Platelet-Derived Nitric Oxide and Coronary Risk Factors

Ikeda, Hisao; Takajo, Yoshinori; Murohara, Toyoaki; Ichiki, Kazuya; Adachi, Hisashi; Haramaki, Nobuya; Katoh, Atsushi; Imaizumi, Tsutomu

doi:10.1161/01.hyp.35.4.904

Cited by 58 publications

(38 citation statements)

References 24 publications

(26 reference statements)

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“…An NO-selective electrode is specifically capable of measuring real-time release of NO from aggregating platelets, 17 and we have previously confirmed that the change in the electrical current obtained by the NO-selective electrode reflects the amount of NO released through the L-arginine/NO pathway in aggregating human platelets. 7 Recently, we demonstrated that the number of coronary risk factors correlates with the degree of an impairment of PDNO release by human platelets, 13 and we had a similar finding in the present study. All these findings suggest that the L-arginine/NO pathway, which is a negative feedback mechanism that inhibits platelet aggregation, is indeed impaired in patients with coronary risk factors.…”

Section: Discussionsupporting

confidence: 89%

“…7,13,14 The NO meter and electrodes were placed in an electromagnetic shield box to avoid electrical perturbation. The electrodes were placed in the chamber containing the gel-filtered platelets and after the addition of Ca 2+ and fibrinogen, followed by ADP (5 mol/ml), the working electrode was supplied with +0.6 V for electrochemical oxidation of NO.…”

Section: Measurements Of Pdno With An No-specific Electrodementioning

confidence: 99%

“…6,7 PDNO release during platelet aggregation is now recognized as a negative-feedback mechanism to inhibit not only platelet aggregation 8 but also platelet recruitment. 9 Coronary risk factors are known to impair both EDNO [10][11][12]7,13,14 however, there has not been a study measuring both EDNO and PDNO simultaneously in the same subjects, so it is still unknown whether impairment of these bioactivities coexist. Therefore, we investigated the relationship between EDNO and PDNO in patients with coronary risk factors.…”

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confidence: 99%

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Coexistence of Impairment of Endothelium-Derived Nitric Oxide and Platelet-Derived Nitric Oxide in Patients With Coronary Risk Factors.

Katoh

Ikeda

Takajo

et al. 2002

Circ J

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ndothelium-derived nitric oxide (EDNO), which accounts for the major biological properties of the endothelium-derived relaxing factor, 1 is synthesized from L-arginine via NO synthase (NOS). 2 NO is a single molecule with profound effects on cardiovascular physiology: it inhibits pathologic processes such as abnormal arterial vasomotion, thrombosis, and vascular smooth muscle cell proliferation. [3][4][5] In humans, platelet-derived NO (PDNO) is also produced by the L-arginine/NO pathway through constitutive NOS. 6 Platelet aggregation is inhibited by L-arginine, a precursor of NO, potentiated by NGmonomethyl-L-arginine, an inhibitor of NOS, 6,7 and is accompanied by an increase in intracellular cyclic guanosine 3', 5'-monophosphate. 6,7 PDNO release during platelet aggregation is now recognized as a negative-feedback mechanism to inhibit not only platelet aggregation 8 but also platelet recruitment. 9 Coronary risk factors are known to impair both EDNO [10][11][12]7,13,14 however, there has not been a study measuring both EDNO and PDNO simultaneously in the same subjects, so it is still unknown whether impairment of these bioactivities coexist. Therefore, we investigated the relationship between EDNO and PDNO in patients with coronary risk factors. Circulation Journal Vol.66, September 2002 Methods Study PatientsThe study group comprised 24 patients (17 men, 7 women; mean age, 67 years; range, 46-78 years) who underwent diagnostic cardiac catheterization and coronary arteriography. Femoral arterial endothelial function and PDNO release were studied in all patients. All cardiovascular medications were withheld for at least 72 h before the study. None of the patients had acute coronary syndromes, heart failure, or valvular heart disease. The study was approved by the institutional ethical committee, and written informed consent was obtained from all patients.The coronary risk factors were hypertension (arterial blood pressure ≥140/90 mmHg), hypercholesterolemia (total serum cholesterol ≥220 mg/dl), current smoking (subjects who smoked ≥15 cigarettes per day for ≥5 years), diabetes mellitus (fasting glucose ≥126 mg/dl and/or plasma glucose ≥200 mg/dl 2 h after glucose administration), age (men ≥45 years old, women ≥55 years old or postmenopausal), 15 and a family history of coronary artery disease. Family history was considered positive if a firstdegree relative had clinical evidence of coronary artery disease at less than 55 years of age in male relatives or less than 65 years in female relatives. 15 Assessment of Femoral Arterial FunctionAfter cardiac catheterization, femoral arterial endothelial function was assessed using a Doppler flow-wire technique as previously described. 16 Briefly, a 5F angiographic catheter was introduced 1 cm beyond the end of a 6F femoral artery sheath and then a 0.018-in Doppler flow-wire (Cardiometrics Inc) was introduced through the catheter to 1 cm beyond the catheter tip to obtain an adequate flow velocity Circ J 2002; 66: 837 -840 (Received February 20, 2002; revised manuscri...

