PDF herunterladen
Thromb Haemost 2003; 89(02): 374-382
DOI: 10.1055/s-0037-1613455
Vascular Development and Vessel Remodelling
Schattauer GmbH

Fibrinolytic capacity increases with age in healthy humans, while endothelium-dependent vasodilation is unaffected

Thorarinn Gudnason
1   Clinical Experimental Research Laboratory, Department of Medicine, Sahlgrenska University Hospital/östra and the Cardiovascular Institute, Göteborg University, Göteborg, Sweden
,
Thórdís Hrafnkelsdóttir
1   Clinical Experimental Research Laboratory, Department of Medicine, Sahlgrenska University Hospital/östra and the Cardiovascular Institute, Göteborg University, Göteborg, Sweden
,
Ulrika Wall
1   Clinical Experimental Research Laboratory, Department of Medicine, Sahlgrenska University Hospital/östra and the Cardiovascular Institute, Göteborg University, Göteborg, Sweden
,
Karl Swedberg
1   Clinical Experimental Research Laboratory, Department of Medicine, Sahlgrenska University Hospital/östra and the Cardiovascular Institute, Göteborg University, Göteborg, Sweden
,
Sverker Jern
1   Clinical Experimental Research Laboratory, Department of Medicine, Sahlgrenska University Hospital/östra and the Cardiovascular Institute, Göteborg University, Göteborg, Sweden
› Institutsangaben
Weitere Informationen

Publikationsverlauf

Received 04. März 2002

Accepted after revision 15. Oktober 2002

Publikationsdatum:
07. Dezember 2017 (online)

Auch verfügbar auf
    Lizenzen und Reprints

Summary

The capacity for stimulated endothelial release of tissue-type plasminogen activator (tPA) and endothelium-dependent vasodilation is diminished in patients with cardiovascular risk factors. We examined the effect of age on desmopressin-stimulated tPA release and endothelium-dependent vasodilation, using the perfused-forearm model. Thirty-two healthy subjects were divided into quartiles by age (mean age 24, 36, 54, and 72 years, respectively). Baseline fibrinolytic parameters, baseline forearm blood flow (FBF), and increase in stimulated FBF were all similar across age. By contrast, the capacity for desmopressin-stimulated release of tPA increased linearly by age. For tPA antigen, the total amount released (area-under-the-curve) was 1015, 1282, 2139, and 2845 ng/L tissue (p = 0.011) and the peak release rates were 62, 80, 113, and 163 ng/min/L tissue (p = 0.008) in the age-quartiles, respectively. A similar significant age-related response was observed for tPA activity. We conclude that in healthy individuals there is an up-regulation of the fibrinolytic response by age.

