Download PDF
Thromb Haemost 2014; 112(05): 951-959
DOI: 10.1160/th14-01-0059
Blood Coagulation, Fibrinolysis and Cellular Haemostasis
Schattauer GmbH

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

Trude Aspelin
1   Department of Medical Biochemistry, Oslo University Hospital, Ullevål, Oslo, Norway
,
Morten Eriksen
2   Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, Oslo, Norway
,
Arnfinn Ilebekk
2   Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, Oslo, Norway
,
Alessandro Cataliotti
2   Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, Oslo, Norway
,
Cathrine Rein Carlson
2   Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, Oslo, Norway
3   KG Jebsen Cardiac Research Center and Center for Heart Failure Research, University of Oslo, Oslo, Norway
,
Torstein Lyberg
1   Department of Medical Biochemistry, Oslo University Hospital, Ullevål, Oslo, Norway
› Author Affiliations Financial support: Cathrine Rein Carlson is supported by the Norwegian Research Council.
Further Information

Publication History

Received: 20 January 2014

Accepted after major revision: 16 June 2014

Publication Date:
20 November 2017 (online)

    Permissions and Reprints

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

  • 1 Haack KK, Tougas MR, Jones KT. et al. A novel bioassay for detecting GPCR heterodimerisation: transactivation of beta 2 adrenergic receptor by bradykinin receptor. J Biomol Screen 2010; 15: 251-260.
    CrossrefPubMedGoogle Scholar
  • 2 Hanke S, Nurnberg B, Groll DH. et al. Cross talk between beta-adrenergic and bradykinin B(2) receptors results in cooperative regulation of cyclic AMP accumulation and mitogen-activated protein kinase activity. Mol Cell Biol 2001; 21: 8452-8460.
    CrossrefPubMedGoogle Scholar
  • 3 Pin JP, Neubig R, Bouvier M. et al. International Union of Basic and Clinical Pharmacology. LXVII. Recommendations for the recognition and nomenclature of G protein-coupled receptor heteromultimers. Pharmacol Rev 2007; 59: 5-13.
    CrossrefPubMedGoogle Scholar
  • 4 Brown NJ, Gainer JV, Murphey LJ. et al. Bradykinin stimulates tissue plasminogen activator release from human forearm vasculature through B(2) receptor-dependent, NO synthase-independent, and cyclooxygenase-independent pathway. Circulation 2000; 102: 2190-2196.
    CrossrefPubMedGoogle Scholar
  • 5 Kimura E, Hashimoto K, Furukawa S. et al. Changes in bradykinin level in coronary sinus blood after the experimental occlusion of a coronary artery. Am Heart J 1973; 85: 635-647.
    CrossrefPubMedGoogle Scholar
  • 6 Ilebekk A, Aspelin T, Eriksen M. et al. Reduced release of vasoconstrictors from the porcine heart after repeated periods of ischaemia. Scand Cardiovasc J 2005; 39: 60-66.
    CrossrefPubMedGoogle Scholar
  • 7 Schomig A. Catecholamines in myocardial ischaemia. Systemic and cardiac release. Circulation 1990; 82: II13-II22.
    PubMedGoogle Scholar
  • 8 Osterlund B, Jern C, Seeman-Lodding H. et al. Intracoronary beta2 receptor activation induces dynamic local t-PA release in the pig. Thromb Haemost 2003; 90: 796-802.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 9 Minai K, Matsumoto T, Horie H. et al. Bradykinin stimulates the release of tissue plasminogen activator in human coronary circulation: effects of angiotensin-converting enzyme inhibitors. J Am Coll Cardiol 2001; 37: 1565-1570.
    CrossrefPubMedGoogle Scholar
  • 10 Aspelin T, Eriksen M, Ilebekk A. et al. Different cardiac tissue plasminogen activator release patterns by local stimulation of the endothelium and sympathetic nerves in pigs. Blood Coagul Fibrinolysis 2012; 23: 714-722.
    CrossrefPubMedGoogle Scholar
  • 11 Aspelin T, Eriksen M, Lindgaard AK. et al. Cardiac fibrinolytic capacity is markedly increased after brief periods of local myocardial ischaemia, but declines following successive periods in anesthetized pigs. J Thromb Haemost 2005; 3: 1947-1954.
