An in vivo Model for the Assessment of Acute Fibrinolytic Capacity of the Endothelium

Summary

The effects on blood flow and plasma fibrinolytic and coagulation parameters of intraarterial substance P, an endothelium dependent vasodilator, and sodium nitroprusside, a control endothelium independent vasodilator, were studied in the human forearm circulation. At subsystemic locally active doses, both substance P (2-8 pmol/min) and sodium nitroprusside (2-8 μg/min) caused dose-dependent vasodilatation (p <0.001 for both) without affecting plasma concentrations of PAI-1, von Willebrand factor antigen or factor VIII:C activity. Substance P caused local increases in t-PA antigen and activity (p <0.001) in the infused arm while sodium nitroprusside did not. At higher doses, substance P increased blood flow and t-PA concentrations in the noninfused arm. We conclude that brief, locally active and subsystemic infusions of intraarterial substance P cause a rapid and substantial local release of t-PA which appear to act via a flow and nitric oxide independent mechanism. This model should provide a useful and selective method of assessing the in vivo capacity of the forearm endothelium to release t-PA acutely.

• References

• 1 Levin EG, del Zoppo GJ. Localization of tissue plasminogen activator in the endothelium of a limited number of vessels. Am J Pathol 1994; 144: 855-861
• 2 Van den Eijnden-SchrauwenY, Kooistra T, de VriesREM, Emeis JJ. Studies on the acute release of tissue-type plasminogen activator from human endothelial cells in vitro and in rats in vitro: evidence for a dynamic storage pool. Blood 1995; 85: 3510-3517
• 3 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: 249-258
• 4 Carmeliet P, Schoonjans L, Kieckens L, Ream B, Degen J, Bronson R, de Vos R, van den OordJJ, Collen D, Mulligan RC. Physiological consequence of loss of plasminogen activator gene function in mice. Nature 1994; 368: 419-424
• 5 Brommer EJP. The level of extrinsic plasminogen activator (t-PA) during clotting as a determinant of the rate of fibrinolysis; inefficiency of activators added afterwards. Thromb Res 1984; 34: 109-115
• 6 Fox KAA, Robison AK, Knabb RM, Rosamond TL, Sobel BE, Bergmann SR. Prevention of coronary thrombosis with subthrombolytic doses of tissue-type plasminogen activator. Circulation 1984; 72: 1346-1354
• 7 Ludlam CA, Peake IR, Allen N, Davies BL, Furlong RA, Bloom AL. Factor VIE and fibrinolytic response to deamino-8-D-arginine vasopressin in normal subjects and dissociate response in some patients with haemophilia and von Willebrand’s disease. Br J Haematol 1980; 45: 499-511
• 8 Duprez D, Baele G, de Buyzere M, Vandenbroecke P, Clement DL. Comparison of the fibrinolytic response to desmopressin acetate (DDAVP) infusion versus venous occlusion in patients with coronary artery disease. Eur Heart J 1991; 12: 800-802
• 9 Ridker PM, Gaboury CL, Conlin PR, Seely EW, Williams GH, Vaughan DE. Stimulation of plasminogen activator inhibitor in vitro by infusion of angiotensin n. Circulation 1993; 87: 1969-1973
• 10 Webb DJ. The pharmacology of human blood vessels in vitro . J Vase Res 1995; 32: 02-15
• 11 Benjamin N, Calver A, Collier J, Robinson B, Vallance P, Webb D. Measuring forearm blood flow and interpreting the responses to drugs and mediators. Hypertension 1995; 25: 918-923
• 12 Plumpton C, Haynes WG, Webb DJ, Davenport AP. Phosphoramidon inhibition of the in vitro conversion of big endothelin-1 to endothelin-1 in the human forearm. Br J Pharmacol 1995; 116: 1821-1828
• 13 Stjäme P, Rinder J, Delay-Goyet P. Effects of NK1 receptor antagonists on vasodilation induced by chemical and electrical activation of sensory C-fibre afferents in different organs. Acta Physiol Scand 1994; 152: 153-161
