Stimulation of nitric oxide production contributes to the antiplatelet and antithrombotic effect of new peptide pENW (pGlu-Asn-Trp)

Liu, Yamin; Luo, Wenjing; Yang, Huan; Fang, Wei; Xi, Tao; Li, Yunman; Xiong, Jing

doi:10.1016/j.thromres.2015.05.016

Cited by 8 publications

(4 citation statements)

References 54 publications

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“…For example, we showed that NO inhibits platelet exocytosis (Matsushita et al, 2003). Others have shown that activators of NO can inhibit platelet function (Doni et al, 1991;Liu et al, 2015). Our work extends these prior studies and shows that calcium-calmodulin signaling, and NOS activity, mediates acetylcholine inhibition of platelet activation.…”

Section: Discussionsupporting

confidence: 84%

Acetylcholine Inhibits Platelet Activation

Bennett

Ture

Schmidt

et al. 2019

J Pharmacol Exp Ther

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Platelets are key mediators of thrombosis. Many agonists of platelet activation are known, but fewer endogenous inhibitors of platelets, such as prostacyclin and nitric oxide (NO), have been identified. Acetylcholinesterase inhibitors, such as donepezil, can cause bleeding in patients, but the underlying mechanisms are not well understood. We hypothesized that acetylcholine is an endogenous inhibitor of platelets. We measured the effect of acetylcholine or analogs of acetylcholine on human platelet activation ex vivo. Acetylcholine and analogs of acetylcholine inhibited platelet activation, as measured by P-selectin translocation and glycoprotein IIb IIIa conformational changes. Conversely, we found that antagonists of the acetylcholine receptor, such as pancuronium, enhance platelet activation. Furthermore, drugs inhibiting acetylcholinesterase, such as donepezil, also inhibit platelet activation, suggesting that platelets release acetylcholine. We found that NO mediates acetylcholine inhibition of platelets. Our data suggest that acetylcholine is an endogenous inhibitor of platelet activation. The cholinergic system may be a novel target for antithrombotic therapies.

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Section: Discussionsupporting

confidence: 84%

Acetylcholine Inhibits Platelet Activation

Bennett

Ture

Schmidt

et al. 2019

J Pharmacol Exp Ther

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“…The rat ferric chloride model has been used in a number of studies to evaluate thrombosis, particularly in the context of antithrombotic therapies. The controls (no therapy) in our study had an average TTO of~12 min; other studies using various parameters of ferric chloride concentration and time of application, as well as filter paper dimensions, have control TTO data from 7.8-8.7 min [19,20] to greater than 30 min [8,21,22], with many values between these times [23][24][25][26][27][28][29][30][31][32][33]. We selected our particular ferric chloride induction parameters to provide a moderate injury so that heparin therapy might have an influence, as was determined to be the case.…”

Section: Discussionmentioning

confidence: 63%

Timing of Heparin Administration Modulates Arterial Occlusive Thrombotic Response in Rats

Matrai

Kastetter

Cooley

2020

JCDD

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Background: The timing for initiation of effective antithrombotic therapy relative to the onset of arterial thrombosis may influence outcomes. This report investigates the hypothesis that early administration of heparin anticoagulation relative to the onset of thrombotic occlusion will effect a reduction in occlusion. Methods: A standard rat model of experimental thrombosis induction was used, injuring the carotid artery exposure with FeCl 3 -saturated filter paper, followed by flow monitoring for onset of occlusion and subsequent embolization events. Intravenous heparin administration (200 units/mL) was timed relative to the initiation of injury or onset of near occlusion, compared with controls (no heparin administration). Results: No occlusion was found for delivery of heparin 5 min prior to thrombus induction, whereas all vessels occluded without heparin. Unstable (embolic) thrombi were seen with heparin given at or shortly after initial occlusion. Only 9% (1/11) of the vessels had permanent occlusion when heparin was given at the time of thrombotic onset (p < 0.0001 vs. unheparinized), while 50% occluded when heparin was delayed by 5 min (p > 0.05). Conclusions: These findings provide evidence that antithrombotic therapy may need to be administered prior to the onset of anticipated loss of patency, with less effectiveness when given after occlusion has occurred.

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“…For example, we showed that NO inhibits platelet exocytosis (37). Others have shown that activators of NO can inhibit platelet function (38, 39). Our work extends these prior studies and shows that calcium-calmodulin signaling and NOS activity mediate acetylcholine inhibition of platelet activation.…”

Section: Discussionmentioning

confidence: 99%

Acetylcholine inhibits platelet activation and regulates hemostasis

Bennett

et al. 2018

Preprint

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22Word Count: 5145 23 Figure Count: 5 figures 24 25 26 42 platelets express members of the acetylcholine signaling pathway including CHRNA2, CHRNA7,43 CHRNB1, and ACHE. Platelets from mice lacking Chrna7 are hyperactive when stimulated by 44 thrombin and resistant to inhibition by acetylcholine. Furthermore, acetylcholinesterase 45 inhibitors prolonged bleeding in wild-type mice. Knockout mice lacking Chrna7 subunits of the 46 acetylcholine receptor display prolonged bleeding as well. 47 52 Abbreviations 53 NO nitric oxide 54 CHRNA7 cholinergic receptor neuronal nicotinic alpha polypeptide 7 55 GPIIbIIIA glycoprotein IIb IIIa 56 AChR acetylcholine receptors 57 AChE acetylcholinesterase 58 TRAP thrombin receptor activating peptide 6 59 PAR1 protease activated receptor 1 60 P2Y12 purinergic receptor P2Y 61 GPVI glycoprotein VI 62 NOS3 nitric oxide synthase isoform 3 63 L-NAME L-nitroarginine methyl ester

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Stimulation of nitric oxide production contributes to the antiplatelet and antithrombotic effect of new peptide pENW (pGlu-Asn-Trp)

Cited by 8 publications

References 54 publications

Acetylcholine Inhibits Platelet Activation

Acetylcholine Inhibits Platelet Activation

Timing of Heparin Administration Modulates Arterial Occlusive Thrombotic Response in Rats

Acetylcholine inhibits platelet activation and regulates hemostasis

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