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Cardiopulmonary bypass increases plasma bradykinin concentrations
Immunopharmacology 43 Ž1999. 145–147 www.elsevier.comrlocaterimmpharm
Cardiopulmonary bypass increases plasma bradykinin concentrations M. Cugno a , J. Nussberger c , P. Biglioli b, M.G. Giovagnoni a , M. Gardinali a , A. Agostoni a,) a
Department of Internal Medicine, IRCCS Maggiore Hospital, UniÕersity of Milan, Milan, Italy DiÕision of Cardiac Surgery, IRCCS Foundation Monzino, UniÕersity of Milan, Milan, Italy c Hypertension DiÕision, UniÕersity Hospital Lausanne, Switzerland
b
Accepted 24 February 1999
Abstract An increase of bradykinin ŽBK. plasma levels together with the activation coagulation cascade, fibrinolysis, complement and cytokines was observed during cardiopulmonary bypass ŽCPB.. Since the procedure of extracorporeal circulation completely excludes the lung, the major site of BK catabolism, our data suggest that a reduced catabolism could contribute to the increase of BK during CPB. q 1999 Published by Elsivier Science B.V. All rights reserved. Keywords: Bradykinin; Cardiopulmonary bypass; Catabolism
1. Introduction Hemodynamic complications including extravascular fluid accumulation and hypotensive episodes are frequently associated with cardiopulmonary bypass ŽCPB. and can be attributed to a generalized inflammatory response ŽHall et al., 1997.. The nonapeptide bradykinin ŽBK. is a potent vasodilator which increases vascular permeability ŽBhoola et al., 1992.. During activation of the contact system, BK is generated by kallikrein cleaving high molecular weight kininogen. BK may mediate the inflammatory reaction in CPB ŽDowning and Edmunds, 1992.. In )
Corresponding author. Department of Internal Medicine, University of Milan, Via Pace, 15, 20122 Milan, Italy. Tel.: q00390 2 -5 5 1 8 0 2 2 5 ; fa x : q 0 0 3 9 -0 2 -5 5 1 8 0 3 5 4 ; e -m a il: [email protected]
the present study, we measured plasma levels of BK in patients with coronary artery disease undergoing CPB, using a sensitive and specific method recently developed ŽNussberger et al., 1998.. BK levels were compared with the activation of contact system, coagulation, fibrinolysis, complement system and with the levels of the cytokine tumor necrosis factor, and analyzed in relation to changes of blood pressure.
2. Patients and methods Twenty-one patients undergoing CPB for coronary operation were studied. Intraarterial blood pressure was measured in the radial artery by a pressure transducer. Blood samples were obtained from the venous line of the bypass system before surgery Žbaseline., after heparin infusion, 15 min after the
0162-3109r99r$ - see front matter q 1999 Published by Elsevier Science B.V. All rights reserved. PII: S 0 1 6 2 - 3 1 0 9 Ž 9 9 . 0 0 0 7 2 - 7
146
Mean arterial pressure Žmm Hg. Bradykinin Žfmolrml. Cleaved HK Ž% of total HK.
Baseline
Before ECC
85 Ž62–123. 1.90 Ž0.36–9.80. 16 Ž3–39.
77 Ž48–98. 2.68 Ž0.69–13.10. 14 Ž3–28.
ECC 15 min UU
75 Ž56–90. 5.71UU Ž0.50–61.92. 12 Ž1–18.
End of ECC UUU
Ž49–93. 68.5 9.81UUU Ž0.32–90.16. 12 Ž2–21.
End of operation
Recovery Ž24 h.
81 Ž62–89. 7.07UU Ž0.86–41.86. 14 Ž2–21.
78.5 Ž56–106. 2.81 Ž0.40–9.87. 17 Ž3–39.
