Abstract
Objective: It is well known that lung embolism is associated with an increase in pulmonary vascular resistance. Since the mechanisms of pulmonary vascular reactions during embolism are still unclear, the aim of this study was to investigate the potential involvement of endothelin-1 (ET-1) and thromboxane A2 (TXA2) as mediators of the pulmonary artery pressure (PAP) increase after embolism using the selective ETA receptor antagonist LU135252 [1], the ETB receptor antagonist BQ788 [2], and the cy-clooxygenase inhibitor diclofenac.
Design: Prospective experimental study in rabbits.
Setting: Experimental laboratory in a university teaching hospital.
Subjects: 36 adult rabbits of either sex.
Interventions: The experiments were performed in 36 isolated and ventilated rabbit lungs which were perfused with a buffer solution containing 10 % of autologous blood. Embolism was induced by the injection of 0.75 ml air into the pulmonary artery.
Measurements and results: PAP and lung weight, reflecting edema formation, were continuously recorded. Perfusate samples were drawn intermittently to determine TXA2 and ET-1 concentrations. Air injection resulted in an immediate increase in PAP up to 22.8 ± 1.4 mm Hg at 2.5 min (control, n=6), which was parallelled by an enhanced generation of TXA2. No relevant edema formation occurred during the observation period. Pretreatment with the ETA receptor antagonist LU135 252 significantly reduced the pressure reaction after air embolism (p<0.001) whereas the ETB receptor antagonist BQ788 (n=6) was without marked effects. The administration of diclofenac (n=6) did not alter the PAP increase 2.5 min after embolism, but significantly reduced the pressure reaction during the further observation period (p<0.001). The application of LU135 252 and diclofenac together (n=6) also significantly reduced the PAP increase from 2.5 min during the total observation period (p < 0.001).
Conclusions: The acute pressure reaction after air embolism is mainly mediated via ET-1 by an ETA receptor related mechanism. TXA2 seems to maintain this reaction for a longer time.
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References
Yanagisawa M, Kurihara H, Kimura S, Tomobe Y, Kobayashi M, Mitsui Y, Yazaki Y, Katsutoshi G, Masaki T (1988) A novel potent vasoconstrictor peptide produced by vascular endothelial cells. Nature 332: 411–415
Arai H, Hori S, Aramori H, Ohkubo H, Nakanishi S (1990) Cloning and expression of a cDNA encoding an endothelin receptor. Nature 348: 730–732
Sakurai T, Yanagisawa M, Takuwa Y, Miyazaki H, Kimura S, Goto K, Masaki T (1990) Cloning of a cDNA encoding a non-isopeptide-selective subtype of the endothelin receptor. Nature 348: 732–735
Giaid A, Yanagisawa M, Langleben D, Michel RP, Levy R, Shennib H, Kimura S, Masaki T, Duguid WP, Path FRC, Stewart DJ (1993) Expression of endothelial in the lungs of patients with pulmonary hypertension. N Engl J Med 328:1732–1739
Chen WY, Yu J, Wang JY (1995) Decreased production of endothelin-1 in asthmatic children after immunotherapy. J Asthma 32:29–35
Vittori E, Marini M, Fasoli A, DeFranchis R, Mattoli S (1992) Increased expression of endothelin in bronchial epithelial cells of asthmatic patients and effects of corticosteroids. Am Rev Respir Dis 146:1320–1325
Mitaka C, Hirata Y, Makita K, Nagura T, Tsunoda Y, Amaha K (1993) Endothelin-1 and atrial natriuretic peptide in septic shock. Am Heart J 126: 466–468