Keywords

Fibrinolysis - tissue-type plasminogen activator - endothelium - human - ageing
 

  • References

  • 1 Hamsten A, Wiman B, de Faire U, Blomback M. Increased plasma levels of a rapid inhibitor of tissue plasminogen activator in young survivors of myocardial infarction. N Engl J Med 1985; 313 (25) 1557-63.
    CrossrefPubMedSuche in Google Scholar
  • 2 Hoffmeister HM, Jur M, Ruf-Lehmann M, Helber U, Heller W, Seipel L. Endothelial tissue-type plasminogen activator release in coronary heart disease: Transient reduction in endothelial fibrinolytic reserve in patients with unstable angina pectoris or acute myocardial infarction. J Am Coll Cardiol 1998; 31 (03) 547-51.
    CrossrefPubMedSuche in Google Scholar
  • 3 Thogersen AM, Jansson JH, Boman K, Nilsson TK, Weinehall L, Huhtasaari F. et al. High plasminogen activator inhibitor and tissue plasminogen activator levels in plasma precede a first acute myocardial infarction in both men and women: evidence for the fibrinolytic system as an independent primary risk factor. Circulation 1998; 98 (21) 2241-7.
    CrossrefPubMedSuche in Google Scholar
  • 4 Wiman B, Andersson T, Hallqvist J, Reuter-wall C, Ahlbom A, deFaire U. Plasma levels of tissue plasminogen activator/plasminogen activator inhibitor-1 complex and von Wille-brand factor are significant risk markers for recurrent myocardial infarction in the Stock-holm Heart Epidemiology Program (SHEEP) study. Arterioscler Thromb Vasc Biol 2000; 20 (08) 2019-23.
    CrossrefPubMedSuche in Google Scholar
  • 5 Newby DE, Witherow FN, Wright RA, Bloomfield P, Ludlam CA, Boon NA. et al. Hypercholesterolaemia and lipid lowering treatment do not affect the acute endogenous fibrinolytic capacity in vivo. Heart 2002; 87 (01) 48-53.
    CrossrefPubMedSuche in Google Scholar
  • 6 Walmsley D, Hampton KK, Grant PJ.. Contrasting fibrinolytic responses in type 1 (insulin-dependent) and type 2 (non-insulin-dependent) diabetes. Diabet Med 1991; 8 (10) 954-9.
    CrossrefPubMedSuche in Google Scholar
  • 7 Allen RA, Kluft C, Brommer EJ. Acute effect of smoking on fibrinolysis: increase in the activity level of circulating extrinsic (tissue-type) plasminogen activator. Eur J Clin Invest 1984; 14 (05) 354-61.
    CrossrefPubMedSuche in Google Scholar
  • 8 Jern S, Wall U, Bergbrant A, Selin-Sjogren L, Jern C.. Endothelium-dependent vasodilation and tissue-type plasminogen activator release in borderline hypertension. Arterioscler Thromb Vasc Biol 1997; 17 (12) 3376-83.
    CrossrefPubMedSuche in Google Scholar
  • 9 Wall U, Jern C, Bergbrant A, Jern S. Enhanced levels of tissue-type plasminogen activator in borderline hypertension. Hypertension 1995; 26 (05) 796-800.
    CrossrefPubMedSuche in Google Scholar
  • 10 Hrafnkelsdottir T, Wall U, Jern C, Jern S. Impaired capacity for endogenous fibrinolysis in essential hypertension [letter]. Lancet 1998; 352 9140 1597-8.
    CrossrefPubMedSuche in Google Scholar
  • 11 Allen RA, Kluft C, Brommer EJ. Effect of chronic smoking on fibrinolysis. Arteriosclerosis 1985; 5 (05) 443-50.
    CrossrefPubMedSuche in Google Scholar
  • 12 Newby DE, Wright RA, Labinjoh C, Ludlam CA, Fox KA, Boon NA. et al. Endothelial dysfunction, impaired endogenous fibrinolysis, and cigarette smoking: a mechanism for arterial thrombosis and myocardial infarction. Circulation 1999; 99 (11) 1411-5.
    CrossrefPubMedSuche in Google Scholar
  • 13 Avellone G, Di Garbo V, Cordova R, Rotolo G, Abruzzese G, Raneli G. et al. Blood coagulation and fibrinolysis in obese NIDDM patients. Diabetes Res 1994; 25 (02) 85-92.
    PubMedSuche in Google Scholar
  • 14 Vogel RA. Coronary risk factors, endothelial function, and atherosclerosis: a review. Clin Cardiol 1997; 20 (05) 426-32.
    CrossrefPubMedSuche in Google Scholar
  • 15 De Vriese AS, Verbeuren TJ, Van de Voorde J, Lameire NH, Vanhoutte PM. Endothelial dysfunction in diabetes. Br J Pharmacol 2000; 130 (05) 963-74.
    CrossrefPubMedSuche in Google Scholar
  • 16 Panza JA, Casino PR, Kilcoyne CM, Quyyumi AA. Impaired endothelium-dependent vasodilation in patients with essential hypertension: evidence that the abnormality is not at the muscarinic receptor level. J Am Coll Cardiol 1994; 23 (07) 1610-6.
    CrossrefPubMedSuche in Google Scholar
  • 17 Vanhoutte PM, Boulanger CM. Endothelium-dependent responses in hypertension. Hypertens Res 1995; 18 (02) 87-98.
    CrossrefPubMedSuche in Google Scholar
