Visualization of nitric oxide production by individual platelets during adhesion in flowing blood

Cozzi, Marzia; Guglielmini, Giuseppe; Battiston, Monica; Momi, Stefania; Lombardi, Elisabetta; Miller, E. C.; Zanet, Denise De; Mazzucato, M.; Gresele, Paolo; Marco, Luigi De

doi:10.1182/blood-2014-06-579474

Cited by 32 publications

(25 citation statements)

References 56 publications

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“…Thrombin and collagen might increase cGMP levels slightly involving Lyn kinase, although this has not been confirmed by other studies 1, 53. Platelet‐derived NO might contribute to sGC activation and platelet NO synthesis has recently been observed by microscopy 54. Stimulation of NO production by L‐nebivolol results in reduced thrombosis in mice,55 however, the presence of any NO‐synthase in platelets has been disputed,51, 56 indicating that NO might be released from other currently unknown sources.…”

Section: Interactions At Receptor Levelmentioning

confidence: 83%

“…1,53 Platelet-derived NO might contribute to sGC activation and platelet NO synthesis has recently been observed by microscopy. 54 Stimulation of NO production by L-nebivolol results in reduced thrombosis in mice, 55 however, the presence of any NO-synthase in platelets has been disputed, 51,56 indicating that NO might be released from other currently unknown sources. Crossactivation of cGMP production by platelet activators like VWF has 57 Similarly, platelets from patients lacking sGC expression do not aggregate well in response to low ADP concentrations, and platelet adhesion to collagen and VWF is attenuated.…”

Section: No and Sgcmentioning

confidence: 99%

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Cyclic nucleotide‐dependent inhibitory signaling interweaves with activating pathways to determine platelet responses

Nagy

Smolenski

2018

Research and Practice in Thrombosis and Haemostasis

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Platelets are regulated by extracellular cues that impact on intracellular signaling. The endothelium releases prostacyclin and nitric oxide which stimulate the synthesis of cyclic nucleotides cAMP and cGMP leading to platelet inhibition. Other inhibitory mechanisms involve immunoreceptor tyrosine‐based inhibition motif‐containing receptors, intracellular receptors and receptor desensitization. Inhibitory cyclic nucleotide pathways are traditionally thought to represent a passive background system keeping platelets in a quiescent state. In contrast, cyclic nucleotides are increasingly seen to be dynamically involved in most aspects of platelet regulation. This review focuses on crosstalk between activating and cyclic nucleotide‐mediated inhibitory pathways highlighting emerging new hub structures and signaling mechanisms. In particular, interactions of plasma membrane receptors like P2Y12 and GPIb/IX/V with the cyclic nucleotide system are described. Furthermore, differential regulation of the RGS18 complex, second messengers, protein kinases, and phosphatases are presented, and control over small G‐proteins by guanine‐nucleotide exchange factors and GTPase‐activating proteins are outlined. Possible clinical implications of signaling crosstalk are discussed.

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Section: Interactions At Receptor Levelmentioning

confidence: 83%

Section: No and Sgcmentioning

confidence: 99%

Cyclic nucleotide‐dependent inhibitory signaling interweaves with activating pathways to determine platelet responses

Nagy

Smolenski

2018

Research and Practice in Thrombosis and Haemostasis

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“…The intensification of the signal was dependent on the presence of the NOS substrate (L-arginine), as well as of the competitive NOS inhibitor (L-NMMA). Despite the low concentrations of nitric oxide produced in platelets (compared to the endothelial cells) [82], it appears to have an important role in the aggregation of thrombocytes. According to Tymvios et al, platelet aggregation is regulated by endogenous NO.…”

Section: Nos Pathway In Platelets (Figure 4)mentioning

confidence: 97%

“…Subjects to doubt were, among others, contamination of the probes with another blood cells [77], lack of specificity of used assays [78], measurement of cGMP activity or the amount of L-citrulline as indicators of NOS activity without considering other metabolic pathways [79,80], or measurement of inorganic NO metabolites [81]. Finally, Cozzi et al directly visualized the nitric oxide production by collagen-induced platelets using an NO-specific fluorescent agent-4-amino-5-methylamino-2′,7′-difluorofluorescein diacetate (DAF-FM) [82]. This agent reacts with NO and provides a fluorescent signal.…”

Section: Nos Pathway In Platelets (Figure 4)mentioning

confidence: 99%

Intraplatelet L-Arginine-Nitric Oxide Metabolic Pathway: From Discovery to Clinical Implications in Prevention and Treatment of Cardiovascular Disorders