Munter K, Hergenröder S, Unger L, Kirchengast M (1996) Oral treatment with an ETA-receptor antagonist inhibits neointima formation induced by endothelial injury. Pharm Pharmacol Lett 6: 90–92
Riechers H, Albrecht HP, Amberg W, Baumann E, Bernard H, Böhm HJ, Klinge D, Kling A, Müller S, Raschack M, Unger L, Walker N, Wernet W (1996) Discovery and optimization of a novel class of orally active nonpeptidic endothelin-A receptor antagonists. J Med Chem 39: 2123–2128
Ishikawa K, Ihara M, Noguchi K, Toshikai M, Mino N, Saeki T, Fukuroda T, Fukami T, Ozaki S, Nagase T, Nishikibe M, Yano M (1994) Biochemical and pharmacological profile of a potent and selective endothelin B-receptor antagonist, BQ788. Proc Natl Acad Sci USA 91:4892–4896
Thiemermann C, Lidbursy PS, Thomas GR, Vane JR (1989) Endothelin-1 releases prostacyclin and inhibits ex vivo platelet aggregation in the anesthetized rabbit. J Cardiovasc Pharmacol 13 (Suppl 5):S138-S141
Macquin-Mavier I, Levame M, Istin N, Harf A (1989) Mechanisms of endothelin mediated bronchoconstriction in the guinea pig. J Pharmacol Exp Ther 250: 740–745
Del Basso P, Argiolas L (1995) Cardiopulmonary effects of endothelin-1 in the guinea pig: role of thromboxane A2. J Cardiovasc Pharmacol 26 (Suppl 3):S120-S122
Koch T, Duncker HP, Rosenkranz S, Van Ackern K, Neuhof H (1992) Alterations of filtration coefficients in pulmonary edema of different pathogenesis. J Appl Physiol 73 (6):2396–2402
Seeger W, Walmrath D, Menger M, Neuhof H (1986) Increased lung vascular permeability after arachidonic acid and hydrostatic challenge. J Appl Physiol 61:1781–1789
Peskar BA, Steffens CH, Peskar BM (1979) Radioimmunoassay of 6-keto-prostaglandin F1-alpha in biological material. In: DaPrada M, Peskar BA (eds) Radioimmunoassay of Drugs and Hormones in Cardiovascular Medicine. Elsevier/North-Holland, Amsterdam, p 239
Fukuroda T, Ozaki S, Ihara M, Ishikawa K, Yano M, Nishikibe M (1994) Synergistic inhibition by BQ-123 and BQ-788 of endothelin-1-induced concentrations of the rabbit pulmonary artery. Br J Pharmacol 113: 336–338
Helmsworth JA, Gall EA, Perrin EV, Braley SA, Flege JB, Kaplan S, Keirle AM (1963) Occurrence of emboli during perfusion with an oxygenator pump. Surgery 53:177–185
Spencer MP (1976) Decompression limits for compressed air determined by ultrasonically detected blood bubbles. J Appl Physiol 40: 229–235
Iwao Y, Masuda J, Ochiai R, Higa S, Takeda J, Sekiguchi H, Nagano M (1995) Does pulmonary air embolism affect the pulsatility of pulmonary capillary blood flow in dogs? (Abstract) Nippon Kyobu Shikkan Gakkai Zasshi 29 (3):338–344
Josephson S (1970) Pulmonary hemodynamics during experimental air embolism. Scand J Clin Lab Invest 115 (Suppl):S9-S30
Perkett EA, Brigham KL, Meyrick B (1988) Continuous air embolization into sheep causes sustained pulmonary hypertension and increased pulmonary vasoreactivity. Am J Pathol 132: 444–454
Wang D, Li MH, Hsu K, Shen CY, Chen HI, Lin YC (1992) Air embolism-induced lung injury in isolated rat lungs. J Appl Physiol 72 (4):1235–1242
Schmeck J, Koch T, Neuhof H, Van Ackern K (1998) Endothelin-1 is not involved in pulmonary hypertension after lung embolism in isolated perfused rabbit lungs. Appl Cardiopulm Pathophysiol 6: 241–246
Wagner OF, Vierhapper H, Gasic S, Nowotny P, Waldhäusl W (1992) Regional effects and clearance of endothelin-1 across pulmonary and splanchnic circulation. Eur J Clin Invest 22: 277–282