    CrossrefPubMedGoogle Scholar
  • 12 Bjorkman JA, Jern S, Jern C. Cardiac sympathetic nerve stimulation triggers coronary t-PA release. Arterioscler Thromb Vasc Biol 2003; 23: 1091-1097.
    CrossrefPubMedGoogle Scholar
  • 13 Smith D, Gilbert M, Owen WG. Tissue plasminogen activator release in vivo in response to vasoactive agents. Blood 1985; 66: 835-839.
    PubMedGoogle Scholar
  • 14 Emeis JJ. Perfused rat hindlegs. A model to study plasminogen activator release. Thromb Res 1983; 30: 195-203.
    CrossrefPubMedGoogle Scholar
  • 15 Lameris TW, van den Meiracker AH, Boomsma F. et al. Catecholamine handling in the porcine heart: a microdialysis approach. Am J Physiol 1999; 277: H1562-H1569.
    PubMedGoogle Scholar
  • 16 Brown NJ, Nadeau JH, Vaughan DE. Selective stimulation of tissue-type plasminogen activator (t-PA) in vivo by infusion of bradykinin. Thromb Haemost 1997; 77: 522-525.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 17 Jern C, Selin L, Tengborn L. et al. Sympathoadrenal activation and muscarinic receptor stimulation induce acute release of tissue-type plasminogen activator but not von Willebrand factor across the human forearm. Thromb Haemost 1997; 78: 887-891.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 18 Brown NJ, Gainer JV, Stein CM. et al. Bradykinin stimulates tissue plasminogen activator release in human vasculature. Hypertension 1999; 33: 1431-1435.
    CrossrefPubMedGoogle Scholar
  • 19 Barki-Harrington L, Luttrell LM, Rockman HA. Dual inhibition of beta-adrenergic and angiotensin II receptors by a single antagonist: a functional role for receptor-receptor interaction in vivo. Circulation 2003; 108: 1611-1618.
    CrossrefPubMedGoogle Scholar
  • 20 Murugaiah KD, O’Donnell JM. Facilitation of norepinephrine release from cerebral cortex is mediated by beta 2-adrenergic receptors. Life Sci 1995; 57: L327-L332.
    PubMedGoogle Scholar
  • 21 Boehm S, Huck S. Noradrenaline release from rat sympathetic neurones triggered by activation of B2 bradykinin receptors. Br J Pharmacol 1997; 122: 455-462.
    CrossrefPubMedGoogle Scholar
  • 22 Yamamoto C, Miyamoto A, Sakamoto M. et al. Lead perturbs the regulation of spontaneous release of tissue plasminogen activator and plasminogen activator inhibitor-1 from vascular smooth muscle cells and fibroblasts in culture. Toxicology 1997; 117: 153-161.
    CrossrefPubMedGoogle Scholar
  • 23 Wang Y, Hand AR, Wang YH. et al. Functional and morphologic evidence of the presence of tissue-plasminogen activator in vascular nerves: implications for a neurologic control of vessel wall fibrinolysis and rigidity. J Neurosci Res 1998; 53: 443-453.
    CrossrefPubMedGoogle Scholar
  • 24 Moreau ME, Garbacki N, Molinaro G. et al. The kallikrein-kinin system: current and future pharmacological targets. J Pharmacol Sci 2005; 99: 6-38.
    CrossrefPubMedGoogle Scholar
  • 25 Scharfstein J, Andrade D, Svensjo E. et al. The kallikrein-kinin system in experimental Chagas disease: a paradigm to investigate the impact of inflammatory edema on GPCR-mediated pathways of host cell invasion by Trypanosoma cruzi. Front Immunol 2012; 3: 396.
    PubMedGoogle Scholar
  • 26 Meszaros JG, Gonzalez AM, Endo-Mochizuki Y. et al. Identification of G protein-coupled signaling pathways in cardiac fibroblasts: cross talk between G(q) and G(s). Am J Physiol Cell Physiol 2000; 278: C154-C162.
    CrossrefPubMedGoogle Scholar
  • 27 Stein M, Deegan R, He H. et al. Beta-adrenergic receptor-mediated release of norepinephrine in the human forearm. Clin Pharmacol Ther 1993; 54: 58-64.
    CrossrefPubMedGoogle Scholar
  • 28 Kubista H, Boehm S. Molecular mechanisms underlying the modulation of exocytotic noradrenaline release via presynaptic receptors. Pharmacol Ther 2006; 112: 213-242.