  • 18 Heitzer T, Yla-Herttuala S, Luoma J, Kurtz S, Munzel T, Just H. et al. Cigarette smoking potentiates endothelial dysfunction of forearm resistance vessels in patients with hyper-cholesterolemia. Role of oxidized LDL. Circulation 1996; 93 (07) 1346-53.
    CrossrefPubMedSuche in Google Scholar
  • 19 Landmesser U, Hornig B, Drexler H. Endothelial dysfunction in hypercholesterolemia: mechanisms, pathophysiological importance, and therapeutic interventions. Semin Thromb Hemost 2000; 26 (05) 529-37.
    Thieme ConnectPubMedSuche in Google Scholar
  • 20 Celermajer DS, Sorensen KE, Georgakopoulos D, Bull C, Thomas O, Robinson J. et al. Cigarette smoking is associated with dose-related and potentially reversible impairment of endothelium-dependent dilation in healthy young adults. Circulation 1993; 88 5 PT 1 2149-55.
    CrossrefPubMedSuche in Google Scholar
  • 21 Vanhoutte PM. Ageing and endothelial dysfunction. Eur Heart J 2002; 4 SUPPL A A8-17.
    CrossrefPubMedSuche in Google Scholar
  • 22 Gerhard M, Roddy MA, Creager SJ, Creager MA. Aging progressively impairs endothelium-dependent vasodilation in forearm resistance vessels of humans. Hypertension 1996; 27 (04) 849-53.
    CrossrefPubMedSuche in Google Scholar
  • 23 Taddei S, Virdis A, Mattei P, Ghiadoni L, Gennari A, Fasolo CB. et al. Aging and endothelial function in normotensive subjects and patients with essential hypertension. Circulation 1995; 91 (07) 1981-7.
    CrossrefPubMedSuche in Google Scholar
  • 24 Taddei S, Virdis A, Mattei P, Ghiadoni L, Fasolo CB, Sudano I. et al. Hypertension causes premature aging of endothelial function in humans. Hypertension 1997; 29 (03) 736-43.
    CrossrefPubMedSuche in Google Scholar
  • 25 Taddei S, Galetta F, Virdis A, Ghiadoni L, Salvetti G, Franzoni F. et al. Physical activity prevents age-related impairment in nitric oxide availability in elderly athletes. Circulation 2000; 101 (25) 2896-901.
    CrossrefPubMedSuche in Google Scholar
  • 26 Chauhan A, More RS, Mullins PA, Taylor G, Petch MC, Schofield PM.. Aging-associated endothelial dysfunction in humans is reversed by L-arginine. J Am Coll Cardiol 1996; 28 (07) 1796-804.
    CrossrefPubMedSuche in Google Scholar
  • 27 Egashira K, Inou T, Hirooka Y, Kai H, Sugimachi M, Suzuki S. et al. Effects of age on endothelium-dependent vasodilation of resistance coronary artery by acetylcholine in humans. Circulation 1993; 88 (01) 77-81.
    CrossrefPubMedSuche in Google Scholar
  • 28 Zeiher AM, Drexler H, Saurbier B, Just H. Endothelium-mediated coronary blood flow modulation in humans. Effects of age, atherosclerosis, hypercholesterolemia, and hypertension. J Clin Invest 1993; 92 (02) 652-62.
    CrossrefPubMedSuche in Google Scholar
  • 29 Meyers DG, Haire WD, Rasmussen JK, Boyd EJ. Tissue plasminogen activator release and plasminogen activator inhibitor levels in coronary artery disease. Angiology 1991; 42 (07) 561-7.
    CrossrefPubMedSuche in Google Scholar
  • 30 Stegnar M, Keber D, Pentek M, Vene N, Kluft C. Age and sex differences in resting and postocclusion values of tissue plasminogen activator in a healthy population. Fibrinolysis 1988; Supp 2 (02) 121-2.
    PubMedSuche in Google Scholar
  • 31 Buczko W, Iacoviello L, De Curtis A, Amore C, Donati MB. Aging and tissue plasminogen activator release. Thromb Haemost 1991; 66 (06) 745
    Thieme ConnectPubMedSuche in Google Scholar
  • 32 Emeis JJ, Brouwer A, Barelds RJ, Horan MA, Durham SK, Kooistra T.. On the fibrinolytic system in aged rats, and its reactivity to endo-toxin and cytokines. Thromb Haemost 1992; 67 (06) 697-701.
    Thieme ConnectPubMedSuche in Google Scholar
  • 33 Iacoviello L, D’Adamo MC, De Curtis A, Buczko W, Donati MB. Enhanced vascular plasminogen activator (t-PA) release by epinephrine in aged rats. Thromb Haemost 1995; 73 (05) 841-4.
    Thieme ConnectPubMedSuche in Google Scholar
  • 34 Emeis JJ, van den Eijnden-Schrauwen Y, van den Hoogen CM, de Priester W, Westmuckett A, Lupu F. An endothelial storage granule for tissue-type plasminogen activator. J Cell Biol 1997; 139 (01) 245-56.
    CrossrefPubMedSuche in Google Scholar
  • 35 Emeis JJ. Regulation of the acute release of tissue-type plasminogen activator from the endothelium by coagulation activation products. Ann NY Acad Sci 1992; 667: 249-58.
    CrossrefPubMedSuche in Google Scholar
  • 36 Giles AR, Nesheim ME, Herring SW, Hoogendoorn H, Stump DC, Heldebrant CM. The fibrinolytic potential of the normal primate following the generation of thrombin in vivo. Thromb Haemost 1990; 63 (03) 476-81.
