Effect of BM-573[N-terbutyl-N '-[2-(4 '-methylphenylamino)-5-nitro-benzenesulfonyl] urea], a dual thromboxane synthase inhibitor and thromboxane receptor antagonist, in a porcine model of acute pulmonary embolism
[en] The aim of this study was to evaluate the effect of BM-573 [N-terbutyl-N'-[2-(4'-methylphenylamino)-5-nitro-benzenesulfonyl] urea], a dual thromboxane A(2) synthase inhibitor and receptor antagonist, on the hemodynamic response to acute pulmonary embolism. Six anesthetized pigs were infused with placebo ( placebo group) and compared with six other pigs receiving a continuous infusion of BM-573 ( BM group). Pulmonary embolization with 0.3 g/kg autologous blood clots was carried out 30 min after the start of the infusion. Right ventricular pressure-volume loops were recorded using a conductance catheter, and end-systolic ventricular elastance was periodically assessed by varying right ventricular preload. Pulmonary vascular properties were studied by use of a four-element wind-kessel model. Hemodynamic data, including assessment of right ventricular-arterial coupling, were collected at baseline and every 30 min for 4 h. Blood samples were collected to assess gas exchange, thromboxane A(2), and prostacyclin plasma levels and to evaluate platelet aggregation. Mean pulmonary arterial pressure in the placebo group increased significantly more than in the BM group, mainly because of an additional increase in pulmonary vascular resistance. Arterial and end-systolic ventricular elastances increased also more in the placebo group, whereas right ventricular efficiency decreased. BM-573 prevented both platelet aggregation induced by U-46619 (9,11-dideoxy-11alpha, 9alpha-epoxymethanoprostaglandin F-2alpha) or by arachidonic acid, and thromboxane A(2) overproduction, whereas prostacyclin liberation was preserved. Oxygenation, however, was not significantly improved. We conclude that in this animal model of acute pulmonary embolism, infusion of BM-573 reduced pulmonary vasoconstriction. As a result, right ventricular-vascular coupling values were maintained at a maximal efficiency level.
Disciplines :
Pharmacy, pharmacology & toxicology
Author, co-author :
Ghuysen, Alexandre ; Université de Liège - ULiège > Département des sciences de la santé publique > Réanimation - Urgence extrahospitalière
Lambermont, Bernard ; Centre Hospitalier Universitaire de Liège - CHU > Frais communs médecine
Dogné, Jean-Michel ; Université de Liège - ULiège > Département de pharmacie > Département de pharmacie
Kolh, Philippe ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Service de biochimie et de physiologie humaines, normale et pathologique
Tchana-Sato, Vincent ; Centre Hospitalier Universitaire de Liège - CHU > Chirurgie cardio-vasculaire
Morimont, Philippe ; Centre Hospitalier Universitaire de Liège - CHU > Frais communs médecine
Magis, David ; Université de Liège - ULiège > Département de mathématique > Département de mathématique
D'Orio, Vincenzo ; Université de Liège - ULiège > Département des sciences cliniques > Médecine d'urgence - bioch. et phys. hum. normales et path.
Language :
English
Title :
Effect of BM-573[N-terbutyl-N '-[2-(4 '-methylphenylamino)-5-nitro-benzenesulfonyl] urea], a dual thromboxane synthase inhibitor and thromboxane receptor antagonist, in a porcine model of acute pulmonary embolism
Publication date :
September 2004
Journal title :
Journal of Pharmacology and Experimental Therapeutics
ISSN :
0022-3565
eISSN :
1521-0103
Publisher :
Amer Soc Pharmacology Experimental Therapeutics, Bethesda, United States - Maryland
Born GV and Cross MJ (1963) The aggregation of blood platelets. J Physiol (Lond) 168:178-195.
Burkhoff D and Sagawa K (1986) Ventricular efficiency predicted by an analytical model. Am J Physiol 250:R1021-R1027.
Cheng Y, Austin SC, Rocca B, Koller BH, Coffman TM, Grosser T, Lawson JA, and FitzGerald GA (2002) Role of prostacyclin in the cardiovascular response to thromboxane A2. Science (Wash DC) 296:539-541.
de Vroomen M, Cardozo RH, Steendijk P, van Bel F, and Baan J (2000) Improved contractile performance of right ventricle in response to increased RV afterload in newborn lamb. Am J Physiol 278:H100-H105.
