Collagen-Induced Platelet-Derived Electrical Currents in Nonsmokers and Smokers
As Fig 3 shows, the collagen-induced platelet-derived electrical current was significantly smaller in smokers than in nonsmokers (P<.001). Electrical current obtained from smokers did not correlate with the number of cigarettes smoked per day, the smoking period, and the plasma nicotine concentration (data not shown).
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Collagen-Induced Intraplatelet cGMP in Nonsmokers and Smokers
Intraplatelet cGMP levels in the absence of collagen were 2.6±0.8 and 2.5±1.0 pmol/109 platelets in seven nonsmokers and six smokers, respectively. As Fig 4 shows, the collagen-induced intraplatelet cGMP was significantly lower in smokers than in nonsmokers (P<.05). The addition of L-arginine significantly augmented collagen-induced intraplatelet cGMP in nonsmokers and smokers (6.3±1.9 versus 3.4±1.5 pmol/109 platelets for nonsmokers versus smokers; P<.05). The increased level of intraplatelet cGMP was significantly lower in smokers than in nonsmokers (P<.05). The addition of L-NMMA significantly inhibited the collagen-induced increase in intraplatelet cGMP. There was no significant difference in the collagen-induced intraplatelet cGMP levels between nonsmokers and smokers in the presence of L-NMMA. As Fig 5 shows, collagen-induced intraplatelet cGMP exhibited significant correlation with the electrical current (r=.73; P<.01; n=13).
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Effects of L-Arginine or L-NMMA on Collagen-Induced Platelet Aggregation in Nonsmokers and Smokers
As Fig 6 shows, there was no significant difference in collagen-induced platelet aggregation between seven nonsmokers and six smokers (79±7.8% versus 84±7.6%, nonsmokers versus smokers; P=NS). The addition of L-arginine caused a dose-dependent inhibition of collagen-induced platelet aggregation in nonsmokers and smokers. The inhibitory effect of L-arginine on collagen-induced platelet aggregation was significantly smaller in smokers than in nonsmokers (P<.05). The addition of L-NMMA reversed the effect of L-arginine on collagen-induced platelet aggregation. There was no significant difference in collagen-induced platelet aggregation in the presence of L-NMMA between nonsmokers and smokers.
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) and smokers (
). Note that the addition of L-arginine caused a dose-dependent inhibition of collagen-induced platelet aggregation in nonsmokers and smokers (*P<.05 vs the absence of L-arginine). Furthermore, the inhibitory effect of L-arginine on collagen-induced platelet aggregation was significantly smaller in smokers than in nonsmokers ( |
Discussion |
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Epidemiological data have shown that cigarette smoking has a number of adverse effects on the cardiovascular system.14 Previous clinical studies have demonstrated that long-term smoking is associated with the hypercoagulable state, suggesting that long-term smoking promotes platelet aggregation and thrombosis.22 23 However, little information is available on the effects of long-term smoking on platelet function. In the present study, the most important findings are that the levels of both collagen-induced platelet-derived electrical current and intraplatelet cGMP were significantly lower in smokers than in nonsmokers and that the increase in intraplatelet cGMP caused by the addition of L-arginine was significantly smaller in smokers than in nonsmokers. Furthermore, the inhibitory effect of L-arginine on collagen-induced platelet aggregation was significantly smaller in smokers than in nonsmokers. Taken together, these findings may provide evidence that long-term smoking reduces platelet-derived NO release, resulting in augmented platelet aggregation.
Methodological Considerations
In the present study, we assumed that the change in electrical current reflected the amount of NO released from aggregated platelets on the basis of the following findings. First, electrical current showed an excellent correlation with the concentration of SNAP, a direct NO donor. This finding is consistent with the result of recent studies on the same NO-selective electrode.26 31 32 33 34 A previous study demonstrated that 1 mmol/L SNAP corresponds to 1.3 µmol/L NO.26 The estimated amount of NO released from single platelet in nonsmokers was 3.1±1.2x10-19 mol/platelet. This amount in nonsmokers is comparable to the results obtained from a previous study with an NO-selective electrode.29 Second, the electrical current showed high correlation with the collagen concentration from 1 to 5 µg/mL. These findings support previous data demonstrating that collagen induces platelet-derived NO release.28 29 Third, NO is formed from L-arginine by an NADPH-dependent enzyme (NO synthase). The arginine analogue L-NMMA competitively inhibits the formation of NO.35 36 In this study, the collagen-induced electrical current and intraplatelet cGMP were significantly increased by the addition of L-arginine and significantly attenuated by the addition of L-NMMA. These findings suggest the existence of an L-arginine–NO pathway in human platelets, in agreement with results of recent studies,8 28 29 although the constitution of their electrodes was different from ours. Fourth, we have found good correlation between the collagen-induced intraplatelet cGMP and electrical current. These findings support previous results in which the increase in intraplatelet cGMP level is shown to depend on the increase in NO release.8 37 Taken together, these results may indicate that the electrode used in this study is sensitive enough to detect the release of NO from aggregated platelets.
