Summary
The possibility of minimizing organ damage following cardiopulmonary bypass (CPB) was examined. In the control group,n = 21, upon completion of CPB, elevation of the lysosomal enzyme β-glucuronidase, which is a sensitive indicator of cellular damage, was affected by the concentration of granulocyte elastase (r = 0.59) or the endothelial-derived constricting factor, endothelin, (r = 0.8). Renal damage, which was detected by an increase in renal tubular enzymes (N-acetyl-β-D-glucosaminidase and γ-glutamyltranspeptidase) in urine, was also affected by endothelin (r = 0.79, r = 0.56), elastase (r = 0.6, r = 0.71), and by free hemoglobin levels (r = 0.76, r = 0.82). Next, the efficacy of pharmacological intervention for the prevention of renal damage was evaluated. During CPB, the administration of an elastase inhibitor (ulinastatin, 3 × 105IU),n = 8, or a calcium antagonist (nicaldipine HCl, elastase release inhibitor; 5 γ/kg per min),n = 8, significantly reduced the elevation of β-glucuronidase and renal tubular enzymes (p < 0.05). Although the ulinastatin and nicardipine groups demonstrated low values of elastase in the Intensive Care Unit (ICU), only the values of the nicardipine group reached statistical significance (p < 0.05). A reduction in endothelin levels compared to the control group was observed in the nicardipine group. However, preventive and counteractive effects of nicardipine against vasoconstriction caused by endothelin were also considered to play an important role in the prevention of renal damage. The addition of haptoglobin (4,000 IU) to the priming solution of the CPB also reduced levels of renal tubular enzymes (p < 0.05). We concluded that elastase, endothelin, and free hemoglobin were causes of renal damage during CPB. The administration of ulinastatin, nicardipine, or haptoglobin possibly prevent apparent renal dysfunction after CPB.
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Chenoweth DE, Cooper SW, Hugli TE, Stewart RW, Blackstone EH, Kirklin JW (1981) Complement activation during cardiopulmonary bypass. Evidence for generation of C3a and C5a anaphylatoxins. N Engl J Med 304:497–503
Hammerschmidt DE, Stroncek DF, Bowers TK, Lammi-Keefe CJ, Kurth DM, Ozalins A, Nicoloff DM, Lillehei RC, Craddock PR, Jacob HS (1981) Complement activation and neutropenia occurring during cardiopulmonary bypass. J Thoracic Cardiovasc Surg 81:370–377
Kirklin JK, Westaby S, Blackstone EH, Kirklin JW, Chenoweth DE, Pacifico AD (1983) Complement and the damaging effects of cardiopulmonary bypass. J Thorac Cardiovasc Surg 86:845–857
Wachtfogel YT, Kucich U, Greenplate J, Gluszko P, Abrams W, Weinbaum G, Wenger RK, Rucinski B, Niewiarowski S, Edmunds LH Jr, Colman RW (1987) Human neutrophil degranulation during extracorporeal circulation. Blood 69:324–330
Hashimoto K, Miyamoto H, Suzuki K, Horikoshi S, Matsui M, Arai T, Kurosawa H (1992) Evidence of organ damage following a cardiopulmonary bypass. The role of elastase and vasoactive mediators. J Thoracic Cardiovasc Surg 104:666–672
Yanagisawa M, Kurihara H, Kimura S, Tomobe Y, Kobayashi M, Mitsui Y, Yazaki Y, Goto K, Masaki T (1988) A novel potent vasoconstrictor peptide produced by vascular endothelial cells. Nature 332:411–415
Yeb TJ, Brackney EL, Hall DP, Ellison RG (1964) Renal complications of open-heart surgery: Predisposing factors, prevention, and management. J Thorac Cardiovasc Surg 47:79–97
Ohnishi H, Kosuzume H, Ashida Y, Kato K, Suzuki Y, Honjo I (1983) Therapeutic effects of human urinary trypsin inhibitor on acute experimental pancreatitis. Folia Pharmacol Japon 81:235–244
Shibutani Y, Kunihiro Y (1986) Preventive effects of ulinastatin on tissue degradation. Yakuri to chiryo 14:6057–6072
Riegel W, Spillner G, Schlosser V, Hörl WH (1988) Plasma levels of main granulocyte components during cardiopulmonary bypass. J Thorac Cardiovasc Surg 95:1014–1019
Kokot K, Teschner M, Schaefer RM, Heidland A (1987) Stimulation and inhibition of elastase release from human neutrophils dependent on the calcium messenger system. Miner Electrolyte Metab 13:133–140
Parkes DG, Reid AF, Coghlan JP, Scoggins BA, Whitworth JA (1991) Effects of calcium channel blockade on the hemodynamic responses to endothelin infusion in conscious sheep. A J Hypertens 4:719–722
Hashimoto K, Kurosawa H, Horikoshi S, Miyamoto H, Suzuki K (1993) Perfusion pressure control by adenosine triphosphate given during cardiopulmonary bypass. Ann Thorac Surg 55:123–126