Gawryś

Gajecki

Szahidewicz-Krupska

et al. 2020

Oxidative Medicine and Cellular Longevity

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Despite the development of new drugs and other therapeutic strategies, cardiovascular disease (CVD) remains still the major cause of morbidity and mortality in the world population. A lot of research, performed mostly in the last three decades, revealed an important correlation between “classical” demographic and biochemical risk factors for CVD, (i.e., hypercholesterolemia, hyperhomocysteinemia, smoking, renal failure, aging, diabetes, and hypertension) with endothelial dysfunction associated directly with the nitric oxide deficiency. The discovery of nitric oxide and its recognition as an endothelial-derived relaxing factor was a breakthrough in understanding the pathophysiology and development of cardiovascular system disorders. The nitric oxide synthesis pathway and its regulation and association with cardiovascular risk factors were a common subject for research during the last decades. As nitric oxide synthase, especially its endothelial isoform, which plays a crucial role in the regulation of NO bioavailability, inhibiting its function results in the increase in the cardiovascular risk pattern. Among agents altering the production of nitric oxide, asymmetric dimethylarginine—the competitive inhibitor of NOS—appears to be the most important. In this review paper, we summarize the role of L-arginine-nitric oxide pathway in cardiovascular disorders with the focus on intraplatelet metabolism.

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“…It has been found that NOS2 and NOS3 are expressed in platelets. 3 Physiologically, in an intact vasculature, circulating platelets are maintained in an inactive state by NO and prostacyclin (PGI2) released by endothelial cells lining the blood vessels. 4 NO has a significant role in the regulating vascular tone and in the controlling blood pressure.…”

Section: Introductionmentioning

confidence: 99%

Comparison of bleeding time changes in essential hypertension patients on losartan or amlodipine: a prospective observational study

Narendranath¹,

Ld²,

Arun³

et al. 2016

Int J Basic Clin Pharmacol

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Background: Hypertension leads to vascular damage due to high pressure exerted on arteriolar wall and also promotes atherothrombosis in large and medium sized blood vessels. Thrombosis is an extension of haemostasis and platelets have a crucial role in the formation of atherothrombosis. Increased platelet activity is a risk factor in hypertensive patients and leads to cardio-and cerebrovascular events and target organ damage. Anti-platelet aggregatory treatment in these high risk patients have become a crucial step in their treatment. Recent data indicate that angiotensin II type 1 blockers or AT1 receptor blockers (ARBs) like Losartan and dihydropyridine class of L-type calcium channel antagonist like Amlodipine have anti-platelet activity. These two classes of drugs are frequently administered in hypertensive either alone and in combinations. This study aims to compare the anti-platelet activity of Losartan and Amlodipine. Anti-platelet activity in addition to anti-hypertensive activity of these drugs would be beneficial in treating hypertensive who are at high risk of atherosclerosis and atherothrombosis, if they are selectively prescribed these agents. Methods: This was an observational study. Sixty (n=60) patients diagnosed with essential hypertension, attending medicine outpatient department of a tertiary care hospital were enrolled in the study. Out of them thirty (n=30) were patients who were prescribed losartan. Rest of the patients (n=30) were ones prescribed amlodipine. It was ensured that the patients of both the groups were on respective medication for at least one month. Another thirty (n=30) normotensive subjects acted as control. The bleeding time was evaluated for all three groups using Duke method of bleeding time estimation. Results: Data was analysed using SPSS software version 20. One way ANOVA was used to analyse the data. This was followed by post hoc Tukey's test. The mean bleeding time(in minutes) of Losartan group was 2.583±0.263 SD, Amlodipine group was 2.214±0155 SD and control group was 1.998±0.198 SD. Statistically significant p value of <0.001 was observed in losartan and amlodipine groups. Conclusions: Our study shows that the mean bleeding time of Losartan group and amlodipine group were significantly higher than that of Control group. It was further observed that the mean bleeding time of losartan was higher than that of amlodipine group indicating a better antiplatelet action by losartan than amlodipine. Additional antiplatelet activity could be desirable to treat hypertensive patients with high atherothrombotic and/or thromboembolic risk.

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Visualization of nitric oxide production by individual platelets during adhesion in flowing blood

Cited by 32 publications

References 56 publications

Cyclic nucleotide‐dependent inhibitory signaling interweaves with activating pathways to determine platelet responses

Cyclic nucleotide‐dependent inhibitory signaling interweaves with activating pathways to determine platelet responses

Intraplatelet L-Arginine-Nitric Oxide Metabolic Pathway: From Discovery to Clinical Implications in Prevention and Treatment of Cardiovascular Disorders

Comparison of bleeding time changes in essential hypertension patients on losartan or amlodipine: a prospective observational study

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