Impaired Platelet-Derived NO Release and Augmented Platelet Aggregability in Long-term Smokers
In the present study, the collagen-induced electrical current was significantly smaller in smokers than in nonsmokers, which may indicate that the release of NO from platelets during aggregation is less in smokers than in nonsmokers. The collagen-induced intraplatelet cGMP was significantly lower in smokers than in nonsmokers. Furthermore, the increase in intraplatelet cGMP level induced by L-arginine was significantly smaller in smokers than in nonsmokers. Because the effect of NO is mediated by cGMP, these findings further support that the NO release during platelet aggregation may be impaired in long-term smokers. The guanylate cyclase–cGMP system plays a key role in regulating platelet functions during aggregation.8 11 Therefore, it is assumed that platelet aggregation may be greater in smokers than in nonsmokers.
In the present study, collagen-induced platelet aggregation in the absence of L-arginine did not differ between nonsmokers and smokers. In a previous study, the IC50 of authentic NO, which can inhibit collagen-induced platelet aggregation, was shown to be 2.5±0.3x10-7 mol/L.6 Under our experimental conditions, the concentrations of NO released from aggregated platelets in the absence of L-arginine were considered to be 5.3±1.9x10-8 and 2.5±0.6x10-8 mol/L in nonsmokers and smokers, respectively. Accordingly, the concentrations of platelet-derived NO obtained in this study may have been too low to inhibit platelet aggregation in the absence of L-arginine.
The addition of L-arginine caused a dose-dependent inhibition of collagen-induced platelet aggregation in the present study. These findings indicate that the L-arginine–NO pathway in platelets plays an active role in modulating platelet aggregation. Furthermore, it is noteworthy that the inhibitory effect of L-arginine on collagen-induced platelet aggregation was significantly smaller in smokers than in nonsmokers. This most likely resulted from reduced platelet-derived NO in smokers. Taken together, our results suggest that the L-arginine–NO pathway as a negative-feedback mechanism of platelet aggregation may be impaired in long-term smokers. Because we cannot determine from our data whether this impairment of platelet-derived NO release in long-term smokers is related to substrate deficiency, a reduction in NO synthase activity, or degradation of NO, further investigations are required.
Other conceivable mechanisms of increased platelet aggregability in long-term smokers are considered. It has been known that smokers generate more thromboxane A2, an eicosanoid released by activated platelets, than nonsmokers, leading to increased platelet aggregability.23 Smokers also have a higher plasma level of fibrinogen, which is a cofactor for platelet aggregation and increases blood viscosity.22 Furthermore, long-term smoking is shown to reduce activity of platelet monoamine oxidase, an enzyme that catalyzes the degradation of catecholamine.38 This increases catecholamine levels, leading to increased platelet aggregability. Although no significant increases in plasma fibrinogen or catecholamine levels were observed in long-term smokers in the present study, they may be involved in the higher platelet aggregability in long-term smokers in addition to the impairment of NO release from platelets.
Study Limitations
In this study, we measured collagen-induced NO release from washed platelets by measuring increases in electrical currents with the NO-selective electrode. We found decreased electrical currents associated with decreased intraplatelet cGMP levels in smokers, suggesting decreased biological activity of NO. This raises the question of whether the decreased biological activity was due to the decreased actual release of NO or the increased degradation of NO. Because smoking is associated with increased oxidative stress, which is known to favor the degradation of radicals like NO,39 it is conceivable that biological activity was reduced, whereas the actual release of NO remained unaffected or was even increased in smokers. In fact, Tschudi et al40 recently reported that the release of NO from mesenteric resistance arteries in SHRSP measured by the NO-selective electrode was smaller than in control Wistar-Kyoto rats. In their study, however, the release of NO was comparable between SHRSP and Wistar-Kyoto rats in the presence of the superoxide scavenger superoxide dismutase, suggesting that a higher production of the radical accounts for the decreased release of NO in SHRSP.40 Therefore, the conclusion that long-term smoking impairs the L-arginine–NO pathway is not fully supported by the data presented. To address this issue, it is important to measure reactive NO intermediates such as peroxynitrite and NO metabolites (nitrite and nitrate) in platelets.
