Stable angina and acute coronary syndromes are associated with nitric oxide resistance in platelets

Chirkov, Yuliy Y.; Holmes, Andrew S.; Stewart, Simon; Wuttke, Ronald D.; Sage, P.; Horowitz, John D.

doi:10.1016/s0735-1097(01)01238-4

Cited by 70 publications

(63 citation statements)

References 30 publications

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“…Also, NO fails to inhibit platelet aggregation to the same extent in patients with stable angina or acute coronary syndromes compared with nonischemic patients. 28 Consistent with these data, we found an in vivo insulin infusion to increase cGMP in platelets of insulin-sensitive but not insulin-resistant obese subjects. However, we cannot conclude that this is an exclusively NO-mediated defect, because direct NO donors or NO synthase inhibitors were not used.…”

Section: Discussionsupporting

confidence: 88%

Inhibition of Platelet-Collagen Interaction

Westerbacka

Yki‐Järvinen

Turpeinen

et al. 2002

ATVB

120

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Abstract-Insulin resistance is associated with an increased risk of atherothrombotic vascular disease, but the mechanisms are poorly understood. We determined how insulin in vivo regulates platelet activation in nonobese and obese subjects by using methods mimicking thrombus formation. Twelve nonobese (aged 42Ϯ2 years, body mass index 24.0Ϯ0.4 kg/m 2 ) and 14 obese (aged 43Ϯ1 years, body mass index 37.2Ϯ1.5 kg/m 2 ) subjects were studied under euglycemic hyperinsulinemic (3-hour insulin infusion of 1 mU · kg Ϫ1 · min Ϫ1) conditions. Before and at the end of hyperinsulinemia, the following were determined: (1) platelet-related early hemostasis (shear rate of Ϸ4000 s Ϫ1) by platelet function analysis; (2) platelet deposition to collagen during whole-blood perfusion (shear rate of 1600 s Ϫ1 ); (3) aggregation responses to collagen, thrombin receptor-activating peptide, ADP, and epinephrine; and (4) platelet cGMP concentrations. Insulin action on glucose metabolism was 69% lower in the obese subjects (1.6Ϯ0.2 mg · kg Ϫ1 · min Ϫ1) than in the nonobese subjects (5.4Ϯ0.4 mg · kg Ϫ1 · min Ϫ1, PϽ0.0001). The in vivo insulin infusion inhibited platelet deposition to collagen from 4.3Ϯ0.6ϫ10 6 to 3.5Ϯ0.4ϫ10 6 per square centimeter in the nonobese subjects (PϽ0.05) but failed to do so in the obese subjects (5.2Ϯ0.8ϫ10 6 versus 5.5Ϯ0.7ϫ10 6 per square centimeter, PϭNS; PϽ0.01 versus nonobese subjects). Epinephrine-and ADP-primed closure times by platelet function analysis were prolonged by insulin in the nonobese but not the obese subjects (PϽ0.05 for between-group difference). In the nonobese subjects, insulin decreased aggregation to all agonists and significantly increased platelet cGMP concentrations (2.5Ϯ0.3 versus 3.2Ϯ0.5 pmol/10 9 for before versus after insulin, respectively; PϽ0.01). In the obese subjects, insulin did not alter collagen-induced aggregation or cGMP concentrations (1.9Ϯ0.2 versus 1.8Ϯ0.1 pmol/10 9 for before versus the end of in vivo hyperinsulinemia, respectively; PϭNS). These data demonstrate that normal in vivo insulin action inhibits platelet interaction with collagen under conditions mimicking thrombus formation and reduces aggregation to several agonists. These platelet-inhibitory actions of insulin are blunted or absent in obese subjects and could provide 1 mechanism linking insulin resistance to atherothrombotic disease. Key Words: insulin Ⅲ collagen Ⅲ nitric oxide Ⅲ obesity Ⅲ cGMP I nsulin resistance predisposes individuals to atherothrombotic vascular disease, but the mechanisms are incompletely understood. Human platelets have insulin receptors that participate in the regulation of platelet functions. 1 In vitro and in vivo studies have demonstrated that insulin inhibits platelet aggregation in healthy nonobese subjects. [2][3][4] In obese 2 and hypertensive 5 subjects, this antiaggregating effect of in vitro insulin has been shown to be blunted. These data suggest that insulin resistance also involves platelets, but it is currently unknown whether the resistance of platelets to insulin occ...

