Characterization of P2x1 purinoreceptors on rat platelets: effect of clopidogrel

Savi, Pierre; Bornia, Josette; Salel, Véronique; Delfaud, M; Herbert, Jean‐Marc

doi:10.1046/j.1365-2141.1997.3133126.x

Cited by 50 publications

(30 citation statements)

References 20 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Clopidogrel (Sanofi-Synthelabo, Toulouse, France) at 10 mg ⅐ kg Ϫ1 ⅐ day Ϫ1 (20), aspirin at 30 mg ⅐ kg Ϫ1 ⅐ day Ϫ1 , or sorbinil (Pfizer, Groton, CT) at 65 mg ⅐ kg Ϫ1 ⅐ day Ϫ1 (17) was given to diabetic and control rats. Clopidogrel and aspirin were incorporated into pellets of the customary grain-based rodent diet (Bio-Serv, Frenchtown, NJ) with red and green food dye, respectively, to prevent incorrect delivery of treatment.…”

Section: Methodsmentioning

confidence: 99%

Aspirin at Low-Intermediate Concentrations Protects Retinal Vessels in Experimental Diabetic Retinopathy Through Non–Platelet-Mediated Effects

et al. 2005

View full text Add to dashboard Cite

The prevention of diabetic retinopathy requires drugs that leverage the benefits of glycemic control without adding the burden of side effects. Aspirin at dosages of 1-1.5 g/day has prevented manifestations of diabetic retinal microangiopathy in a clinical trial as well as in studies with dogs. Because lower and safer doses of aspirin could be used if its beneficial effects on retinopathy were due to antithrombotic effects, we compared the effects of a selective antiplatelet drug (clopidogrel) to those of aspirin in streptozotocin-induced diabetic rats. Clopidogrel did not prevent neuronal apoptosis, glial reactivity, capillary cell apoptosis, or acellular capillaries in the retina of diabetic rats. Aspirin, at doses yielding serum levels (<0.6 mmol/l) well below the anti-inflammatory range for humans, prevented apoptosis of capillary cells and the development of acellular capillaries but did not prevent neuroglial abnormalities. The aldose reductase inhibitor sorbinil, used as the benchmark for the effect of the other drugs, prevented all abnormalities. The diabetic rat retina showed increased expression of the transcription factor CCAAT/enhancerbinding protein-␤, one of the known targets of low-intermediate concentrations of aspirin. Thus we found a spectrum of drug efficacy on the prevention of experimental diabetic retinopathy, ranging from the absent effect of a selective antiplatelet drug to the prevention of all abnormalities by an aldose reductase inhibitor. Aspirin at low-intermediate concentrations selectively prevented microangiopathy. The minimal effective dose of aspirin should now be sought. Diabetes 54:3418 -3426, 2005 D iabetic retinopathy remains a sight-threatening complication of diabetes despite decades of efforts to identify drugs that can leverage the prevention afforded by glycemic control. Aspirin has been studied several times in this context, with results that may appear inconsistent but actually are worthy of scrutiny in light of evolving knowledge. The Early Treatment Diabetic Retinopathy Study (ETDRS), the largest of the clinical trials testing aspirin, concluded that aspirin (650 mg/day) has no clinically important beneficial effects on the progression of retinopathy (1). The trial was performed in patients with mild to severe nonproliferative or early proliferative diabetic retinopathy. Having learned from the Diabetes Control and Complications Trial that intervening after retinopathy is clinically evident is much less successful than primary prevention (2), it is safe not to extrapolate the EDTRS results to prevention. The Dipyridamole Aspirin Microangiopathy of Diabetes Study, which enrolled patients with early diabetic retinopathy (a lesssevere degree of retinopathy than that seen in the ETDRS), showed that aspirin (990 mg/day) was able to slow the progression of microaneurysms by Ͼ50% over the 3-year duration of the study (3). Microaneurysms are only a surrogate end point of diabetic retinopathy, but they have high predictive value for worsening retinopathy (4,5). When aspirin ...

show abstract

Section: Methodsmentioning

confidence: 99%

Aspirin at Low-Intermediate Concentrations Protects Retinal Vessels in Experimental Diabetic Retinopathy Through Non–Platelet-Mediated Effects

et al. 2005

View full text Add to dashboard Cite

show abstract

“…It was suggested that human platelets express a P2X1 receptor, which mediates rapid Ca 2+ entry, in contrast to the P2Y receptors which evoke release of calcium from intracellular stores [268]. Clopidogrel did not affect the binding of α,β-meATP to platelet P2X1 receptors [269]. The P2X1 receptor cDNA and protein was identified on human platelets, but not leukocytes [270][271][272].…”