Clinical Implications
The present study may provide some clinical implications. Previous studies have demonstrated that long-term smoking is associated with abnormalities of endothelial vasodilator capacities of coronary and forearm arteries in humans without other risk factors.17 19 20 From the basis of results from this study and these previous studies, the L-arginine–NO pathway may be impaired not only in the endothelium but also in the platelets. Long-term smoking is known to lower levels of HDL cholesterol and to elevate levels of fibrinogen and epinephrine.23 Thus, long-term smoking may impair the L-arginine–NO pathway and may cause platelet aggregation, resulting in thrombosis and atherosclerosis in conjunction with other risk factors. In conclusion, the present study, to the best of our knowledge, provides the first demonstration that long-term smoking impairs the platelet-derived NO release to regulate platelet aggregation. Therefore, these findings may contribute to the understanding of the pathophysiological link between long-term smoking and smoking-related adverse cardiovascular effects.
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Selected Abbreviations and Acronyms |
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Received May 1, 1996; revision received July 15, 1996; accepted July 18, 1996.
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 N. Haramaki, H. Ikeda, K. Takenaka, A. Katoh, R. Sugano, S.-i. Yamagishi, H. Matsuoka, and T. Imaizumi Fluvastatin Alters Platelet Aggregability in Patients With Hypercholesterolemia: Possible Improvement of Intraplatelet Redox Imbalance via HMG-CoA Reductase Arterioscler. Thromb. Vasc. Biol., June 1, 2007; 27(6): 1471 - 1477. [Abstract] [Full Text] [PDF]
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S. R. Willoughby, S. Stewart, A. S. Holmes, Y. Y. Chirkov, and J. D. Horowitz Platelet Nitric Oxide Responsiveness: A Novel Prognostic Marker in Acute Coronary Syndromes Arterioscler. Thromb. Vasc. Biol., December 1, 2005; 25(12): 2661 - 2666. [Abstract] [Full Text] [PDF]
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 H. Morita, H. Ikeda, N. Haramaki, H. Eguchi, and T. Imaizumi Only two-week smoking cessation improves platelet aggregability and intraplatelet redox imbalance of long-term smokers J. Am. Coll. Cardiol., February 15, 2005; 45(4): 589 - 594. [Abstract] [Full Text] [PDF]
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J. A. Ambrose and R. S. Barua The pathophysiology of cigarette smoking and cardiovascular disease: An update J. Am. Coll. Cardiol., May 19, 2004; 43(10): 1731 - 1737. [Abstract] [Full Text] [PDF]
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 S. Tsiara, M. Elisaf, and D. P. Mikhailidis Influence of Smoking on Predictors of Vascular Disease Angiology, September 1, 2003; 54(5): 507 - 530. [Abstract] [PDF]
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Y. Takajo, H. Ikeda, N. Haramaki, T. Murohara, and T. Imaizumi Augmented oxidative stress of platelets in chronic smokers: Mechanisms of impaired platelet-derived nitric oxide bioactivity and augmented platelet aggregability J. Am. Coll. Cardiol., November 1, 2001; 38(5): 1320 - 1327. [Abstract] [Full Text] [PDF]
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N. Haramaki, H. Ikeda, Y. Takajo, A. Katoh, S. Kanaya, S. Shintani, R. Haramaki, T. Murohara, and T. Imaizumi Long-Term Smoking Causes Nitroglycerin Resistance in Platelets by Depletion of Intraplatelet Glutathione Arterioscler. Thromb. Vasc. Biol., November 1, 2001; 21(11): 1852 - 1856. [Abstract] [Full Text] [PDF]
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J. Loscalzo Nitric Oxide Insufficiency, Platelet Activation, and Arterial Thrombosis Circ. Res., April 27, 2001; 88(8): 756 - 762. [Abstract] [Full Text] [PDF]
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 H. Ikeda, Y. Takajo, T. Murohara, K. Ichiki, H. Adachi, N. Haramaki, A. Katoh, and T. Imaizumi Platelet-Derived Nitric Oxide and Coronary Risk Factors Hypertension, April 1, 2000; 35(4): 904 - 907. [Abstract] [Full Text] [PDF]
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J. H. Markovitz, L. Tolbert, and S. E. Winders Increased Serotonin Receptor Density and Platelet GPIIb/IIIa Activation Among Smokers Arterioscler. Thromb. Vasc. Biol., March 1, 1999; 19(3): 762 - 766. [Abstract] [Full Text] [PDF]
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J. E. Freedman, B. Ting, B. Hankin, J. Loscalzo, J. F. Keaney Jr, and J. A. Vita Impaired Platelet Production of Nitric Oxide Predicts Presence of Acute Coronary Syndromes Circulation, October 13, 1998; 98(15): 1481 - 1486. [Abstract] [Full Text] [PDF]
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