M. Cugno et al.r Immunopharmacology 43 (1999) 145–147
Table 1 Mean arterial pressure and plasma levels of bradykinin and cleaved high molecular weight kininogen ŽHK. in 21 patients with coronary artery disease undergoing cardiopulmonary bypass. Plasma samples were collected from right atrium and intraarterial blood pressure was measured in the radial artery at baseline conditions, before extracorporeal circulation after surgical procedure of connection Žbefore ECC., after 15 min of ECC ŽECC 15 min., at the end of ECC, at the end of operation and 24 h later Žrecovery.. Results are expressed as medians with ranges in parentheses. UU P - 0.01; UUU P - 0.001 vs. baseline
M. Cugno et al.r Immunopharmacology 43 (1999) 145–147
beginning of extracorporeal circulation ŽECC., at the end of ECC, at the end of surgery and at the day after surgery Žrecovery.. We measured plasma BK and several parameters of the contact system wactivated factor XII ŽFXIIa., cleavage of high molecular weight kininogen ŽHK.x, of the coagulation cascade wprothrombin fragment F1 q 2 and thrombin–antithrombin ŽTAT. complexesx, of the fibrinolytic system wplasmin–antiplasmin ŽPAP. complexesx, of the complement system wC3ax as well as the cytokine tumor necrosis factor a ŽTNF-a .. The BK-nonapeptide was specifically measured using a new method which combines liquid-phase extraction, high performance liquid chromatography and radioimmunoassay ŽNussberger et al., 1998.. FXIIa was measured by a sandwich enzyme-linked immunosorbent assay ŽELISA . ŽShield Diagnostic, Dundee, UK.. Cleavage of HK was assessed by sodium dodecylsulphate-polyacrilamide gel electrophoresis ŽSDS-PAGE. and immunoblotting analysis ŽCugno et al., 1994.. We further measured: prothrombin fragment 1 q 2 by a sandwich ELISA ŽEnzygnost F1 q 2, Behring Diagnostics, Marburg, Germany.; TAT complexes by a sandwich ELISA ŽEnzygnost TAT micro; Behring Diagnostics.; PAP complexes by a sandwich ELISA ŽEnzygnost PAP micro; Behring Diagnostics.; C3a by radioimmunoassay ŽAmersham, England.; TNF-a by solid-phase immunoassay ŽEnzyme Amplified Sensitivity Immunoassay, EASIA, Biosource, Flerus, Belgium.. All results were corrected for hemodilution.
147
TNF-a Ž P - 0.01.. All these parameters further increased during ECC, remained elevated until the end of operation and had returned to normal at recovery. PAP complexes increased with ECC, remained elevated until the end of operation and fell below basal values at recovery Ž P - 0.0001.. There was no correlation between BK and any of the parameters tested, neither before, during or after ECC. There was, however, at the end of ECC a significant inverse correlation between BK levels and the weaning time Žthe time in which the pulmonary circulation is progressively restored while ECC is still ongoing., i.e., the longer the lung had been at least partially perfused at the time of sampling Žend of ECC., the lower were plasma BK levels Ž r s y0.636; P s 0.003.. In conclusion, our results demonstrate a progressive increase in plasma BK levels during CPB. This increase of plasma BK may be due to reduced catabolism since during CPB the lung Žthe major site of BK catabolism. is completely excluded, the generation of BK by HK cleavage does not appear enhanced and no correlation was found with the activation of contact system, coagulation, fibrinolysis, complement and cytokines. Despite the absence of correlation between individual changes in plasma BK and changes in blood pressure, the increase in median BK and decrease of blood pressure coincided, suggesting a role for BK as a mediator of hypotension in CPB.
References 3. Results and conclusion Table 1 summarizes the blood pressure, BK and HK results. Median arterial pressure was decreased throughout the period of ECC. Plasma BK concentration was normal at baseline, prior to ECC and 24 h later at recovery, but it was significantly increased throughout the operation from 15 min after the beginning of ECC Ž P s 0.001. to the end of operation Ž P s 0.001. with a peak at the end of ECC Ž P 0.0001.. The cleavage of HK remained unchanged during the entire observation period. The surgical procedure alone Žbefore ECC. increased FXIIa Ž P - 0.0001., TAT complexes Ž P 0.001., F1 q 2 Ž P - 0.003., C3a Ž P - 0.0001. and
Bhoola, K.D., Figueroa, C.D., Worthy, K., 1992. Bioregulation of kinins: kallikrein, kininogens and kininases. Pharmacol. Rev. 44, 1–80. Cugno, M., Cicardi, M., Agostoni, A., 1994. Activation of the contact system and fibrinolysis in autoimmune acquired angioedema: a rationale for prophylactic use of tranexamic acid. J. Allergy Clin. Immunol. 93, 870–876. Downing, S.W., Edmunds, L.H. Jr., 1992. Release of vasoactive substances during cardiopulmonary bypass. Ann. Thorac. Surg. 54, 1236–1243. Hall, R.I., Stafford Smith, M., Rocker, G., 1997. The systemic inflammatory response to cardiopulmonary bypass: pathophysiological, therapeutic, and pharmacological considerations. Anesth. Analg. 85, 766–782. Nussberger, J., Cugno, M., Amstutz, C., Cicardi, M., Pellacani, A., Agostoni, A., 1998. Plasma bradykinin in angio-oedema. Lancet 351, 1693–1697.
