title: β-blockade abolishes the augmented cardiac tPA release induced by transactivation of heterodimerised bradykinin receptor-2 and β2-adrenergic receptor in vivo.
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 non-stimulated 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.
authors: Trude Aspelin, Institute for Experimental Medical Research, Oslo University Hospital, Ullevål, Postbox 4956 Nydalen, 0424 Oslo, Norway, Tel.: +47 22119685, Fax: +47 23016799, E-mail: trude.aspelin@medisin.uio.no.
authors: Trude
authors: T
authors: Aspelin
authors: Morten
authors: M
authors: Eriksen
authors: Arnfinn
authors: A
authors: Ilebekk
authors: Alessandro
authors: A
authors: Cataliotti
authors: Cathrine Rein
authors: CR
authors: Carlson
authors: Torstein
authors: T
authors: Lyberg
mesh_terms: D058672:Adrenergic beta-2 Receptor Antagonists / Q000494:pharmacology*; D000818:Animals; D001920:Bradykinin / Q000494:pharmacology; D019281:Dimerization; D005260:Female; D006352:Heart Ventricles / Q000187:drug effects / Q000378:metabolism*; D047468:Immunoprecipitation; D008297:Male; D008955:Models, Cardiovascular; D009206:Myocardium / Q000378:metabolism; D009638:Norepinephrine / Q000378:metabolism; D011433:Propranolol / Q000494:pharmacology; D043782:Receptor, Bradykinin B2 / Q000737:chemistry / Q000502:physiology*; D018343:Receptors, Adrenergic, beta-2 / Q000737:chemistry / Q000502:physiology*; D034421:Sus scrofa; D013552:Swine; D010959:Tissue Plasminogen Activator / Q000378:metabolism*; D015533:Transcriptional Activation
chemical_list: D058672:Adrenergic beta-2 Receptor Antagonists; D043782:Receptor, Bradykinin B2; D018343:Receptors, Adrenergic, beta-2; D011433:Propranolol; D010959:Tissue Plasminogen Activator; D001920:Bradykinin; D009638:Norepinephrine
keywords: Tissue plasminogen activator; beta-2-adrenergic receptor; beta-blocker; bradykinin receptor-2; receptor heterodimerisation