Section: P2x1 Receptorsmentioning

confidence: 99%

Blood cells: an historical account of the roles of purinergic signalling

Burnstock

2015

Purinergic Signalling

View full text Add to dashboard Cite

The involvement of purinergic signalling in the physiology of erythrocytes, platelets and leukocytes was recognised early. The release of ATP and the expression of purinoceptors and ectonucleotidases on erythrocytes in health and disease are reviewed. The release of ATP and ADP from platelets and the expression and roles of P1, P2Y 1 , P2Y 12 and P2X1 receptors on platelets are described. P2Y 1 and P2X1 receptors mediate changes in platelet shape, while P2Y 12 receptors mediate platelet aggregation. The changes in the role of purinergic signalling in a variety of disease conditions are considered. The successful use of P2Y 12 receptor antagonists, such as clopidogrel and ticagrelor, for the treatment of thrombosis, myocardial infarction and stroke is discussed.

show abstract

“…The latter is the target for specific antithrombotic drugs (reviewed by Gachet 7 ). Platelets express the P2X 1 member of the P2X family of ligand-gated ion channels, 8 which mediates a rapid ATP-induced Ca 2ϩ influx. 9,10 Because of the fast desensitizing property of the P2X 1 ion channel 11 and the lack of specific platelet P2X 1 antagonists and because platelet studies have mainly been performed ex vivo at low extracellular Ca 2ϩ concentrations in citrated plasma, the function of P2X 1 in platelet activation only recently started to be unraveled, and a physiologic role of ATP in this process is now being considered.…”

Section: Introductionmentioning

confidence: 99%

Overexpression of the platelet P2X1 ion channel in transgenic mice generates a novel prothrombotic phenotype

Oury

Kuijpers

Tóth-Zsámboki

et al. 2003

Blood

121

126

View full text Add to dashboard Cite

We have generated transgenic mice overexpressing the human P2X 1 ion channel in the megakaryocytic cell lineage. Platelets from transgenic mice exhibited a gain of P2X 1 ionotropic activity as determined by more prominent P2X 1 -mediated Ca 2؉ influx and platelet shape change. P2X 1 overexpression enhanced platelet secretion and aggregation evoked by low doses of collagen, convulxin, or the thromboxane A 2 mimetic U46619. In contrast, transgenic platelet responses to adenosine diphosphate (ADP) or thrombin were normal. Perfusing whole blood from transgenic mice over collagen fibers at a shear rate of 1000 seconds ؊1 resulted in increased P2X 1 -dependent aggregate formation and phosphatidylserine exposure. Platelet hyperreactivity to collagen was correlated with up-regulated extracellular signal-regulated kinase 2 (ERK2) phosphorylation. Accordingly, the MEK1/2 inhibitor U0126 potently inhibited the collagen-induced aggregation of transgenic platelets when stirred or when perfused over a collagen surface. In a viscometer, shear stress caused potent aggregation of transgenic platelets under conditions in which wild-type platelets did not aggregate. In an in vivo model of thromboembolism consisting of intravenous injection of a low dose of collagen plus epinephrine, transgenic mice died more readily than wild-type mice. Preinjection of U0126 not only fully protected transgenic mice against thrombosis, it also enhanced the survival of wild-type mice injected with a higher collagen dose. Hence, the platelet P2X 1 ion channel plays a role in hemostasis and thrombosis through its participation in collagen-, thromboxane A 2 -, and shear stress-triggered platelet responses. Activation of the ERK2 pathway is instrumental in these processes. (Blood. 2003;

show abstract

Characterization of P2x1 purinoreceptors on rat platelets: effect of clopidogrel

Abstract: Summary. This study aimed to determine the binding characteristics of [

Cited by 50 publications

References 20 publications

Aspirin at Low-Intermediate Concentrations Protects Retinal Vessels in Experimental Diabetic Retinopathy Through Non–Platelet-Mediated Effects

Aspirin at Low-Intermediate Concentrations Protects Retinal Vessels in Experimental Diabetic Retinopathy Through Non–Platelet-Mediated Effects

Blood cells: an historical account of the roles of purinergic signalling

Overexpression of the platelet P2X1 ion channel in transgenic mice generates a novel prothrombotic phenotype

Contact Info

Product

Resources

About