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Section: Discussionsupporting

confidence: 88%

Inhibition of Platelet-Collagen Interaction

Westerbacka

Yki‐Järvinen

Turpeinen

et al. 2002

ATVB

120

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“…113 Finally, therapy with statins also appears to improve platelet reactivity to GTN in patients with stable or unstable coronary syndromes. 13 …”

Section: Statinsmentioning

confidence: 99%

Nitrate Therapy

2011

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A lthough the short-term vasodilatory properties of organic nitrates are potent and well known, a number of vascular and extravascular changes have been shown to compromise their hemodynamic effects on long-term administration. Among these changes, systemic phenomena such as neurohormonal activation and intravascular volume expansion 1 as well as specific vascular changes such as increased vascular superoxide (O 2 ·Ϫ ) production, 2 increased sensitivity to vasoconstrictors, 3 and decreased responsiveness to nitric oxide (NO) donors 4,5 have long been identified as playing a role. Several hypotheses have been proposed to explain these abnormalities, and over the last 15 years, our groups have focused on the concept that an inappropriate production of reactive oxygen species (ROS), an impairment in the scavenging of these mediators (Figure 1), or both might have a crucial mechanistic importance in all these modifications. 6,7 Independently of the role of ROS in tolerance, the possibility that nitrate-induced oxidative stress might affect patients' prognosis has important implications, and the observation that long-term therapy with most of the drugs in this class causes endothelial dysfunction, the prognostic significance of which is well accepted in patients with coronary artery disease, hypertension, and heart failure, 8 should not be taken as an academic curiosity.Beyond these as-yet insufficiently investigated prognostic implications, recognition of the role of ROS suggests that a number of interventions thought to interfere with the vascular redox balance might also retard or prevent the development of nitrate tolerance and nitrate-induced side effects. Evidence that therapy with angiotensin-converting enzyme (ACE) inhibitors, angiotensin-1 receptor blockers, certain ␤-blockers, statins, and vitamins such as folic acid or vitamin C beneficially influence nitrate tolerance and glyceryl trinitrate (GTN)-induced endothelial dysfunction suggests that nitrate therapy might have profoundly different implications since these therapies have become diffusely available. In addition, the recognition of important differences in the mechanisms triggered by different nitrates should also be attributed clinical relevance, and evidence suggests that, rather than the generic nitrate tolerance, more specific expressions (GTN tolerance, isosorbide mononitrate [ISMN] tolerance, etc) should be used. 9 This review summarizes the current concepts underlying tolerance and endothelial dysfunction in response to longterm therapy with different nitrates and addresses the question of whether the use of these drugs remains indicated despite these side effects. The Hemodynamic Effects of NitratesVenous capacitance vessels, large and medium-sized coronary arteries, and collateral vessels are most sensitive to GTN, whereas coronary and peripheral arterioles with a diameter Ͻ100 m are relatively more resistant. In the setting of stable angina, the preferential venodilatation induced by antiischemic doses of GTN results in venous pooling an...