Cardiopulmonary bypass increases plasma bradykinin concentrations M. Cugno a , J. Nussberger c , P. Biglioli b, M.G. Giovagnoni a , M. Gardinali a , A. Agostoni a,) a
Department of Internal Medicine, IRCCS Maggiore Hospital, UniÕersity of Milan, Milan, Italy DiÕision of Cardiac Surgery, IRCCS Foundation Monzino, UniÕersity of Milan, Milan, Italy c Hypertension DiÕision, UniÕersity Hospital Lausanne, Switzerland
b
Accepted 24 February 1999
Abstract An increase of bradykinin ŽBK. plasma levels together with the activation coagulation cascade, fibrinolysis, complement and cytokines was observed during cardiopulmonary bypass ŽCPB.. Since the procedure of extracorporeal circulation completely excludes the lung, the major site of BK catabolism, our data suggest that a reduced catabolism could contribute to the increase of BK during CPB. q 1999 Published by Elsivier Science B.V. All rights reserved. Keywords: Bradykinin; Cardiopulmonary bypass; Catabolism
1. Introduction Hemodynamic complications including extravascular fluid accumulation and hypotensive episodes are frequently associated with cardiopulmonary bypass ŽCPB. and can be attributed to a generalized inflammatory response ŽHall et al., 1997.. The nonapeptide bradykinin ŽBK. is a potent vasodilator which increases vascular permeability ŽBhoola et al., 1992.. During activation of the contact system, BK is generated by kallikrein cleaving high molecular weight kininogen. BK may mediate the inflammatory reaction in CPB ŽDowning and Edmunds, 1992.. In )
Corresponding author. Department of Internal Medicine, University of Milan, Via Pace, 15, 20122 Milan, Italy. Tel.: q00390 2 -5 5 1 8 0 2 2 5 ; fa x : q 0 0 3 9 -0 2 -5 5 1 8 0 3 5 4 ; e -m a il: [email protected]
the present study, we measured plasma levels of BK in patients with coronary artery disease undergoing CPB, using a sensitive and specific method recently developed ŽNussberger et al., 1998.. BK levels were compared with the activation of contact system, coagulation, fibrinolysis, complement system and with the levels of the cytokine tumor necrosis factor, and analyzed in relation to changes of blood pressure.
2. Patients and methods Twenty-one patients undergoing CPB for coronary operation were studied. Intraarterial blood pressure was measured in the radial artery by a pressure transducer. Blood samples were obtained from the venous line of the bypass system before surgery Žbaseline., after heparin infusion, 15 min after the
0162-3109r99r$ - see front matter q 1999 Published by Elsevier Science B.V. All rights reserved. PII: S 0 1 6 2 - 3 1 0 9 Ž 9 9 . 0 0 0 7 2 - 7
146
Mean arterial pressure Žmm Hg. Bradykinin Žfmolrml. Cleaved HK Ž% of total HK.
Baseline
Before ECC
85 Ž62–123. 1.90 Ž0.36–9.80. 16 Ž3–39.
77 Ž48–98. 2.68 Ž0.69–13.10. 14 Ž3–28.
ECC 15 min UU
75 Ž56–90. 5.71UU Ž0.50–61.92. 12 Ž1–18.
End of ECC UUU
Ž49–93. 68.5 9.81UUU Ž0.32–90.16. 12 Ž2–21.
End of operation
Recovery Ž24 h.
81 Ž62–89. 7.07UU Ž0.86–41.86. 14 Ž2–21.
78.5 Ž56–106. 2.81 Ž0.40–9.87. 17 Ž3–39.
