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Thromb Haemost 2004; 91(05): 1019-1025
DOI: 10.1160/TH03-11-0693
Endothelium and Vascular Development
Schattauer GmbH

Evidence of a net release of tissue-type plasminogen activator across the human cerebral vasculature

Christina Jern
1   Institute of Clinical Neuroscience Sahlgrenska University Hospital, University of Göteborg, Göteborg, Sweden
2   Department of Clinical Genetics Sahlgrenska University Hospital, University of Göteborg, Göteborg, Sweden
,
Christian Blomstrand
1   Institute of Clinical Neuroscience Sahlgrenska University Hospital, University of Göteborg, Göteborg, Sweden
,
Anne Westerlind
3   Institute of Surgery, Department of Cardiothoracic Anesthesia and Intensive Care, Sahlgrenska University Hospital, University of Göteborg, Göteborg, Sweden
› Author AffiliationsFinancial support: This work was supported by grants from the Swedish Medical Research Council (2002-5618), the Swedish Heart Lung Foundation, the Tore Nilsson Foundation, the Swedish Stroke Association, the Rune & Ulla Amlövs Foundation for Neurological Research, the Yngve Land Foundation for Neurological Research, the Scandinavian Heart Center, and the Sahlgrenska University Hospital Foundation.
Further Information

Publication History

Received 14 November 2003

Accepted after revision 08 February 2004

Publication Date:
01 December 2017 (online)

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Summary

We have earlier described models for measuring local net release rates of tissue-type plasminogen activator (t-PA) in vivo across skeletal, coronary, pulmonary, and splanchnic vascular beds. Aim of the present study was to investigate whether there is a net release of t-PA across the human cerebral vascular bed and whether an acute regulated release can be induced by sympathoadrenal activation. Fourteen male subjects undergoing elective coronary artery bypass grafting were investigated prior to surgery and during sternotomy-induced sympathoadrenal activation. Blood samples were obtained simultaneously from the radial artery and the jugular bulb. Blood flow velocity in the middle cerebral artery (VMCA) was determined by transcranial Doppler. Cerebral net release of t-PA was calculated as the arterio-venous concentration gradient times VMCA. Prior to surgery there was a significant cerebral net release of t-PA (131 and 42 ng/min for t-PA antigen and activity, respectively). The release was significantly induced by sternotomy (to 271 and 80 ng/min, respectively). No significant cerebral net release of plasminogen activator inhibitor type 1 (PAI-1) was detected throughout the experiment. The results show that there is a basal net release of t-PA across the human cerebral vascular bed and that sympathoadrenal activation induces a local regulated release of t-PA.

Keywords

Tissue-type plasminogen activator - plasminogen activator inhibitor type 1 - release - endothelium - cerebral blood flow
 