Delcroix M, Melot C, Lejeune P, Leeman M, and Naeije R (1990) Effects of vasodilators on gas exchange in acute canine embolic pulmonary hypertension. Anesthesiology 72:77-84.
Delcroix M, Melot C, Lejeune P, Leeman M, and Naeije R (1992) Cyclooxygenase inhibition aggravates pulmonary hypertension and deteriorates gas exchange in canine pulmonary embolism. Am Rev Respir Dis 145:806-810.
Dickstein ML, Yano O, Spotnitz HM, and Burkhoff D (1995) Assessment of right ventricular contractile state with the conductance catheter technique in the pig. Cardiovasc Res 29:820-826.
Dogne JM, Benoit P, de Leval X, Rolin S, Kolh P, Ghuysen A, Tchana-Sato V, and Masereel B (2002) Antithrombotic properties of BM-573, an original dual thromboxane receptor antagonist and thromboxane synthase inhibitor. Pathophysiol Haemost Thromb 32S2:60.
Dogne JM, de Leval X, Delarge J, David JL, and Masereel B (2000a) New trends in thromboxane and prostacyclin modulators. Curr Med Chem 7:609-628.
Dogne JM, de Leval X, Neven P, Rolin S, Wauters J, David JL, Delarge J, and Massereel B (2000b) Effects of a novel non-carboxylic thromboxane A2 receptor antagonist (BM-531) derived from torasemide on platelet function. Prostaglandins Leukot Essent Fatty Acids 62:311-317.
Dogne JM, Hanson J, De Leval X, Tchana-Sato V, Kolh P, De Leval L, Rolin S, Ghuysen A, Segers P, Lambermont B, Masereel B, and Pirotte B (2004) Pharmacological characterization of N-terbutyl-N′-[2-(4′- methylphenylamino)-5-nitro-benzenesulfonyllurea (BM-573), a novel thromboxane A2 receptor antagonist and thromboxane synthase inhibitor in a rat model of arterial thrombosis and its effects on bleeding time. J Pharmacol Exp Ther 309:498-505.
Dogne JM, Wouters J, Rolin S, Michaux C, Pochet L, Durant F, Delarge J, and Masereel B (2001) Design, synthesis and biological evaluation of a sulfonylcyanoguanidine as thromboxane A2 receptor antagonist and thromboxane synthase inhibitor. J Pharm Pharmacol 53:669-680.
FitzGerald GA (1991) Mechanisms of platelet activation: thromboxane A2 as an amplifying signal for other agonists. Am J Cardiol 68:11B-15B.
Fourie PR, Coetzee AR, and Bolliger CT (1992) Pulmonary artery compliance: its role in right ventricular-arterial coupling. Cardiovasc Res 26:839-844.
Fukushima M and Kobayashi T (1986) Effects of thromboxane synthase inhibition on air emboli lung injury in sheep. JAppl Physiol 60:1828-1833.
Garcia-Szabo R, Johnson A, and Malik AB (1988) Thromboxane increases pulmonary vascular resistance and transvascular fluid and protein exchange after pulmonary microembolism. Prostaglandins 35:707-721.
Garcia Szabo RR, Minnear FL, Bizios R, Johnson A, and Malik AB (1983) Role of thromboxane in the pulmonary response to pulmonary microembolization. Chest 83:76S-78S.
Grant BJ and Paradowski LJ (1987) Characterization of pulmonary arterial input impedance with lumped parameter models. Am J Physiol 252:H585-H593.
Hofman WF and Ehrhart IC (1987) Effects of cyclooxygenase inhibition on pulmonary vascular responses to serotonin. J Appl Physiol 62:1192-1200.
Hon JK, Steendijk P, Khan H, Wong K, and Yacoub M (2001) Acute effects of pulmonary artery banding in sheep on right ventricle pressure-volume relations: relevance to the arterial switch operation. Acta Physiol Scand 172:97-106.
Ishihara Y, Uchida Y, and Kitamura S (1986) Effect of thromboxane synthetase inhibitors (OKY-046, OKY-1580) on experimentally induced air embolism in anesthetized dogs. Prostaglandins Leukot Med 21:197-206.
Johnson A and Malik AB (1985) Pulmonary transvascular fluid and protein exchange after thrombin-induced microembolism. Differential effects of cyclooxygenase inhibitors. Am Rev Respir Dis 132:70-76.
Kass DA and Kelly RP (1992) Ventriculo-arterial coupling: concepts, assumptions and applications. Ann Biomed Eng 20:41-62.
