Extracellular Nucleotides ATP and UTP Induce a Marked Acute Release of Tissue-type Plasminogen Activator In Vivo in Man

Summary

Extracellular nucleotides such as ATP and UTP are released by activation of platelets and ischemic tissue injury. The aim of the present study was to investigate whether ATP and UTP can induce acute tPA release from the vascular endothelium in vivo. Nine healthy subjects were studied in a perfused-forearm model during stepwise intraarterial infusions of ATP and UTP (10-200 nmol/min), and UTP during inhibition of prostanoid and NO synthesis by indomethacin and L-NMMA. ATP and UTP induced a similar and marked stimulation of forearm tPA release which increased 11- and 18-fold above baseline (p ≤ 0.01 for both) in conjunction with pronounced vasodilation. Neither the acute tPA release nor the vasodilation could be abrogated by NO and prostanoid synthesis inhibition. The similar effect of ATP and UTP suggests that P2Y rather than adenosine receptors mediate the response. Release of extracellular nucleotides in ischemic tissue may induce a pronounced activation of the endogenous fibrinolytic system.

Keywords

Vascular endothelium - tissue plasminogen activator - extracellular nucleotides - ATP - UTP - P2Y receptors

• References

• 1 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.
• 2 Buga GM, Gold ME, Fukuto JM, Ignarro LJ. Shear stress-induced release of nitric oxide from endothelial cells grown on beads. Hypertension 1991; 17 (Suppl. 02) 187-93.
• 3 Lupu C, Kruithof EK, Kakkar VV, Lupu F. Acute release of tissue factor pathway inhibitor after in vivo thrombin generation in baboons. Thromb Haemost 1999; 82 (Suppl. 06) 1652-8.
• 4 Tranquille N, Emeis JJ. The simultaneous acute release of tissue-type plasminogen activator and von Willebrand factor in the perfused rat hindleg region. Thromb Haemost 1990; 63 (Suppl. 03) 454-8.
• 5 Born G. Aggregation of blood platelets by adenosine diphosphate and its reversal. Nature 1962; 194: 927-9.
• 6 Born GV. Observations on the change in shape of blood platelets brought about by adenosine diphosphate. J Physiol (Lond) 1970; 209 (Suppl. 02) 487-511.
• 7 Przyklenk K, Whittaker P. Brief antecedent ischemia enhances recombinant tissue plasminogen activator-induced coronary thrombolysis by adenosine-mediated mechanism. Circulation 2000; 102 (Suppl. 01) 88-95.
• 8 Smalley DM, Fitzgerald JE, O’Rourke J. Adenosine diphosphate stimulates the endothelial release of tissue-type plasminogen activator but not von Willebrand factor from isolated-perfused rat hind limbs. Thromb Haemost 1993; 70 (Suppl. 06) 1043-6.
• 9 Coade SB, Pearson JD. Metabolism of adenine nucleotides in human blood. Circ Res 1989; 65 (Suppl. 03) 531-7.
• 10 Gordon JL. Extracellular ATP: effects, sources and fate. Biochem J 1986; 233 (Suppl. 02) 309-19.
• 11 Lazarowski ER, Harden TK. Quantitation of extracellular UTP using a sensitive enzymatic assay. Br J Pharmacol 1999; 127 (Suppl. 05) 1272-8.
• 12 Nicholas RA, Watt WC, Lazarowski ER, Li Q, Harden K. Uridine nucleotide selectivity of three phospholipase C-activating P2 receptors: identification of a UDP-selective, a UTP-selective, and an ATP- and UTP-specific receptor. Mol Pharmacol 1996; 50 (Suppl. 02) 224-9.
• 13 Greenfield ADM, Whitney RJ, Mowbray JF. Methods for the investigation of peripheral blood flow. Brit med Bull 1963; 19 (Suppl. 02) 101-9.