Neumann S, Hennrich N, Gunzer G, Lang H (1984) Enzyme-linked immunoassay for human granulocyte elastase in complex with alpha1-proteinase inhibitor. In: Horl WH, Heidland A, (eds) Proteases: Potential role in health and disease. Plenum Press, New York, pp 379–390
Shimizu T, Ishimaru S, Furukawa K, Nagatomo M, Toyoda T (1991) Plasma free-hemoglobin and renal function in open heart surgery. Clin Report 25:4527–4537
Nobunaga M (1961) Study on β-glucuronidase. Clinical application of the assay method of β-glucuronidase activity using p-nitrophenylglucuronide as the substrate. Fukuoka Igaku Zasshi 52:300–311
Gnanadurai TV, Branthwaite MA, Colbeck JF, Welman E (1977) Lysosomal enzyme release during cardiopulmonary bypass. Anaesthesia 32:743–748
Kobayashi S, Nagai Y (1978) Human leucocyte neural proteases, with special reference to collagen metabolism. J Biochem 84:559–567
Yasutake A, Powers JC (1981) Reactivity of human leukocyte elastase and porcine pancreatic elastase toward peptide 4-nitroanilides containing model desmosine residues. Evidence that human leukocyte elastase is selective for cross-linked regions of elastin. Biochemistry 20:3675–3679
Fritz H, Jochum M, Duswald K-H, Dittmer H, Kortmann H, Neumann S, Lang H (1984) Granulocyte proteinases as mediators of unspecific proteolysis in inflammation; A review. In: Werner M, Goldberg DM (eds) Selected topics in clinical enzymology, vol. 2. Walter de Gruyter & Co., Berlin pp 305–328
Matheson NR, Wong PS, Travis J (1979) Enzymatic inactivation of human alpha-1-proteinase inhibitor by neutrophil myeloperoxidase. Biochem Biophys Res Commun 88:402–409
Mishima A, Takeuchi Y, Usami S, Kotani H, Suzuki Y, Yura J (1990) Effects of ulinastatin on plasma polymorphonuclear leukocyte elastase activity and respiratory function in patients undergoing cardiopulmonary bypass. Jpn J Thorac Surg 38:607–612
Kawai T, Wada Y, Nishiyama K et al. (1991) Usefulness of ulinastatin as a radial scavenger for protection of reperfusion injury after myocardial ischemia in open heart surgery. J Jap Assoc Thorac Surg 39:2157–2162
Ais G, Novo C, López-Farré A, Romeo JM, López-Novoa JM (1989) Effect of endothelin on systemic and regional hemodynamics in rats. Eur J Pharmacol 170:113–116
King AJ, Pfeffer JM, Pfeffer MA, Brenner BM (1990) Systemic hemodynamic effects of endothelin in rats. Am J Physiol 258:H787–792
Miller WL, Redfield MM, Burnett JC Jr (1989) Integrated cardiac, renal, and endocrine actions of endothelin. J Clin Invest 83:317–320
Firth JD, Ratcliffe PJ, Raine AEG, Ledingham JGG (1988) Endothelin: An important factor in acute renal failure? Lancet:1179–1181
Miura S, Kurose I, Fukumura D, Suematsu M, Sekizuka E, Tashiro H, Serizawa H, Asako H, Tsuchiya M (1991) Ischemic bowel necrosis induced by endothelin-1: An experimental model in rats. Digestion 48:163–172
Haag-Weber M, Schollmeyer P, Hörl WH (1988) Granulocyte activation during haemodialysis in the absence of complement activation: Inhibition by calcium channel blockers. Eur J Clin Invest 18:380–385
Malis CD, Cheung JY, Leaf A, Bonventre JV (1983) Effects of verapamil in models of ischemic acute renal failure in the rat. Am J Physiol 245:F735–42
Burke TJ, Arnold PE, Gordon JA, Bulger RE, Dobyan DC, Schrier RW (1984) Protective effect of intrarenal calcium membrane blockers before or after renal ischemia. Functional, morphological, and mitochondrial studies. J Clin Invest 74:1830–1841
Lalish JJ (1955) The role of brown pigment in experimental hemoglobinuric nephrosis. Arch Pathol 60:387–392
Meroney WH, Rubini ME (1959) Kidney function during acute tubular necrosis: Clinical studies and a theory. Metabolism 8:1–15
Jaenike JR, Schneeberger EE (1966) The renal lesion associated with hemoglobinemia. II. Its structural characteristics in the rat. J Exp Med 123:537–545
Hoffmeister FS, Regelson W, Wilkens H (1965) Acute renal failure. Experimental production and prevention. Lab Invest 14:1506–1522
Baker SB, Dawes RL (1964) Experimental haemoglobinuric nephrosis. J Pathol Bacteriol 7:49–56
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Hashimoto, K., Nomura, K., Nakano, M. et al. Pharmacological intervention for renal protection during cardiopulmonary bypass. Heart Vessels 8, 203–210 (1993). https://doi.org/10.1007/BF01744743
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DOI: https://doi.org/10.1007/BF01744743