Platelet Nitric Oxide and Superoxide Release During the Development of Nitrate Tolerance

McVeigh, Gary E.; Hamilton, Paul; Wilson, Martin; Hanratty, Colm G.; Leahey, William J.; Devine, Adrian; Morgan, David; Dixon, Lana; McGrath, Lawrence T.

doi:10.1161/01.cir.0000021600.84149.78

Cited by 42 publications

(39 citation statements)

References 40 publications

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“…al 39 reported reduced hemodynamic effects in diabetic patients and (as mentioned above) that GTN-induced inhibition of platelet aggregability is blunted in patients with coronary artery disease or diabetes. To date, it remains unclear whether these different forms of reduced responsiveness to nitrates share common mechanisms (eg, dysfunction of downstream NO signaling pathways) or should rather be considered 2 distinct entities.…”

Section: Nitrate Tolerancementioning

confidence: 84%

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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Section: Nitrate Tolerancementioning

confidence: 84%

Nitrate Therapy

2011

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“…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. 18 NO detection was decreased in the eNOS uncoupled group, as was endothelium-dependent and -independent vasodilation.…”

Section: Discussionmentioning

confidence: 99%

“…Platelet O 2 ·Ϫ production was measured by lucigenin-enhanced chemiluminescence, as described by McVeigh et al 11,12 Samples were analyzed in the presence of the eNOS inhibitor L-NAME (1 mmol/L) to allow for NO scavenging of O 2 ·Ϫ , superoxide dismutase (200 u/mL) to confirm the identity of O 2 ·Ϫ , and diphenyliodonium (DPI); 100 mol/L) and quinacrine (1.0 mmol/L), potent inhibitors of flavoprotein C containing oxidoreductases including NAD(P)H and eNOS.…”

Section: Measurement Of Superoxide Productionmentioning

confidence: 99%

“…[7][8][9] Platelets contain all components of the L-arginine-nitric oxide pathway 10 and represent an accessible alternative to endothelial cells for functional studies. 11,12 Furthermore, as platelets share similar contractile systems with vascular smooth muscle, activity of the NO pathway and O 2 ·Ϫ generation in platelets may relate to changes in smooth muscle tone. Using this model, we examined whether eNOS uncoupling occurs in human CCF and investigated the functional consequences of eNOS uncoupling in relation to changes in platelet-derived NO and forearm blood flow.…”

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confidence: 99%

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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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“…9 Assessing the effects of wave reflection in altering the pressure pulse waveshape has proven valuable in marking altered structure or tone in the vasculature and is a sensitive tool for studying the hemodynamic actions of drug interventions. 3,13 For example, nitroglycerin administration produces marked changes in the pressure pulse waveshape, which can be dissociated from a change in total peripheral resistance or the pulse transit time measured by aortic pulse wave velocity. 14,15 The effects are explained by changes in the mechanical properties of peripheral muscular arteries that result in improved impedance matching and attenuation of wave reflection in response to nitroglycerin.…”

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confidence: 99%

Editorial Commentary

McVeigh¹

2003

Hypertension

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R isk factors for cardiovascular disease mediate their effects by altering the structure, properties, and function of wall and endothelial components of arterial blood vessels. 1 The ability to detect and monitor change in the physical properties of arteries, representative of the cumulative and integrated influence of hemodynamic, metabolic, and inflammatory stimuli in impairing arterial wall integrity, holds potential to intervene at a preclinical stage to prevent or attenuate disease progression. The importance of assessing arterial wall integrity has been highlighted by recent studies demonstrating that a decrease in the pulsatile function of large arteries represents an independent predictor for future cardiovascular events. 2 Information about the interaction between the left ventricle and the physical properties of the arterial circulation can be derived by the descriptive and quantitative analysis of the arterial pressure pulse waveform. 3 Consistent characteristic changes in the pressure pulse waveshape have been described with aging and disease states predisposing to an increase in vascular events. One such age-related change involves a steepening of the pressure decay in diastole, largely determined by impaired buffering function of the proximal aorta. 3,4 Loss of the oscillatory waveform that distorts the proximal portion of diastole from a pure exponential represents a further early and consistent finding with aging and risk factors for cardiovascular disease including hypertension, smoking, and diabetes mellitus. [3][4][5][6][7] This feature arises from reflection of the incident pressure wave generated by the left ventricle from peripheral reflecting sites with a major contribution originating from impedance mismatches in small arteries and arterioles. The progressive appearance of the reflected wave in systole and eventual summation with the forward incident wave results in augmentation of the systolic blood pressure. Given the proximity of the central aorta to the major peripheral reflecting sites in the lower limbs, augmentation of the systolic blood pressure occurs in this vessel before changes are recorded in the upper limb vessels. Recently, techniques based on the determination of a pressure transfer function between the radial artery and the aorta have been employed to provide an estimate of central pressure wave reflection. 8 In this issue of Hypertension, Millasseau et al 9 report on the accuracy of employing a generalized transfer function to the radial artery pressure pulse waveform to provide an estimate of the aortic augmentation index. The accuracy of the approach was assessed against data derived directly from the carotid pressure pulse waveform or after application of a transfer function to the waveform. The authors confirm prior observations that indicate the use of a general transfer function can show a considerable amount of bias and variation that limits the utility of this approach in accurately predicting the central augmentation index. 10,11 Further support for this content...

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Platelet Nitric Oxide and Superoxide Release During the Development of Nitrate Tolerance

Cited by 42 publications

References 40 publications

Nitrate Therapy

Nitrate Therapy

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

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