β-blockade abolishes the augmented cardiac tPA release induced by transactivation of heterodimerised bradykinin receptor-2 and β2 -adrenergic receptor in vivo

Trude Aspelin, Morten Eriksen, Arnfinn Ilebekk, Alessandro Cataliotti, Cathrine Rein Carlson, Torstein Lyberg

Research output: Contribution to journalArticle

3 Scopus citations

Abstract

Bradykinin (BK) receptor-2 (B2R) and β2-adrenergic receptor (β2AR) have been shown to form heterodimers in vitro. However, in vivo proofs of the functional effects of B2R-β2AR heterodimerisation are missing. Both BK and adrenergic stimulation are known inducers of tPA release. Our goal was to demonstrate the existence of B2R-β2AR heterodimerisation in myocardium and to define its functional effect on cardiac release of tPA in vivo. We further investigated the effects of a non-selective β-blocker on this receptor interplay. To investigate functional effects of B2R-β2AR heterodimerisation (i. e. BK transactivation of β2AR) in vivo, we induced serial electrical stimulation of cardiac sympathetic nerves (SS) in normal pigs that underwent concomitant BK infusion. Both SS and BK alone induced increases in cardiac tPA release. Importantly, despite B2R desensitisation, simultaneous BK infusion and SS (BK+SS) was characterised by 2.3 ± 0.3-fold enhanced tPA release compared to SS alone. When β-blockade (propranolol) was introduced prior to BK+SS, tPA release was inhibited. A persistent B2R-β2AR heterodimer was confirmed in BK-stimulated and nonstimulated left ventricular myocardium by immunoprecipitation studies and under non-reducing gel conditions. All together, these results strongly suggest BK transactivation of β2AR leading to enhanced β2AR-mediated release of tPA. Importantly, non-selective β-blockade inhibits both SS-induced release of tPA and the functional effects of B2R-β2AR heterodimerisation in vivo, which may have important clinical implications.

Original languageEnglish (US)
Pages (from-to)951-959
Number of pages9
JournalThrombosis and Haemostasis
Volume112
Issue number5
DOIs
StatePublished - Jan 1 2014

Keywords

  • Beta-2-adrenergic receptor
  • Betablocker
  • Bradykinin receptor-2
  • Receptor heterodimerisation
  • Tissue plasminogen activator

ASJC Scopus subject areas

  • Hematology

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