  • References

  • 1 Wun T-C, Capuano A. Spontaneous fibrinolysis in whole human plasma. Identification of tissue activator-related protein as the major plasminogen activator causing spontaneous activity in vitro. J Biol Chem 1985; 260: 5061-6.
    PubMedGoogle Scholar
  • 2 Emeis JJ. Regulation of the acute release of tissue-type plasminogen activator from the endothelium by coagulation activation products. Ann N Y Acad Sci 1992; 667: 249-58.
    CrossrefPubMedGoogle Scholar
  • 3 van den Eijnden-Schrauwen Y, Kooistra T, de Vries RE. et al. Studies on the acute release of tissue-type plasminogen activator from human endothelial cells in vitro and in rats in vivo: evidence for a dynamic storage pool. Blood 1995; 85: 3510-7.
    PubMedGoogle Scholar
  • 4 Jern C, Eriksson E, Tengborn L. et al. Changes of plasma coagulation and fibrinolysis in response to mental stress. Thromb Haemost 1989; 62: 767-71.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 5 Larsson PT, Wiman B, Olsson G. et al. Influence of metroprolol treatment on sympatho-adrenal activation of fibrinolysis. Thromb Haemost 1990; 63: 482-7.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 6 Chandler WL, Levy WC, Stratton JR. The circulatory regulation of TPA and UPA secretion, clearance, and inhibition during exercise and during the infusion of isoproterenol and phenylephrine. Circulation 1995; 92: 2984-94.
    CrossrefPubMedGoogle Scholar
  • 7 von Kanel R, Dimsdale JE. Effects of sympathetic activation by adrenergic infusions on hemostasis in vivo. Eur J Haematol 2000; 65: 357-69.
    CrossrefPubMedGoogle Scholar
  • 8 de Boer A, Kluft C, Kroon JM. et al. Liver blood flow as the major determinant of the clearance of recombinant human tissue-type plasminogen activator. Thromb Haemost 1992; 67: 83-7.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 9 Emeis J. Normal and abnormal endothelial release of tissue-type plasminogen activator. In: Glas-Greenwalt P. editor. Fibrinolysis in disease. Boca Raton: CRC Press; 1995: 55-64.
    Google Scholar
  • 10 Jern C, Selin L, Jern S. In vivo release of tissue-type plasminogen activator across the human forearm during mental stress. Thromb Haemost 1994; 72: 285-91.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 11 Jern S, Selin L, Bergbrant A. et al. Release of tissue-type plasminogen activator in response to muscarinic receptor stimulation in human forearm. Thromb Haemost 1994; 72: 588-94.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 12 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: 887-91.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 13 Stein CM, Brown N, Vaughan DE. et al. Regulation of local tissue-type plasminogen activator release by endothelium-dependent and endothelium-independent agonists in human vasculature. J Am Coll Cardiol 1998; 32: 117-22.
    CrossrefPubMedGoogle Scholar
  • 14 Jern C, Seeman-Lodding H, Biber B. et al. An experimental multiple-organ model for the study of regional net release/uptake rates of tissue-type plasminogen activator in the intact pig. Thromb Haemost 1997; 78: 1150-6.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 15 Seeman-Lodding H, Häggmark S, Jern C. et al. Systemic levels and preportal organ release of tissue-type plasminogen activator are enhanced by PEEP in the pig. Acta Anaesthesiol Scand 1999; 43: 623-33.
    CrossrefPubMedGoogle Scholar
  • 16 Österlund B, Holmgren A, Häggmark S. et al. Surgical stress induces acute coronary release of tissue-type plasminogen activator in the pig. Acta Anaesthesiol Scand 2000; 44: 1226-31.
    CrossrefPubMedGoogle Scholar
  • 17 Björkman JA, Jern S, Jern C. Cardiac sympathetic nerve stimulation triggers coronary t-PA release. Arterioscler Thromb Vasc Biol 2003; 23: 1091-7.
    CrossrefPubMedGoogle Scholar
  • 18 Kirnö K, Friberg P, Grzegorczyk A. et al. Thoracic epidural anesthesia during coronary artery bypass surgery: Effects on cardiac sympathetic activity, myocardial blood flow and metabolism, and central hemodynamics. Anesth Analg 1994; 79: 1075-81.
    PubMedGoogle Scholar
  • 19 Newby DE, Wright RA, Labinjoh C. et al. Endothelial dysfunction, impaired endogenous fibrinolysis, and cigarette smoking. A mechanism for arterial thrombosis and myocardial infarction. Circulation 1999; 99: 1411-5.
    CrossrefPubMedGoogle Scholar
  • 20 Newby DE, McLeod AL, Uren NG. et al. Impaired coronary tissue plasminogen activator release is associated with coronary atherosclerosis and cigarette smoking: direct link between endothelial dysfunction and atherothrombosis. Circulation 2001; 103: 1936-41.