M. Cugno et al.r Immunopharmacology 43 (1999) 145–147
Table 1 Mean arterial pressure and plasma levels of bradykinin and cleaved high molecular weight kininogen ŽHK. in 21 patients with coronary artery disease undergoing cardiopulmonary bypass. Plasma samples were collected from right atrium and intraarterial blood pressure was measured in the radial artery at baseline conditions, before extracorporeal circulation after surgical procedure of connection Žbefore ECC., after 15 min of ECC ŽECC 15 min., at the end of ECC, at the end of operation and 24 h later Žrecovery.. Results are expressed as medians with ranges in parentheses. UU P - 0.01; UUU P - 0.001 vs. baseline
M. Cugno et al.r Immunopharmacology 43 (1999) 145–147
beginning of extracorporeal circulation ŽECC., at the end of ECC, at the end of surgery and at the day after surgery Žrecovery.. We measured plasma BK and several parameters of the contact system wactivated factor XII ŽFXIIa., cleavage of high molecular weight kininogen ŽHK.x, of the coagulation cascade wprothrombin fragment F1 q 2 and thrombin–antithrombin ŽTAT. complexesx, of the fibrinolytic system wplasmin–antiplasmin ŽPAP. complexesx, of the complement system wC3ax as well as the cytokine tumor necrosis factor a ŽTNF-a .. The BK-nonapeptide was specifically measured using a new method which combines liquid-phase extraction, high performance liquid chromatography and radioimmunoassay ŽNussberger et al., 1998.. FXIIa was measured by a sandwich enzyme-linked immunosorbent assay ŽELISA . ŽShield Diagnostic, Dundee, UK.. Cleavage of HK was assessed by sodium dodecylsulphate-polyacrilamide gel electrophoresis ŽSDS-PAGE. and immunoblotting analysis ŽCugno et al., 1994.. We further measured: prothrombin fragment 1 q 2 by a sandwich ELISA ŽEnzygnost F1 q 2, Behring Diagnostics, Marburg, Germany.; TAT complexes by a sandwich ELISA ŽEnzygnost TAT micro; Behring Diagnostics.; PAP complexes by a sandwich ELISA ŽEnzygnost PAP micro; Behring Diagnostics.; C3a by radioimmunoassay ŽAmersham, England.; TNF-a by solid-phase immunoassay ŽEnzyme Amplified Sensitivity Immunoassay, EASIA, Biosource, Flerus, Belgium.. All results were corrected for hemodilution.
147
TNF-a Ž P - 0.01.. All these parameters further increased during ECC, remained elevated until the end of operation and had returned to normal at recovery. PAP complexes increased with ECC, remained elevated until the end of operation and fell below basal values at recovery Ž P - 0.0001.. There was no correlation between BK and any of the parameters tested, neither before, during or after ECC. There was, however, at the end of ECC a significant inverse correlation between BK levels and the weaning time Žthe time in which the pulmonary circulation is progressively restored while ECC is still ongoing., i.e., the longer the lung had been at least partially perfused at the time of sampling Žend of ECC., the lower were plasma BK levels Ž r s y0.636; P s 0.003.. In conclusion, our results demonstrate a progressive increase in plasma BK levels during CPB. This increase of plasma BK may be due to reduced catabolism since during CPB the lung Žthe major site of BK catabolism. is completely excluded, the generation of BK by HK cleavage does not appear enhanced and no correlation was found with the activation of contact system, coagulation, fibrinolysis, complement and cytokines. Despite the absence of correlation between individual changes in plasma BK and changes in blood pressure, the increase in median BK and decrease of blood pressure coincided, suggesting a role for BK as a mediator of hypotension in CPB.
References 3. Results and conclusion Table 1 summarizes the blood pressure, BK and HK results. Median arterial pressure was decreased throughout the period of ECC. Plasma BK concentration was normal at baseline, prior to ECC and 24 h later at recovery, but it was significantly increased throughout the operation from 15 min after the beginning of ECC Ž P s 0.001. to the end of operation Ž P s 0.001. with a peak at the end of ECC Ž P 0.0001.. The cleavage of HK remained unchanged during the entire observation period. The surgical procedure alone Žbefore ECC. increased FXIIa Ž P - 0.0001., TAT complexes Ž P 0.001., F1 q 2 Ž P - 0.003., C3a Ž P - 0.0001. and
Bhoola, K.D., Figueroa, C.D., Worthy, K., 1992. Bioregulation of kinins: kallikrein, kininogens and kininases. Pharmacol. Rev. 44, 1–80. Cugno, M., Cicardi, M., Agostoni, A., 1994. Activation of the contact system and fibrinolysis in autoimmune acquired angioedema: a rationale for prophylactic use of tranexamic acid. J. Allergy Clin. Immunol. 93, 870–876. Downing, S.W., Edmunds, L.H. Jr., 1992. Release of vasoactive substances during cardiopulmonary bypass. Ann. Thorac. Surg. 54, 1236–1243. Hall, R.I., Stafford Smith, M., Rocker, G., 1997. The systemic inflammatory response to cardiopulmonary bypass: pathophysiological, therapeutic, and pharmacological considerations. Anesth. Analg. 85, 766–782. Nussberger, J., Cugno, M., Amstutz, C., Cicardi, M., Pellacani, A., Agostoni, A., 1998. Plasma bradykinin in angio-oedema. Lancet 351, 1693–1697.