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“…9,13 Evidence is also emerging that circulating blood platelets exhibit a range of functional abnormalities in patients with coronary risk factors 14 -16 and with overt ischemic heart disease. [17][18][19] We have previously demonstrated the phenomenon of platelet resistance to the antiaggregatory effects of nitric oxide (NO) and prostacyclin in patients with stable angina pectoris. 20,21 In addition, we have recently documented that the presence of ACS is associated with more marked impairment of platelet responses to NO than are present in patients with stable angina pectoris.…”

mentioning

confidence: 99%

“…20,21 In addition, we have recently documented that the presence of ACS is associated with more marked impairment of platelet responses to NO than are present in patients with stable angina pectoris. 18,22 Resistance to NO-induced inhibition of platelet aggregation is mediated both by increased concentrations of superoxide anion and by partial inactivation of soluble guanylate cyclase. 21 Furthermore, a number of agents, such as angiotensin-converting enzyme (ACE) inhibitors, 23 the antianginal agent perhexiline, 22 acute insulin therapy, 24 and possibly statins, 25 ameliorate platelet NO resistance.…”

mentioning

confidence: 99%

Platelet Nitric Oxide Responsiveness

Stewart

Holmes

Chirkov

et al. 2005

ATVB

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Objectives-Nitric oxide (NO) is critically important in the regulation of vascular tone and the inhibition of platelet aggregation. We have shown previously that patients with acute coronary syndromes (ACS) or stable angina pectoris have impaired platelet responses to NO donors when compared with normal subjects. We tested the hypotheses that platelet hyporesponsiveness to NO is a predictor of (1) cardiovascular readmission and/or death and (2) all-cause mortality in patients with ACS (unstable angina pectoris or non-Q-wave myocardial infarction). Methods and Results-Patients (nϭ51) with ACS had evaluation of platelet aggregation within 24 hours of coronary care unit admission using impedance aggregometry. Patients were categorized as having "normal" (Ն32% inhibition of ADP-induced aggregation with the NO donor sodium nitroprusside; 10 mol/L; nϭ18) or "impaired" (Ͻ32% inhibition of ADP-induced aggregation; nϭ33) NO responses. We then compared the incidence of cardiovascular readmission and death during a median of 7 years of follow-up in these 2 groups. Key Words: nitric oxide Ⅲ platelets Ⅲ acute coronary syndrome Ⅲ nitric oxide resistance I t is currently considered that elements in the pathophysiology of acute coronary syndromes (ACS), such as acute myocardial infarction (AMI) and unstable angina pectoris (UAP), include antecedent inflammatory states 1 and rupture of coronary atheromatous plaques, 2 followed by activation of platelet adhesion/aggregation, vasospasm, and thrombus formation. 3 There is also considerable evidence that one of the factors predisposing to the development of coronary atheroma and the emergence of ACS is "endothelial dysfunction," generally defined as an impaired vasodilator response 4,5 or a paradoxical constrictor response to endothelium-dependent agents, such as acetylcholine. 6 More recently, it has been recognized that patients with endothelial dysfunction may also exhibit attenuated responses to endothelium-independent vasodilators, such as nitroglycerin (NTG) 7-10 and sodium nitroprusside (SNP). 11,12 This impaired vasodilator response within the coronary circulation is predictive of poor long-term outcomes. 9,13 Evidence is also emerging that circulating blood platelets exhibit a range of functional abnormalities in patients with coronary risk factors 14 -16 and with overt ischemic heart disease. [17][18][19] We have previously demonstrated the phenomenon of platelet resistance to the antiaggregatory effects of nitric oxide (NO) and prostacyclin in patients with stable angina pectoris. 20,21 In addition, we have recently documented that the presence of ACS is associated with more marked impairment of platelet responses to NO than are present in patients with stable angina pectoris. 18,22 Resistance to NO-induced inhibition of platelet aggregation is mediated both by increased concentrations of superoxide anion and by partial inactivation of soluble guanylate cyclase. 21 Furthermore, a number of agents, such as angiotensin-converting enzyme (ACE) inhibitors, 23 the antianginal...

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Stable angina and acute coronary syndromes are associated with nitric oxide resistance in platelets

Cited by 70 publications

References 30 publications

Inhibition of Platelet-Collagen Interaction

Inhibition of Platelet-Collagen Interaction

Nitrate Therapy

Platelet Nitric Oxide Responsiveness

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