    CrossrefPubMedGoogle Scholar
  • 21 Rånby M, Nguyen G, Scarabin PY. et al. Immunoreactivity of tissue plasminogen activator and of its inhibitor complexes. Thromb Haemost 1989; 61: 409-14.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 22 Meijer P, Pollet DE, Wauters J. et al. Specificity of antigen assays of plasminogen activator inhibitor in plasma: Innotest PAI-1 immunoassay evaluated. Clin Chem 1994; 40: 110-5.
    PubMedGoogle Scholar
  • 23 Wall U, Jern S, Tengborn L. et al. Evidence of a local mechanism for desmopressin-induced tissue-type plasminogen activator release in human forearm. Blood 1998; 91: 529-37.
    PubMedGoogle Scholar
  • 24 Gough SCL, Smyllie J, Sheldon J. et al. The anatomical distribution of plasma fibrinolytic activity in man during cardiac catheterization. Thromb Haemost 1992; 68: 442-7.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 25 Sorteberg W. Cerebral artery blood velocity and cerebral blood flow. In: Transcranial Doppler. Newell DW. Aaslid eds, Raven Press, Ltd; New York: 1992: 57-66.
    Google Scholar
  • 26 Wang Y, Jiang X, Hand AR. et al. Additional evidence that the sympathetic nervous system regulates the vessel wall release of tissue plasminogen activator. Blood Coagul Fibrinolysis 2002; 13: 471-81.
    CrossrefPubMedGoogle Scholar
  • 27 Jern S, Wall U, Bergbrant A. et al. Endothelium-dependent vasodilation and tissue type plasminogen activator release in borderline hypertension. Arterioscler Thromb Vasc Biol 1997; 17: 3376-83.
    CrossrefPubMedGoogle Scholar
  • 28 Newby DE, Wright RA, Ludlam CA. et al. An in vivo model for the assessment of acute fibrinolytic capacity of the endothelium. Thromb Haemost 1997; 78: 1242-8.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 29 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: 1565-70.
    CrossrefPubMedGoogle Scholar
  • 30 Chandler WL, Alessi MC, Aillaud MF. et al. Clearance of tissue plasminogen activator (TPA) and TPA/plasminogen activator inhibitor type 1 (PAI-1) complex: relationship to elevated TPA antigen in patients with high PAI-1 activity levels. Circulation 1997; 96: 761-8.
    CrossrefPubMedGoogle Scholar
  • 31 Olofsson BO, Dahlén G, Nilsson TK. Evidence for increased levels of plasminogen activator inhibitor and tissue plasminogen activator in plasma of patients with angiographically verified coronary artery disease. Eur Heart J 1989; 10: 77-82.
    CrossrefPubMedGoogle Scholar
  • 32 Loskutoff DJ, Sawdey M, Keeton M. et al. Regulation of PAI-1 gene expression in vivo. Thromb Haemost 1993; 70: 135-7.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 33 Chomiki N, Henry M, Alessi MC. et al. Plasminogen activator inhibitor-1 expression in human liver and healthy or atherosclerotic vessel walls. Thromb Haemost 1994; 72: 44-53.
    PubMedGoogle Scholar
  • 34 Ridker PM, Hennekens CH, Stampfer MJ, Manson JE, Vaughan DE. Prospective study of endogenous tissue plasminogen activator and risk of stroke. Lancet 1994; 343: 940-3.
    CrossrefPubMedGoogle Scholar
  • 35 Larsen FS, Olsen KS, Hansen BA. et al. Transcranial Doppler is valid for determination of the lower limit of cerebral blood flow autoregulation. Stroke 1994; 25: 1985-8.
    CrossrefPubMedGoogle Scholar
  • 36 Newell DW, Aaslid R, Lam A. et al. Comparison of flow and velocity during dynamic autoregulation in humans. Stroke 1994; 25: 793-7.
    CrossrefPubMedGoogle Scholar
  • 37 Hrafnkelsdóttir T, Wall U, Jern C. et al. Impaired capacity for endogenous fibrinolysis in essential hypertension. Lancet 1998; 352: 1597-8.
    CrossrefPubMedGoogle Scholar
  • 38 Österlund B. Coronary release of t-PA. An experimental and clinical study. Thesis, Umeå University; Sweden: 2002
    Google Scholar
  • 39 Wang X, Xu L, Wang H, Grzanna R, Zhan Y. et al. Inhibition of factor Xa reduces ischemic brain damage after thromboembolic stroke in rats. Stroke 2003; 34: 468-74.
    CrossrefPubMedGoogle Scholar
  • 40 Levin EG, del Zoppo GJ. Localization of tissue plasminogen activator in the endothelium of a limited number of vessels. Am J Pathol 1994; 144: 855-61.
    PubMedGoogle Scholar
  • 41 Schreiber SS, Tan Z, Sun N. et al. Immunohistochemical localization of tissue plasminogen activator in vascular endothelium of stroke-prone regions of the rat brain. Neurosurgery 1998; 43: 909-13.
    CrossrefPubMedGoogle Scholar
  • 42 Strickland S. Tissue plasminogen activator in nervous system function and dysfunction. Thromb Haemost 2001; 86: 138-43.
    Article in Thieme ConnectPubMedGoogle Scholar