Attenuating Effect of Antithrombin III on the Fibrinolytic Activation and Microvascular Derangement in Rat Gastric Mucosa

Summary

The roles for the fibrinolytic activation and disorder of coagulation in formation of gastric ulcer induced by microvascular derangement were investigated. The rat stomach was exposed and repeated electrical stimuli (RES) were applied on the small arterial wall close to the lesser curvature to induce mucosal microcirculatory disturbances. The level of tissue-type plasminogen activator (t-PA), a key enzyme for fibrinolytic activity, in the regional blood of the stomach was significantly elevated immediately after RES. At 5 min after RES, the leakage of FITC-labeled albumin and thrombus formation in the mucosal microvasculature were visually demonstrated by using an intravital microscopic system. At 30 min, hemorrhagic erosions and linear ulcers were observed in the gastric mucosa. Pretreatment with human anti-thrombin-III (AT-III) in the range of 0.1–10 U/kg dose-dependently attenuated both the fibrinolytic activation and microvascular alteration promoted by RES. Human AT-III also prevented RES-induced gastric mucosal injury. Thrombin inhibitory activity in the gastric vein decreased (69.0 ± 2.1%) just after RES, and further reduced at 30 min (47.7 ± 5.3%). The present study suggests a hypothesis that human AT-III has a preventive effect on the gastric mucosal hemorrhagic changes via attenuating the fibrinolytic activation and subsequent microcirculatory disturbances.

• References

• 1 Suematsu M, Suzuki M, Nagata H, Miura S, Houzawa S, Morishita T, Tsuchiya M. Role of neutrophil-mediated oxidative stress in acute gastric mucosal injury induced by microvascular derangement. In: Free Radicals in Digestive Diseases. Tsuchiya M, Kawai K, Kondo M, Yoshikawa T. (eds) Excerpta Medica; Amsterdam: 1988: 67-72
• 2 Kurose I, Suematsu M, Miura S, Suzuki M, Nagata H, Morishita T, Sekizuka E, Tsuchiya M. Involvement of superoxide anion and platelet-activating factor in increased tissue-type plasminogen activator during rat gastric microvascular damages. Thromb Res 1991; 62: 241-8
• 3 Saldeen Y, Ryan JW, Berryer P. A peptide derived from fibrin(ogen) inhibits angiotensin converting enzyme and potentiates the effect of bradykinin. Thromb Res 1981; 23: 465-70
• 4 Levin EG, Marzec U, Anderson J, Marker T. A Thrombin stimulates tissue plusminogcn activator release hum cultuied human endothelial cells. J Clin Invest 1984; 74: 1988-95
• 5 Triantaphyllopoulos DC. Effects of human antithrombin III on mortality and blood coagulation induced in rabbits by endotoxin. Thromb Haemost 1984; 51: 232-5
• 6 Blauhut B, Kramar H, Vinazzer H, Bergmann H. Substitution of antithrombin III in shock and DIC: A randomized study. Thromb Res 1985; 39: 81-9
• 7 Gomez C, Paramo JA, Colucci M, Rocha E. Effect of heparin and/or antithrombin III on the generation of endotoxin-induced plasminogen activator inhibitor. Thromb Haemost 1989; 62: 694-8
• 8 Damus PS, Hicks M, Rosenberg RD. Anticoagulant action of heparin. Nature 1973; 246: 355-7
• 9 Rosenberg JS, Mc Kenna W, Rosenberg RD. Inhibition of human factor IXa by human antithrombin. J Biol Chem 1975; 250: 8883-8
• 10 Stiirzebecher J, Markwardt F. Role of heparin in the inactivation of thrombin, factor Xa, and plasmin by antithrombin III. Thromb Res 1977; 11: 835-46
• 11 Morishita T, Guth P. Effect of exogenous acid on the rat gastric mucosal microcirculation in hemorrhagic shock. Gastroenterology 1987; 82: 1958-64
• 12 Ranby M, Norrman B, Wallen P. A sensitive assay for tissue plasminogen activator. Thromb Res 1982; 27: 743-9
• 13 Declerck PJ, Alessi M-C, Verstreken M, Kruithof EK O, Juhan-Vague I, Collen D. Measurement of plasminogen activator inhibitor 1 (PAI-1) in biologic fluids with a murine monoclonal antibody-based enzyme-linked immunosorbent assay. Blood 1988; 71: 220-5
• 14 Yoshida N, Tachiya K, Moroi M, Matsuda M, Aoki N. Effects of α2-macroglobulin and FDP on the antithrombin III assay system. Acta Haematol Jap 1977; 40: 197-201
• 15 Abildgaad U, Lie M, Odegard OR. Antithrombin (heparin cofactor) assay with new chromogenic substrates (S-2238 and chromozym TH). Thromb Res 1977; 11: 549-55
• 16 Kurose I, Suematsu M, Miura S, Fukumura D, Sekizuka E, Nagata H, Oshio C, Tsuchiya M. Oxyradical generation from leukocyte during endotoxin-induced microcirculatory disturbance in rat mesentery – attenuating effect of cetraxate. Toxicol Appl Pharmacol 1993; 120: 37-44
• 17 Highsmith RF, Rosenberg RD. The inhibition of human plasmin by human antithrombin-heparin cofactor. J Biol Chem 1974; 249: 4335-8
• 18 Dichck D, Quertermous T. Thrombin regulation of mRNA levels of tissue plasminogen activator and plasminogen activator inhibitor-1 in cultured human umbilical vein endothelial cells. Blood 1989; 74: 222-8
• 19 Grulich-Henn J, Muller-Berghaus G. Regulation of endothelial tissue plasminogen activator and plasminogen activator inhibitor type 1 synthesis by diacylglycerol. phorbol ester, and thrombin. Blut 1990; 61: 38-44
• 20 Mulligan MS, Policy MJ, Bayer RJ, Nunn MF, Paulson JC, Ward PA. Neutrophil-dependent acute lung injury. Requirement for P-selection (GMP-140). J Clin Invest 1992; 90: 1600-7
• 21 McEver RP, Beckstcad JH, Moore KL, Marshall-Carlson L, Bainton DF. GMP-140, a platelet a-granule membrane protein, is also synthesized by vascular endothelial cells and is localized in Weibel-Palade bodies. J Clin Invest 1989; 84: 92-9
• 22 McEver RP. Selectins: Novel receptors that mediate leukocyte adhesion during inflammation. Thromb Haemost 1991; 65: 223-8
• 23 Svartholm E, Arvidsson S, Fait K, Haglund U. Influence of prostanoids on gastrointestinal mucosal injury in experimental septic shock. Acta Microbiol Immunol Scand 1989; 97: 61-7
• 24 Miura S, Imaeda H, Shiozaki H, Kurose I, Fukumura D, Tashiro H, Serizawa H, Suematsu M, Sekizuka E, Tsuchiya M. Attenuation of endotoxin-induced intestinal microcirculatory damage by eicosapentanoic acid. Am J Physiol 1993; 264 (Gastrointest. Liver Physiol. 27) G828-G834