• 14 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 (Suppl. 02) 529-37.
• 15 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 (Suppl. 02) 285-91.
• 16 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 (Suppl. 04) 588-94.
• 17 Nakajima K. Pharmacological observations of plasminogen activator release caused by vasoactive agents in isolated perfused pig ears. Thromb Res 1983; 29 (Suppl. 02) 163-74.
• 18 Hrafnkelsdottir T, Wall U, Jern C, Jern S. Impaired capacity for endogenous fibrinolysis in essential hypertension. Lancet 1998; 352 9140 1597-8.
• 19 Wall U, Jern C, Bergbrant A, Jern S. Enhanced levels of tissue-type plasminogen activator in borderline hypertension. Hypertension 1995; 26 (Suppl. 05) 796-800.
• 20 Stein CM, Brown N, Vaughan DE, Lang CC, Wood AJ. Regulation of local tissue-type plasminogen activator release by endothelium-dependent and endothelium-independent agonists in human vasculature. J Am Coll Cardiol 1998; 32 (Suppl. 01) 117-22.
• 21 Malmsjo M, Adner M, Harden TK, Pendergast W, Edvinsson L, Erlinge D. The stable pyrimidines UDPbetaS and UTPgammaS discriminate between the P2 receptors that mediate vascular contraction and relaxation of the rat mesenteric artery. Br J Pharmacol 2000; 131 (Suppl. 01) 51-6.
• 22 Fabre JE, Nguyen M, Latour A, Keifer JA, Audoly LP, Coffman TM. et al. Decreased platelet aggregation, increased bleeding time and resistance to thromboembolism in P2Y1-deficient mice. Nat Med 1999; 5 (Suppl. 10) 1199-202.
• 23 Hrafnkelsdottir T, Wall U, Jern C, Jern S. Desmopressin-induced release of tissue-type plasminogen activator (t-PA) is not reduced by nitric oxide or prostanoid synthesis inhibition. J Hypertens 1999; 17 (Suppl. 03) S162.
• 24 Newby DE, Wright RA, Dawson P, Ludlam CA, Boon NA, Fox KA. et al. The L-arginine/nitric oxide pathway contributes to the acute release of tissue plasminogen activator in vivo in man. Cardiovasc Res 1998; 38 (Suppl. 02) 485-92.
• 25 Rongen GA, Smits P, Thien T. Characterization of ATP-induced vasodilation in the human forearm vascular bed. Circulation 1994; 90 (Suppl. 04) 1891-8.
• 26 Vallance P, Collier J, Moncada S. Effects of endothelium-derived nitric oxide on peripheral arteriolar tone in man. Lancet 1989; 2 8670 997-1000.
• 27 Cockcroft JR, Chowienczyk PJ, Brett SE, Ritter JM. Effect of NGmonomethyl-L-arginine on kinin-induced vasodilation in the human forearm. Br J Clin Pharmacol 1994; 38 (Suppl. 04) 307-10.
• 28 Malmsjo M, Edvinsson L, Erlinge D. P2U-receptor mediated endothelium-dependent but nitric oxide-independent vascular relaxation. Br J Pharmacol 1998; 123 (Suppl. 04) 719-29.
• 29 Malmsjo M, Erlinge D, Hogestatt ED, Zygmunt PM. Endothelial P2Y receptors induce hyperpolarisation of vascular smooth muscle by release of endothelium-derived hyperpolarising factor. Eur J Pharmacol 1999; 364 2-3 169-73.
• 30 Bauersachs J, Popp R, Hecker M, Sauer E, Fleming I, Busse R. Nitric oxide attenuates the release of endothelium-derived hyperpolarizing factor. Circulation 1996; 94 (Suppl. 12) 3341-7.
• 31 Malmsjo M, Bergdahl A, Zhao XH, Sun XY, Hedner T, Edvinsson L. et al. Enhanced acetylcholine and P2Y-receptor stimulated vascular EDHF-dilatation in congestive heart failure. Cardiovasc Res 1999; 43 (Suppl. 01) 200-9.