Patrignani P, Del-Maschio A, Bazzoni G, Daffonchio L, Hernandez A, Modica R, Montesanti L, Volpi D, Patrono C, Dejana E (1991) Inactivation of endothelin by polymorphonuclear leukocyte-derived lytic enzymes. Blood 78(10):2715–2720
Nakamura S, Naruse M, Naruse K, Demura H, Uemura H (1990) Immuno-cytochemical localization of endothelin in cultured bovine endothelial cells. Histochemistry 94: 475–477
Marita T, Kurihara H, Yoshizumi M, Maemura K, Sugiyama T, Nagai R, Yazaki Y (1993) Human polymorphonu-clear leukocytes have dual effects on endothelin-1: the induction of endothelin-1 mRNA expression in vascular endothelial cells and modification of the endothelin-1 molecule. Heart Vessels 8(l):l-6
Kaw S, Hecker M, Southan GJ, Warner TD, Vane JR (1992) Characterization of serine protease-derived metabolites of big endothelin in the cytosolic fraction from human polymorphonuclear leukocytes. J Cardiovasc Res 20 (Suppl 12):S22-S24
Kaw S, Hecker M, Vane JR (1992) The two-step conversion of big endothelin-1 to endothelin 1 and degradation of endothelin-1 by subcellular fractions from human polymorphonuclear leukocytes. Proc Natl Acad Sci USA 89(15):6886–6890
Sessa WC, Kaw S, Zembowicz A, Anggard E, Hecker M, Vane JR (1991) Human polymorphonuclear leukocytes generate and degradate endothelin-1 by two distinct neutral proteases. J Cardiovasc Pharmacol 17(Suppl 7):S34-S38
DiCarlos VS, Chen SJ, Meng QC, Durand J, Yano M, Chen YF, Oparil S (1995) ETA-receptor antagonist prevents and reverses chronic hypoxia-induced pulmonary hypertension in rat. Am J Physiol 269:L690-L697
Hay DWP, Hubbard WC, Undem BJ (1993) Endothelin receptor subtypes in human and guinea-pig pulmonary tissues. Br J Pharmacol 110:1175–1183
Fukuroda T, Kobayashi M, Ozaki S, Yano M, Miyauchi T, Onizuka M, Sugishita Y, Goto K, Nishikibe M (1994) Endothelin receptor subtypes in human versus rabbit pulmonary arteries. J Appl Physiol 76 (5):1976–1982
LaDouceur DM, Flynn MA, Keiser JA, Reynolds E, Haleen S (1993) ETA and ETB receptors coexist on rabbit pulmonary artery vascular smooth muscle mediating contraction. Biochem Biophys Res Commun 196: 209–215
Buchan KW, Magnusson H, Rabe KF, Sumner MJ, Watts IS (1994) Characterisation of the endothelin receptor mediating contraction of human pulmonary artery using BQ123 and Ro 46-2005. Eur J Pharmacol 260: 221–225
Hay DWP, Luttmann MA, Hubbard WC, Undem BJ (1993) Endothelin receptor subtypes in human and guinea-pig pulmonary tissues. Br J Pharmacol 110:1175–1183
Okada M, Yamashita C, Okada M, Okada K (1995) Contribution of endothelin-1 to warm ischemia/reperfusion injury of the rat lung. Am J Respir Crit Care Med 152: 2105–2110
Ishizaki T, Shigemori K, Nakai T, Miyabo S, Hayakawa M, Ozawa T, Voelkel NF, Chang SW (1995) Endothelin-1 potentiates leukotoxin-induced edematous lung injury. J Appl Physiol 79 (4):1106–1111
Del Basso P, Argiolas L (1995) Cardiopulmonary effects of endothelin-1 in the guinea pig: role of thromboxane A2. J Cardiovasc Pharmacol 26 (Suppl 3):S120-S122
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Schmeck, J., Koch, T., Heller, A. et al. The role of endothelin-1 as a mediator of the pressure response after air embolism in blood perfused lungs. Intensive Care Med 24, 605–611 (1998). https://doi.org/10.1007/s001340050622
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DOI: https://doi.org/10.1007/s001340050622