Antiplatelet and Antithrombotic Effects of a Novel Selective Phosphodiesterase 3 Inhibitor, NSP-513, in Mice and Rats

Hirose, Hiroyasu; Kimura, Toshifumi; Okada, Megumu; Itoh, Yoshiki; Ishida, Fumiaki; Mochizuki, Nobuo; Nishibe, Tadayuki; Nishikibe, Masaru

doi:10.1254/jjp.82.188

Cited by 10 publications

(2 citation statements)

References 29 publications

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“…However, there is a difference between the dosage administered to rats and mice. Indeed, it has been reported that the differences in the species of animals used may account for part of the variability in the effective dose and/or results (34,35). The well-defined reason for these differences between rats and mice is not known.…”

Section: Discussionmentioning

confidence: 99%

Chrysophanol-8-O-glucoside, an Anthraquinone Derivative in Rhubarb, Has Antiplatelet and Anticoagulant Activities

et al. 2012

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Abstract. Rhubarb is a widely used traditional medicine and has been reported to elicit a number of biological effects including anti-inflammatory and antiplatelet effects. In the present study, we investigated the effects of anthraquinone derivatives isolated from rhubarb on platelet activity. Of four anthraquinone derivatives isolated from rhubarb examined, chrysophanol-8-O-glucoside (CP-8-O-glc) was found to have the most potent inhibitory effect on collagen-and thrombin-induced platelet aggregation. CP-8-O-glc-treated mice showed significantly prolonged bleeding times. Furthermore, CP-8-O-glc was found to have a significant inhibitory effect on rat platelet aggregation ex vivo and on thromboxane A 2 formation in vitro. In coagulation tests, CP-8-O-glc did not alter prothrombin time, and it prolonged the activated partial thromboplastin time. However, CP-8-O-glc only inhibited platelet phosphatidylserine exposure, but not exert direct inhibition on intrinsic factors. This study demonstrates the antiplatelet and anticoagulant effects of CP-8-O-glc and suggests that this compound might be of therapeutic benefit for the prevention of plateletrelated cardiovascular diseases.

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Section: Discussionmentioning

confidence: 99%

Chrysophanol-8-O-glucoside, an Anthraquinone Derivative in Rhubarb, Has Antiplatelet and Anticoagulant Activities

et al. 2012

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“…This conclusion is based on measurements of thrombus-induced changes in blood flow and measurements of the weight of resultant thrombus following electrical stimulation. 33,34 In these studies, however, platelets were not monitored and the effect of PDE3A inhibition on platelet accumulation during thrombus formation could not be assessed. Studies performed using flow chambers show that elevation of cAMP inhibits platelet adhesion to immobilized von Willebrand factor (VWF) 22 and collagen.…”

Section: Discussionmentioning

confidence: 99%

Initial accumulation of platelets during arterial thrombus formation in vivo is inhibited by elevation of basal cAMP levels

Sim

Merrill-Skoloff

Furie

et al. 2004

Blood

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Platelet accumulation at sites of vascular injury is the primary event in arterial thrombosis. Initial platelet accrual into thrombi is mediated by interactions of platelet adhesion receptors with ligands on the injured endothelium or in the subendothelial matrix. The role of intracellular signals in initial platelet accumulation at sites of endothelial injury, however, is the subject of debate. We have used a newly discovered inhibitor of phosphodiesterase 3A (PDE3A) and the well-characterized PDE3A inhibitor, cilostazol, to modulate 3,5-cyclic adenosine monophosphate (cAMP) levels in an in vivo model that enables the kinetic analysis of platelet accumulation. These studies demonstrate that elevation of basal cAMP levels results in an overall decline in platelet accumulation at the site of vascular injury. In particular, the initial rate of accumulation of platelets is inhibited by elevation of cAMP. Analysis of the kinetics of individual platelets at injury sites using intravital microscopy demonstrates that cAMP directs the rate at which platelets attach to and detach from thrombi. These studies demonstrate that cAMP in circulating platelets controls attachment to and detachment from sites of arteriolar injury. Thus, the status of the intracellular signaling machinery prior to engagement of platelet receptors influences the rate of platelet accumulation during thrombus formation. ( IntroductionWhile it is well established that adhesion molecules affect signaling events that lead to platelet activation, it is also possible that intracellular signals present in circulating platelets prior to interactions with thrombi affect the ability of platelets to incorporate into thrombi. [1][2][3][4][5] The role of intracellular signaling in controlling the initial accumulation of platelets into thrombi at sites of vascular injury, however, is largely unexplored. Critical roles for 3Ј,5Ј-cyclic adenosine monophosphate (cAMP), cAMPdependent protein kinase (protein kinase A [PKA]), and phosphodiesterase 3A (PDE3A) in thrombus formation have been suggested in both in vivo models 6 and clinical studies of arterial thrombosis. [7][8][9][10][11][12] Cyclic AMP inhibits platelets by activating PKA, which phosphorylates several substrates important for the activation of platelets. PDE3A hydrolyzes cAMP to 5Ј-AMP. As a result, PDE3A opposes PKA-mediated platelet inhibition. Phosphorylation of several intracellular PKA substrates is associated with the inhibition of multiple platelet functions. For example, IP 3 receptor phosphorylation by PKA is proposed to downregulate calcium release from intracellular stores. 13,14 PKA phosphorylation of G ␣13 causes inhibition of the RhoA/Rho kinase pathway. 15 PKA inhibits signaling to the cytoskeleton 16,17 and may stabilize the resting cytoskeleton by phosphorylation of cytoskeletal proteins such as actinbinding protein 18 and caldesmon. 19 In addition to the phosphorylation of these intracellular substrates, PKA also inhibits other signaling events such as mitogen-activated protein kinas...

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Current developments in anti-platelet therapy

Mayr

Jilma

2006

Wien Med Wochenschr

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Platelets play a life-saving role in hemostasis and blood clotting at sites of vascular injury and consequently are similarly involved in the pathological counterpart, namely thrombosis. Thus, anti-platelet therapy has become a mainstay in treatment and/or prophylaxis of conditions like myocardial infarction, stroke and other cardiovascular diseases. Acetyl-salicylic acid (ASA, aspirin) is still the most widely used agent and considered as the prototype antiplatelet drug. Since platelet activation occurs via several pathways that are not influenced by ASA, several other compounds have been developed to add to its beneficial effect. Currently four main classes of antiplatelet agents are available for clinical use: acetyl-salicylic acid (ASA), phosphodiesterase (PDE) inhibitors, thienopyridines and the intravenous GPIIb/IIIa antagonists. This article gives a concise review of these four classes of anti-platelet agents, using ASA as the reference standard.

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Antiplatelet and Antithrombotic Effects of a Novel Selective Phosphodiesterase 3 Inhibitor, NSP-513, in Mice and Rats

Cited by 10 publications

References 29 publications

Chrysophanol-8-O-glucoside, an Anthraquinone Derivative in Rhubarb, Has Antiplatelet and Anticoagulant Activities

Chrysophanol-8-O-glucoside, an Anthraquinone Derivative in Rhubarb, Has Antiplatelet and Anticoagulant Activities

Initial accumulation of platelets during arterial thrombus formation in vivo is inhibited by elevation of basal cAMP levels

Current developments in anti-platelet therapy

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