Adrenoceptor α2A signalling countervails the taming effects of synchronous cyclic nucleotide-elevation on thrombin-induced human platelet activation and aggregation

Knut Fälker, Liza U Ljungberg, Caroline Kardeby, Madelene Lindkvist, Allan Sirsjö, Magnus Grenegård

Research output: Contribution to journalArticlepeer-review

Abstract

The healthy vascular endothelium constantly releases autacoids which cause an increase of intracellular cyclic nucleotides to tame platelets from inappropriate activation. Elevating cGMP and cAMP, in line with previous reports, cooperated in the inhibition of isolated human platelet intracellular calcium-mobilization, dense granules secretion, and aggregation provoked by thrombin. Further, platelet alpha granules secretion and, most relevant, integrin αIIaβ3 activation in response to thrombin are shown to be prominently affected by the combined elevation of cGMP and cAMP. Since stress-related sympathetic nervous activity is associated with an increase in thrombotic events, we investigated the impact of epinephrine in this setting. We found that the assessed signalling events and functional consequences were to various extents restored by epinephrine, resulting in full and sustained aggregation of isolated platelets. The restoring effects of epinephrine were abolished by either interfering with intracellular calcium-elevation or with PI3-K signalling. Finally, we show that in our experimental setting epinephrine likewise reconstitutes platelet aggregation in heparinized whole blood, which may indicate that this mechanism could also apply in vivo.

Original languageEnglish
Pages (from-to)96-109
Number of pages14
JournalCellular Signalling
Volume59
Early online date26 Mar 2019
DOIs
Publication statusPublished - Jul 2019

Bibliographical note

Copyright © 2019 Elsevier Inc.

Keywords

  • Blood Platelets/cytology
  • Calcium/metabolism
  • Cyclic AMP/metabolism
  • Cyclic GMP/metabolism
  • Epinephrine/pharmacology
  • Healthy Volunteers
  • Humans
  • Platelet Activation/drug effects
  • Platelet Aggregation/drug effects
  • Receptors, Adrenergic, alpha-2/metabolism
  • Thrombin/pharmacology

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