    CrossrefPubMedGoogle Scholar
  • 29 Seyedi N, Win T, Lander HM. et al. Bradykinin B2-receptor activation augments norepinephrine exocytosis from cardiac sympathetic nerve endings. Mediation by autocrine/paracrine mechanisms. Circ Res 1997; 81: 774-784.
    CrossrefPubMedGoogle Scholar
  • 30 Chulak C, Couture R, Foucart S. Modulatory effect of bradykinin on noradrenaline release in isolated atria from normal and B2 knockout transgenic mice. Eur J Pharmacol 1998; 346: 167-174.
    CrossrefPubMedGoogle Scholar
  • 31 Minshall RD, Yelamanchi VP, Djokovic A. et al. Importance of sympathetic innervation in the positive inotropic effects of bradykinin and ramiprilat. Circ Res 1994; 74: 441-447.
    CrossrefPubMedGoogle Scholar
  • 32 Hatta E, Maruyama R, Marshall SJ. et al. Bradykinin promotes ischaemic norepinephrine release in guinea pig and human hearts. J Pharmacol Exp Ther 1999; 288: 919-927.
    PubMedGoogle Scholar
  • 33 Fogari R, Zoppi A. Antihypertensive drugs and fibrinolytic function. Am J Hypertens 2006; 19: 1293-1299.
    CrossrefPubMedGoogle Scholar
  • 34 Fernhall B, Szymanski LM, Gorman PA. et al. Both atenolol and propranolol blunt the fibrinolytic response to exercise but not resting fibrinolytic potential?. Am J Cardiol 2000; 86: 1398-1400 A6.
    CrossrefPubMedGoogle Scholar
  • 35 Boman K, Jansson JH, Nilsson T. et al. Effects of carvedilol or metoprolol on PAI-1, tPA-mass concentration or Von Willebrand factor in chronic heart failure--a COMET substudy. Thromb Res 2010; 125: e46-e50.
    CrossrefPubMedGoogle Scholar
  • 36 Winther K, Gleerup G, Hedner T. Platelet function and fibrinolytic activity in hypertension: differential effects of calcium antagonists and beta-adrenergic receptor blockers. J Cardiovasc Pharmacol 1991; 18 (Suppl. 09) S41-S44.
    PubMedGoogle Scholar
  • 37 Held C, Hjemdahl P, Rehnqvist N. et al. Fibrinolytic variables and cardiovascular prognosis in patients with stable angina pectoris treated with verapamil or metoprolol. Results from the Angina Prognosis study in Stockholm. Circulation 1997; 95: 2380-2386.
    CrossrefPubMedGoogle Scholar
  • 38 Hrafnkelsdottir T, Gudnason T, Wall U. et al. Regulation of local availability of active tissue-type plasminogen activator in vivo in man. J Thromb Haemost 2004; 2: 1960-1968.
    CrossrefPubMedGoogle Scholar
  • 39 Lang NN, Cruden NL, Tse GH. et al. Vascular B1 kinin receptors in patients with congestive heart failure. J Cardiovasc Pharmacol 2008; 52: 438-444.
    CrossrefPubMedGoogle Scholar
  • 40 Cruden NL, Tse GH, Fox KA. et al. B1 kinin receptor does not contribute to vascular tone or tissue plasminogen activator release in the peripheral circulation of patients with heart failure. Arterioscler Thromb Vasc Biol 2005; 25: 772-777.
    CrossrefPubMedGoogle Scholar
  • 41 Oikawa M, Hsueh AJ. Beta-adrenergic agents stimulate tissue plasminogen activator activity and messenger ribonucleic acid levels in cultured rat granulosa cells. Endocrinology 1989; 125: 2550-2557.
    CrossrefPubMedGoogle Scholar
  • 42 Ozasa N, Morimoto T, Bao B. et al. beta-blocker use in patients after percutaneous coronary interventions: one size fits all? Worse outcomes in patients without myocardial infarction or heart failure. Int J Cardiol 2013; 168: 774-779.
    CrossrefPubMedGoogle Scholar
  • 43 Bao B, Ozasa N, Morimoto T. et al. beta-Blocker therapy and cardiovascular outcomes in patients who have undergone percutaneous coronary intervention after ST-elevation myocardial infarction. Cardiovasc Interv Ther 2013; 28: 139-147.
    CrossrefPubMedGoogle Scholar
  • 44 Johannessen KA, Nordrehaug JE, von der Lippe G. Increased occurrence of left ventricular thrombi during early treatment with timolol in patients with acute myocardial infarction. Circulation 1987; 75: 151-155.
    CrossrefPubMedGoogle Scholar