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Section: Discussionsupporting

confidence: 89%

Section: Measurements Of Pdno With An No-specific Electrodementioning

confidence: 99%

mentioning

confidence: 99%

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Coexistence of Impairment of Endothelium-Derived Nitric Oxide and Platelet-Derived Nitric Oxide in Patients With Coronary Risk Factors.

Katoh

Ikeda

Takajo

et al. 2002

Circ J

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“…30,35 Despite controversy, consistent data suggest that platelet-derived NO participates in platelet inhibition and thrombosis prevention and that conditions characterized by defective platelet NO production, such as hypertension or treatment with some antiretroviral drugs, are associated with an enhanced risk of ischemic cardiovascular events. 18,19,36 Recent data showing impaired cGMP formation and enhanced platelet reactivity in patients with myocardial infarction carrying 2 gene mutations affecting soluble guanylyl cyclase function confirm the importance of NO-mediated platelet inhibition in the prevention of thrombosis. 37 Therefore, to clarify the role of platelet-derived NO in the antithrombotic effects of dl-nebivolol, we used chimeric mice.…”

Section: Discussionmentioning

confidence: 97%

Stimulation of Platelet Nitric Oxide Production by Nebivolol Prevents Thrombosis

Momi

Caracchini

Falcinelli

et al. 2014

ATVB

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H ypertension is associated with an increased risk of arterial thrombotic events, such as stroke and myocardial infarction, 1 in which platelets are deeply involved. Previous studies have shown that β-adrenoceptor blockers reduce platelet activation and aggregation, 2 but this does not seem to be a class effect because not all β-blockers share this property. 3 dl-Nebivolol (a racemic mixture of d-and l-nebivolol) is a third-generation β 1 adrenoceptor-selective antagonist that, besides its β-blockade-mediated hypotensive effect, possesses direct vasodilatory properties through a mechanism involving the l-arginine/nitric oxide (NO) pathway. 4,5 Of the 2 enantiomers forming the racemic mixture of dl-nebivolol, d-nebivolol, which has an ≈200-fold greater affinity for β 1 -adrenoceptors than that of l-nebivolol, seems to be mainly responsible of selective β-blockade, 6 whereas the l-form is the main effector of the endothelium-dependent vasorelaxant effect. 7,8 dl-Nebivolol exerts its vasodilatory action by activating endothelial nitric oxide synthase (eNOS) and by preventing eNOS uncoupling, thus enhancing NO production. 9 Endothelium-derived NO is a powerful inhibitor of platelet activation and an antithrombotic agent. 10,11 Besides endothelium, eNOS is present in other cells, including platelets, [12][13][14] and several in vitro and in vivo observations in animals and in humans suggest that platelet-derived NO plays a significant anti-inflammatory and antithrombotic role. [15][16][17][18][19] dl-Nebivolol was previously reported to inhibit ADP-and collagen-induced aggregation of human platelets in vitro, 20 an effect prevented by the previous exposure of platelets to a NOS inhibitor, such as L-NG-nitroarginine methyl ester, and enhanced by preincubation with l-arginine, the substrate of NOS, suggesting that the antiplatelet effect of dl-nebivolol is mediated by an enhanced release of NO from platelets. 4 © 2014 American Heart Association, Inc. Objective-dl-Nebivolol, a selective β1-adrenergic receptor antagonist, besides its hypotensive activity exerts vasodilatory and platelet inhibitory effects in vitro by a mechanism involving nitric oxide (NO). Our aim was to evaluate whether nebivolol exerts in vivo antithrombotic effects, to unravel the mechanism of this action and to clarify the relative roles of its 2 enantiomers: d-and l-nebivolol. Methods and Results-In wild-type mice, dl-nebivolol, l-nebivolol, and d-nebivolol, but not bisoprolol, reduced mortality consequent to platelet pulmonary thromboembolism induced by the intravenous injection of collagen plus epinephrine (−44%, −45%, −29%, respectively; P<0.05), whereas in eNOS −/− mice only dl-nebivolol and d-nebivolol were effective. dl-Nebivolol, l-and d-nebivolol reduced photochemical damage-induced femoral artery thrombosis in wild-type mice, whereas in eNOS −/− mice only dl-nebivolol and d-nebivolol were active. Moreover, dl-nebivolol and l-nebivolol increased plasma, urinary-, and platelet-derived nitrites and nitrates (NOx), NO degradation products, in ...

