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

Summary

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.

Keywords

Tissue plasminogen activator - receptor heterodimerisation - betablocker - bradykinin receptor-2 - beta-2-adrenergic receptor

• References

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