    Thieme ConnectPubMedSuche in Google Scholar
  • 37 Hrafnkelsdottir T, Erlinge D, Jern S. Extracellular nucleotides ATP and UTP induce a marked acute release of tissue-type plasminogen activator in vivo in man. Thromb Haemost 2001; 85 (05) 875-81.
    Thieme ConnectPubMedSuche in Google Scholar
  • 38 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 (02) 285-91.
    Thieme ConnectPubMedSuche in Google Scholar
  • 39 Jern S, Selin L, Bergbrant A, Jern C. Release of tissue-type plasminogen activator in response to muscarinic receptor stimulation in human forearm. Thromb Haemost 1994; 72 (04) 588-94.
    Thieme ConnectPubMedSuche in Google Scholar
  • 40 Jern C, Selin L, Tengborn L, Jern S.. 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 (02) 887-91.
    Thieme ConnectPubMedSuche in Google Scholar
  • 41 Jern C, Ladenvall P, Wall U, Jern S. Gene polymorphism of t-PA is associated with forearm vascular release rate of t-PA. Arterioscler Thromb Vasc Biol 1999; 19 (02) 454-9.
    CrossrefPubMedSuche in Google Scholar
  • 42 Manhem K, Dotevall A, Wilhelmsen L, Jern S. Preserved tissue-type plasminogen activator release and endothelium-dependent vasodilation in postmenopausal women with NIDDM. J Diabetes Complications 2000; 14 (03) 127-34.
    CrossrefPubMedSuche in Google Scholar
  • 43 Wall U, Jern C, Jern S. High capacity for tissue-type plasminogen activator release from vascular endothelium in vivo. J Hypertens 1997; 15 12 PT 2 1641-7.
    CrossrefPubMedSuche in Google Scholar
  • 44 Wall U, Jern S, Tengborn L, Jern C. Evidence of a local mechanism for desmopressin-induced tissue-type plasminogen activator release in human forearm. Blood 1998; 91 (02) 529-37.
    PubMedSuche in Google Scholar
  • 45 Aldasoro M, Medina P, Vila JM, Otero E, Martinez-Leon JB, Lluch S. Endothelium-dependent relaxation of human saphenous veins in response to vasopressin and desmopressin. J Vasc Surg 1997; 25 (04) 696-703.
    CrossrefPubMedSuche in Google Scholar
  • 46 Hasunuma K, Yamada K, Tamura Y, Yoshida S. Cardiovascular and renin responses to desmopressin in humans: role of prostacyclin and beta-adrenergic systems. Am J Physiol 1991; 260 4 PT 2 H1031-6.
    PubMedSuche in Google Scholar
  • 47 Rector TS, Bank AJ, Tschumperlin LK, Mullen KA, Lin KA, Kubo SH.. Abnormal desmopressin-induced forearm vasodilatation in patients with heart failure: dependence on nitric oxide synthase activity. Clin Pharmacol Ther 1996; 60 (06) 667-74.
    CrossrefPubMedSuche in Google Scholar
  • 48 Toda M, Ayajiki K, Okamura T, Azuma I, Toda N. Desmopressin-induced dog ciliary artery relaxation. Eur J Pharmacol 1998; 344 2-3 197-201.
    CrossrefPubMedSuche in Google Scholar
  • 49 Medina P, Segarra G, Vila JM, Chuan P, Domenech C, Lluch S. V2-receptor-mediated relaxation of human renal arteries in response to desmopressin. Am J Hypertens 1999; 12 2 PT 1 188-93.
    PubMedSuche in Google Scholar
  • 50 Mechaly I, Laurent F, Portet K, Serrano J, Cros G.. Vasopressin V2 (SR121463A) and V1a (SR49059) receptor antagonists both inhibit desmopressin vasorelaxing activity. Eur J Pharmacol 1999; 383 (03) 287-90.
    CrossrefPubMedSuche in Google Scholar
  • 51 Yamada K, Nakayama M, Nakano H, Mimura N, Yoshida S. Endothelium-dependent vaso-relaxation evoked by desmopressin and involvement of nitric oxide in rat aorta. Am J Physiol 1993; 264 2 PT 1 E203-7.
    PubMedSuche in Google Scholar
  • 52 Flordal PA, Svensson J, Ljungström KG. Effects of desmopressin and dextran on coagulation and fibrinolysis in healthy volunteers. Thromb Res 1991; 62 (05) 355-64.
    CrossrefPubMedSuche in Google Scholar
  • 53 DeSouza CA, Shapiro LF, Clevenger CM, Dinenno FA, Monahan KD, Tanaka H. et al. Regular aerobic exercise prevents and restores age-related declines in endothelium-dependent vasodilation in healthy men. Circulation 2000; 102 (12) 1351-7.
    CrossrefPubMedSuche in Google Scholar
  • 54 DeSouza CA, Clevenger CM, Greiner JJ, Smith DT, Hoetzer GL, Shapiro LF. et al. Evidence for agonist-specific endothelial vasodilator dysfunction with ageing in healthy humans. J Physiol (Lond) 2002; 542 PT 1 255-62.
    CrossrefPubMedSuche in Google Scholar
  • 55 Imaizumi T, Takeshita A, Suzuki S, Yoshida M, Ando S, Nakamura M. Age-independent forearm vasodilatation by acetylcholine and adenosine 5’-triphosphate in humans. Clin Sci (Lond) 1990; 78 (01) 89-93.
    CrossrefPubMedSuche in Google Scholar