Augmentation of U46619 induced human platelet aggregation by aspirin

Young JP, Beckerman J, Vicini S, Myers A. Acetylsalicylic acid enhances purinergic receptor-mediated outward currents in rat megakaryocytes. Am J Physiol Cell Physiol 298: C602-C610, 2010. First published December 30, 2009 doi:10.1152/ajpcell.00422.2009.-Purinergic receptor activation increases cytosolic Ca 2ϩ concentration in a fluctuating fashion, triggering oscillatory outward Ca 2ϩ -activated K ϩ currents in rat megakaryocytes (MKs). Whole cell and nystatinperforated patch-clamp techniques were used to analyze changes in ionic conductance in MK with acetylsalicylic acid (ASA), a cyclooxygenase-1 inhibitor and antithrombotic agent. MKs are a model for platelet reactivity, particularly in ASA treatment failure (ASA resistance). Freshly isolated MKs were incubated 30 min in the absence or presence of 1 mM ASA. Using a K ϩ -rich internal solution, we recorded outward currents in response to 10 M ATP, 10 M ADP, and 5 M 2-methyl-thio-ADP (2MeSADP) in the voltage-clamp mode. Agonist-induced currents decreased in amplitude over time, but this decline was attenuated by ASA in both continuous and repeated agonist challenge, indicating increased MK reactivity with ASA treatment. In separate experiments, heterologous desensitization was observed when MKs were stimulated with ADP after exposure to a thromboxane receptor agonist (U46619), indicating cross talk between thromboxane and purinergic pathways. Different cells, treated with ASA or MRS2179 (P2Y1 receptor antagonist), were stimulated with 2MeSADP. The dose-response curve was shifted to the left in both cases, suggesting increased MK reactivity. ASA also caused an increased interval between currents (delay). ASA attenuated desensitization of purinergic receptors and increased delay, again suggesting cross talk between purinergic and thromboxane pathways. These findings may be relevant to ASA resistance, because individual variations in sensitivity to the multiple effects of ASA on signaling pathways could result in insensitivity to its antiplatelet effects in some patients.platelets; patch clamp; ADP; ATP; thromboxane CARDIOVASCULAR DISEASE IS the leading cause of morbidity and mortality in the United States and developed countries (17, 54). Platelet increased reactivity is a key factor in the development of stroke and ischemic heart disease. Therefore, platelets have become a target for pharmacological treatment of cardiovascular complications after percutaneous coronary intervention (angioplasty and stent implant) (37) as well as in stroke prevention and management. Aspirin has been shown to be effective in the acute phase of recurrent stroke (49), whereas purinergic receptor blockade in the CAPRIE study showed more effectiveness than aspirin with lower side effects such as bleeding (1). The use of drug-eluting stents and dual therapy of cyclooxygenase (COX) inhibitors and purinergic receptor P2Y 12 blockers reduces the incidence of thromboembolism and ischemic episodes but with the adverse outcome of more bleeding occurrence (47, 57). Common platelet evaluation...

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“…6). Indeed, platelet aggregometry studies have recently reported that TP stimulation results in desensitization of the P2 pathway (3,7,26).…”

Section: Discussionmentioning

confidence: 99%

Acetylsalicylic acid enhances purinergic receptor-mediated outward currents in rat megakaryocytes

Young¹,

Beckerman

Vicini³

et al. 2010

American Journal of Physiology-Cell Physiology

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Recombinant CC16 inhibits NLRP3/caspase-1-induced pyroptosis through p38 MAPK and ERK signaling pathways in the brain of a neonatal rat model with sepsis

Zhou

Yang

et al. 2019

J Neuroinflammation

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BackgroundSepsis is a critical disease associated with extremely high mortality. Some severe forms of sepsis can induce brain injury, thus causing behavioral and cognitive dysfunction. Pyroptosis is a type of cell death that differs from apoptosis and plays an important role in the occurrence and development of infectious diseases, nervous system-related diseases. A recent study has found that there is pyroptosis in the hippocampus of sepsis-induced brain injury, but its mechanism and treatment scheme have not been evaluated.MethodsWe established immediately a septic rat model by cecal ligation and perforation (CLP) after administration with recombinant club cell protein (rCC16) and/or U46619 in different groups. The clinical performance, survival percentage, vital signs, and neurobehavioral scores were monitored at different time points. Cortical pathological changes were also examined. The expression of cortical nucleotide-binding domain leucine-rich repeat-containing pyrin domain-containing 3 (NLRP3), caspase-1, (p)-p38 mitogen-activated protein kinase (MAPK), and (p)-extracellular signal-related kinase (ERK) was detected by western blotting and immunofluorescence analysis. The levels of interleukin (IL)-1β, IL-6, and tumor necrosis factor alpha in the cortical supernatant were detected by enzyme-linked immunosorbent assay.ResultsCompared with the sham group, the clinical performance, survival percentage, vital signs, and severe cortical pathological changes in the CLP group were worse; NLRP3, caspase-1, and inflammatory factor levels were increased; and phosphorylation of p38 MAPK and ERK was also increased. Meanwhile, multiple indicators were deteriorated further after administration of U46619 in CLP rats. The clinical performance of CLP rats, however, was better after rCC16 administration; cortical pathological changes were attenuated; and NLRP3, caspase-1, and inflammatory factor levels and the phosphorylation of signaling pathway proteins (p38 MAPK and ERK) were reduced. Interestingly, the CLP rats showed the opposite changes in all indicators after administration with both rCC16 and U46619 when compared with those administered rCC16 alone.ConclusionsIn sepsis, rCC16 inhibits cortical pyroptosis through p38 MAPK and ERK signaling pathways. Meanwhile, rCC16 has a protective effect on newborn rats with sepsis, but it is not clear whether its mechanism is directly related to pyroptosis.

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Augmentation of U46619 induced human platelet aggregation by aspirin

Cited by 2 publications

References 28 publications

Acetylsalicylic acid enhances purinergic receptor-mediated outward currents in rat megakaryocytes

Acetylsalicylic acid enhances purinergic receptor-mediated outward currents in rat megakaryocytes

Recombinant CC16 inhibits NLRP3/caspase-1-induced pyroptosis through p38 MAPK and ERK signaling pathways in the brain of a neonatal rat model with sepsis

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