• 14 Pemow B. Substance P. Pharmacol Rev 1983; 35: 085-141
• 15 Aronin N, Coslovsky R, Leman SE. Substance P and neurotensin: their role in the regulation of anterior pituitary function. Annu Rev Physiol 1986; 48: 537-549
• 16 Lundberg J, Hökflet T, Kewenter J, Pettersson G, Ahlman H, Edin R, Dahlstrom A, Nilsson G, Terebius L, Uvnas-Wallensten K, Said S. Substance P-, VIP-, and enkephalin-like immunoreactivity in the human vagus nerve. Gastroenterology 1979; 77: 468-471
• 17 Hökflet T, Elfvin L-G, Schultzberg M, Goldstein M, Nilsson G. On the occurrence of substance P-containing fibers in sympathetic ganglia: immunohistochemical evidence. Brain Res 1977; 132: 29-41
• 18 Smith CH, Barker JN, Morris RW. Neuropeptides induce rapid expression of endothelial cell adhesion molecules and elicit granulocytic infiltration in human skin. J Immunology 1993; 151: 3274-3282
• 19 Cappugi P, Tsampau D. Substance P provokes cutaneous erythema and edema through a histamine-independent pathway. Int J Dermatol 1992; 31: 206-209
• 20 Barnes PJ, Belvisi MG, Rogers DF. Modulation of neurogenic inflammation: novel approaches to inflammatory disease. TiPS 1990; 11: 185-189
• 21 Coiro V, Capretti L, Volpi R, Davoli C, Marcato A, Cavazzini U, Caffarri G, Rossi G, Chiodera P. Stimulation of ACTH/cortisol by intravenously infused substance P in normal men: inhibition by sodium valproate. Neuroendocrinology 1992; 56: 459-463
• 22 Coiro V, Volpi R, Capretti L, Speroni G, Bocchi R, Caffarri G, Colla R, Rossi G, Chiodera P. Intravenously infused substance P enhances basal and growth hormone releasing hormone-stimulated growth hormone secretion in normal men. Peptides 1992; 13: 843-846
• 23 Fanciullacci M, Fedi S, Alessandri M, Pietrini U. Substance P-induced fibrinolysis in the forearm of healthy humans. Experientia 1993; 49: 242-244
• 24 Löfström B, Pemow B, Wahren J. Vasodilating action of substance P in the human forearm. Acta Physiol Scand 1965; 63: 311-324
• 25 Eklund B, Jogestrand T, Pemow B. Effect of substance P on resistance and capacitance vessels in the human forearm. In Substance P edited by von Euler, and von Pemow. Raven Press; New York: 1977
• 26 McEwan JR, Benjamin N, Larkin S, Fuller RW, Dollery CT, MacIntyre I. Vasodilatation by calcitonin gene-related peptide and substance P: a comparison of their effects on resistance and capacitance vessels of human forearms. Circulation 1988; 77: 1072-1080
• 27 Gross DR, Fiscus RR, Arden WA, Maley RH, Lanzo S, Salley RK. Substance P induces biphasic endothelium-dependent relaxations in pig and rabbit carotid arteries. Neuropeptides 1994; 26: 329-341
• 28 Cockcroft JR, Chowienczyk PJ, Brett SE, Ritter JM. Effect of NG-mono-methyl-L-arginine on kinin-induced vasodilation in the human forearm. Br J Clin Pharmac 1994; 38: 307-310
• 29 Newby DE, Boon NA, Webb DJ. Comparison of forearm vasodilatation induced by substance P and acetylcholine: contribution of nitric oxide. Clin Sci 1997; 92: 133-138
• 30 Crossman DC, Larkin SW, Fuller RW, Davies GJ, Maseri A. Substance P dilates epicardial coronary arteries and increases coronary blood flow in humans. Circulation 1989; 80: 475-484
• 31 Holdright DR, Clarke D, Fox K, Poole-Wilson PA, Collins P. The effects of intracoronary substance P and acetylcholine on coronary blood flow in patients with idiopathic dilated cardiomyopathy. Eur Heart J 1994; 15: 1537-1544
• 32 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: 1610-1616
• 33 Casino PR, Kilcoyne CM, Cannon RO, Quyyumi AA, Panza JA. Impaired endothelium-dependent vascular relaxation in patients with hypercholeste-rolaemia extends beyond the muscarinic receptor. Am J Cardiol 1995; 75: 40-44