Klotz TA, Cohn LS, and Zipser RD (1984) Urinary excretion of thromboxane B2 in patients with venous thromboembolic disease. Chest 85:329-335.
Lambermont B, D'Orio V, Gerard P, Kolh P, Detry O, and Marcelle R (1998) Time domain method to identify simultaneously parameters of the windkessel model applied to the pulmonary circulation. Arch Physiol Biochem 106:245-252.
Lambermont B, Kolh P, Dogne JM, Ghuysen A, Tchana-Sato V, Morimont P, Benoit P, Gerard P, Masereel B, Limet R, et al. (2003) Effects of U-46619 on pulmonary hemodynamics before and after administration of BM-573 a novel thromboxane A2 inhibitor. Arch Physiol Biochem 111:217-223.
Lambermont B, Kolh P, Ghuysen A, Segers P, Dogne JM, Tchana-Sato V, Morimont P, Benoit P, Gerard P, Masereel B, et al. (2004) Effect of a novel thromboxane A2 inhibitor on right ventricular-arterial coupling in endotoxic shock. Shock 21:45-51.
Lee JH, Chun YG, Lee IC, Tuder RM, Hong SB, Shim TS, Lim CM, Koh Y, Kim WS, Kim DS, et al. (2001) Pathogenic role of endothelin 1 in hemodynamic dysfunction in experimental acute pulmonary thromboembolism. Am J Respir Crit Care Med 164:1282-1287.
Lelcuk S, Klausner JM, Merhav A, and Rozin RR (1987) Effect of OKY 046, a thromboxane synthase inhibitor, on lung vascular permeability after pulmonary embolism in sheep. Thorax 42:676-680.
Lopes Cardozo RH, Steendijk P, Baan J, Brouwers HA, de Vroomen M, and van Bel F (2000) Right ventricular function in respiratory distress syndrome and subsequent partial liquid ventilation. Homeometric autoregulation in the right ventricle of the newborn animal. Am J Respir Crit Care Med 162:374-379.
Oates JA, FitzGerald GA, Branch RA, Jackson EK, Knapp HR, and Roberts LJ (1988) Clinical implications of prostaglandin and thromboxane A2 formation (1). N Engl J Med 319:689-698.
Perlman MB, Johnson A, and Malik AB (1987) Ibuprofen prevents thrombin-induced lung vascular injury: mechanism of effect. Am J Physiol 252:H605-H614.
Reeves WC, Demers LM, Wood MA, Skarlatos S, Copenhaver G, Whitesell L, and Luderer JR (1983) The release of thromboxane A2 and prostacyclin following experimental acute pulmonary embolism. Prostaglandins Leukot Med 11:1-10.
Rolin S, Dogne JM, Michaux C, Delarge J, and Masereel B (2001) Activity of a novel dual thromboxane A(2)receptor antagonist and thromboxane synthase inhibitor (BM-573) on platelet function and isolated smooth muscles. Prostaglandins Leukot Essent Fatty Acids 65:67-72.
Rolin S, Petein M, Tchana-Sato V, Dogne JM, Benoit P, Lambermont B, Ghuysen A, Kolh P, and Masereel B (2003) BM-573, a dual thromboxane synthase inhibitor and thromboxane receptor antagonist, prevents pig myocardial infarction induced by coronary thrombosis. J Pharmacol Exp Ther 306:59-65.
Rose CE Jr, Van Benthuysen K, Jackson JT, Tucker CE, Kaiser DL, Grover RF, and Weil JV (1983) Right ventricular performance during increased afterload impaired by hypercapnic acidosis in conscious dogs. Circ Res 52:76-84.
Smulders YM (2000) Pathophysiology and treatment of haemodynamic instability in acute pulmonary embolism: the pivotal role of pulmonary vasoconstriction. Cardiovasc Res 48:23-33.
Stein PD and Henry JW (1995) Prevalence of acute pulmonary embolism among patients in a general hospital and at autopsy. Chest 108:978-981.
Uchida T, Kido H, Yamanaga K, Okita M, and Watanabe M (1992) A novel loop diuretic, torasemide, inhibits thromboxane A2-induced contraction in the isolated canine coronary artery. Prostaglandins Leukot Essent Fatty Acids 45:121-124.
Utsonomiya T, Krausz MM, Levine L, Shepro D, and Hechtman HB (1982) Thromboxane mediation of cardiopulmonary effects of embolism. J Clin Investig 70:361-368.