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“…16 Platelet-derived NO release and endothelium-derived NO-mediated vasodilatation is impaired with conventional cardiovascular risk factors, a fact that supports a link between the L-arginine-NO ·Ϫ pathway in platelets and endothelial cells. 17 We have previously used the platelet as a compartmentalized tissue model to study the interaction of NO and O 2 ·Ϫ and the functional consequences associated with altered platelet reactivity. 11,12 All components of the L-arginine-NO pathway present in endothelial cells are found in platelets, and eNOS protein has been identified in platelets by Western blotting.…”

Section: Discussionmentioning

confidence: 99%

Functional Consequences of Endothelial Nitric Oxide Synthase Uncoupling in Congestive Cardiac Failure

Dixon¹,

Morgan²,

Hughes³

et al. 2003

Circulation

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Background-Impaired endothelium-mediated vasodilatation (EMVD) in congestive cardiac failure (CCF) has been linked to decreased nitric oxide (NO) bioavailability because of its interaction with vascular superoxide (O 2 ·Ϫ ), derived predominantly from NAD(P)H-dependent oxidases. When uncoupled from essential cofactors, endothelial nitric oxide synthase (eNOS) produces O 2 ·Ϫ . We studied the functional consequences of eNOS uncoupling in relation to EMVD in patients with CCF. Methods and Results-We employed the platelet as a compartmentalized ex-vivo model to examine O 2 ·Ϫ and NO production. When eNOS is functioning normally, incorporation of N -Nitro-L-Arginine methyl ester (L-NAME, 1 mmol/L), results in increased O 2 ·Ϫ detection, as inhibition of NO production prevents NO scavenging of O 2 ·Ϫ . This was observed in controls and 9 of the CCF patients, in whom O 2 ·Ϫ detection increased by 63% and 101%, respectively. In the remaining 9 CCF patients, incorporation of L-NAME reduced O 2 ·Ϫ production by 39%, indicating O 2 ·Ϫ production by eNOS uncoupling. Detection of platelet-derived NO was significantly greater in eNOS-coupled platelets compared with the uncoupled group (2.8Ϯ1.4 versus 0.9Ϯ0.4 pmol/10 8 platelets, Pϭ0.04). Endothelium-dependent and -independent vasodilator responses to acetylcholine and sodium nitroprusside recorded using venous occlusion plethysmography were significantly impaired in patients exhibiting eNOS uncoupling. Conclusions-This study provides first evidence that platelet eNOS can become uncoupled in human CCF. Impaired endothelium-dependent and -independent vasodilator responses and diminished platelet-derived NO production occurred in association with enzyme uncoupling.

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Platelet-Derived Nitric Oxide and Coronary Risk Factors

Cited by 58 publications

References 24 publications

Coexistence of Impairment of Endothelium-Derived Nitric Oxide and Platelet-Derived Nitric Oxide in Patients With Coronary Risk Factors.

Coexistence of Impairment of Endothelium-Derived Nitric Oxide and Platelet-Derived Nitric Oxide in Patients With Coronary Risk Factors.

Stimulation of Platelet Nitric Oxide Production by Nebivolol Prevents Thrombosis

Functional Consequences of Endothelial Nitric Oxide Synthase Uncoupling in Congestive Cardiac Failure

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