• 34 Wijnberg N, Walter-Larson S, Eriksen C, Nielsen PE. An evaluation of semi-automatic blood pressure manometers against intra-arterial blood pressure. J Ambulatory Monitoring 1988; 1: 303-309
• 35 Declerck PJ, Alessi MC, Verstreken M, Kruithof EKO, Juhan-Vague I, Collen D. Measurement of plasminogen activator inhibitor 1 in biologic fluids with a murine monoclonal antibody-based enzyme-linked immunosorbent assay. Blood 1988; 71: 220-225
• 36 Booth NA, Walker E, Maughan R, Bennett B. Plasminogen activator in normal subjects after exercise and venous occlusion: t-PA circulates as complexes with Cl-inhibitor and PAI-1. Blood 1987; 69: 1600-1604
• 37 Wiman B, Lindahl T, Almqvist A. Evidence for a discrete binding protein of plasminogen activator inhibitor in plasma. Thromb Haemost 1988; 59: 392-395
• 38 Gram J, Kluft C, Jespersen J. Depression of tissue plasminogen activator (t-PA) activity and rise of t-PA inhibition and acute phase reactants in blood of patients with acute myocardial infarction (AMI). Thromb Haemost 1987; 58: 817-821
• 39 Cejka J. Enzyme immunoassay for factor VUI-related antigen. Clin Chem 1982; 28: 1356-1358
• 40 Tranquille N, Emeis JJ. The involvement of products of the phospholipase pathway in the acute release of tissue-type plasminogen activator from perfused rat hindlegs. Eur J Pharmacol 1992; 213: 285-292
• 41 Brown NJ, Nadeau J, Vaughan DE. Selective stimulation of tissue-type plasminogen activator (t-PA) in vivo by infusion of bradykinin. Thromb Haemost 1997; 77: 522-525
• 42 Jem S, Selin L, Bergbrant A, Jem C. Release of tissue-type plasminogen activator in response to muscarinic receptor stimulation in human forearm. Thromb Haemost 1994; 72: 588-594
• 43 Hajjar KA. The endothelial cell tissue plasminogen activator receptor. J Biol Chem 1991; 266: 21962-21970
• 44 Diamond SL, Sharefkin JB, Dieffenbach C, Frasier-Scott K, Mclntire LV, Eskin SG. Tissue plasminogen activator messenger RNA levels increase in cultured human endothelial cells exposed to laminar shear stress. J Cell Physiol 1990; 143: 364-371
• 45 Iba T, Shin T, Sonoda T, Rosalies O, Sumpio BE. Stimulation of endothelial secretion of tissue-type plasminogen activator by repetitive stretch. JSurgRes 1991; 50: 457-460
• 46 Gough SCL, Smyllie J, Sheldon T, Rice PJS, Grant PJ. The anatomical distribution of plasma fibrinolytic activity in man during cardiac catheteri-sation. Thromb Haemost 1992; 68: 442-447
• 47 Pannocchia A, Garis G, Giorgianni A, Stella S, Bosia A, Ghigo D. Nitroprusside has no effect on t-PA and PAI production and release by endothelial cells in culture. Fibrinolysis 1996; 10: 111-115
• 48 Otter M, Kuiper J, van BerkelJC, Rijken DC. Mechanisms of tissue-type plasminogen activator (tPA) clearance by the liver. Ann N Y Acad Sci 1992; 667: 431-442
• 49 Lucore CL, Sobel BE. Interactions of tissue-type plasminogen activator with plasma inhibitors and their pharmacological implications. Circulation 1988; 77: 660-669
• 50 Levin EG, Marzec V, Anderson J, Harker LA. Thrombin stimulates tissue plasminogen activator release from cultured endothelial cells. J Clin Invest 1984; 74: 1988-1995
• 51 Casonato A, Sartori MT, Pontara E. Impaired release of tissue plasminogen activator (t-PA) following DDAVP infusion in von Willebrand’s disease with low platelet von Willebrand factor. Blood Coag Fibrinol 1992; 3: 149-153
• 52 Stroes ES, Koomans HA, de Bruin TWA, & Rabelink TJ. Vascular function in the forearm of hypercholesterolaemic patients off and on lipid-lowering medication. Lancet 1995; 346: 467-471