Recent Insights on the Mechanisms of Liver Preconditioning

Gastroenterology

Volumn 125, Issue 5, 2003, Pages 1480-1491

  Carini, Rita ^a   Albano, Emanuele ^a  

^a UNIVERSITY OF EASTERN PIEDMONT   (Italy)

Author keywords

[No Author keywords available]

Indexed keywords

ADENOSINE; CALCIUM ION; CASPASE; CYTOKINE; HEAT SHOCK PROTEIN; HEAT SHOCK PROTEIN 27; HEAT SHOCK PROTEIN 32; HEAT SHOCK PROTEIN 70; HEME OXYGENASE; MITOGEN ACTIVATED PROTEIN KINASE P38; NITRIC OXIDE; PROTEIN KINASE; PROTEIN KINASE C; REACTIVE OXYGEN METABOLITE; SODIUM ION; UNCLASSIFIED DRUG;

CALCIUM HOMEOSTASIS; CYTOKINE PRODUCTION; ENERGY METABOLISM; ENZYME INACTIVATION; HEPATODUODENAL LIGAMENT; HYPERTHERMIA; KUPFFER CELL; LIGAMENT; LIVER INJURY; LIVER ISCHEMIA; LIVER METABOLISM; LIVER PARENCHYMA; LIVER PRECONDITIONING; LIVER PROTECTION; LIVER SINUSOID; LIVER SURGERY; NEUTROPHIL CHEMOTAXIS; OXIDATIVE STRESS; PH; PRIORITY JOURNAL; REPERFUSION; REPERFUSION INJURY; REVIEW; SALT HOMEOSTASIS;

EID: 0242406853     PISSN: 00165085     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.gastro.2003.05.005     Document Type: Article

References (108)

1. Serracino-Inglott F, Habib NA, Mathie RT. Hepatic ischemia-reperfusion injury. Am J Surg 2001;181:160-166.
2. Jaeschke H. Preservation injury: mechanisms, prevention and consequences. J Hepatol 1996;25:774-780.
3. Selzner M, Clavien P-A. Fatty liver in liver transplantation and surgery. Semin Liver Dis 2001;21:105-113.
4. Koneru B, Dikdan G. Hepatic steatosis and liver transplantation current clinical and experimental perspectives. Transplantation 2002;73:325-330.
5. Rosser BG, Gores GJ. Liver cell necrosis: cellular mechanisms and clinical implications. Gastroenterology 1995;108:252-275.
6. Bronk SF, Gores GJ. Efflux of protons from acidic vesicles contributes to cytosolic acidification of hepatocytes during ATP depletion. Hepatology 1991;14:626-633.
7. 2+, and cytotoxicity in rat hepatocytes. J Biol Chem 1992;267: 6654-6663.
8. Carini R, Autelli R, Bellomo G, Albano E. Alterations of cell volume regulation in the development of hepatocyte necrosis. Exp Cell Res 1999;248:280-293.
9. Jassem W, Fuggle SV, Rela M, Koo DDH, Heaton ND. The role of mitochondria in ischemia/reperfusion injury. Transplantation 2002;73:493-499.
10. Lentsch AB, Kato A, Yoshidome H, McMasters KM, Edwards MJ. Inflammatory mechanisms and therapeutic strategies for warm hepatic ischemia/reperfusion injury. Hepatology 2000;32:169-173.
11. Domenicali M, Caraceni P, Vendemiale G, Grattagliano I, Nardo B, Dall'Agata M, Santoni B, Trevisani F, Cavallari A, Altomare E, Bernardi M. Food deprivation exacerbates mitochondrial oxidative stress in rat liver exposed to ischemia/reperfusion injury. J Nutr 2001;131:105-110.
12. Caraceni P, Ryu HS, Subbotin V, De Maria N, Colantoni A, Roberts L, Trevisani F, Bernardi M, Van Thiel DH. Rat hepatocytes isolated from alcohol-induced fatty liver have an increased sensitivity to anoxic injury. Hepatology 1997;25:943-949.
13. Yellon DM, Dana A. The preconditioning phenomenon. A tool for the scientist or a clinical reality? Circ Res 2000;87:543-550.
14. Murry CE, Jennings RB, Reimer KA. Preconditioning with ischemia: a delay of lethal cell injury in ischemic myocardium. Circulation 1986;74:1124-1136.
15. Cohen MV, Baines CP, Downey JM. Ischemic preconditioning: from adenosine receptor to KATP channel. Annu Rev Physiol 2000;62:79-109.
16. Bolli R. The late phase of preconditioning. Circ Res 2000;87:972-983.
17. Schulz R, Cohen MV, Behrends M, Downey JM, Heusch G. Signal transduction of ischemic preconditioning. Cardiovasc Res 2001;52:181-198.
18. Mubagwa K, Flameng W. Adenosine, adenosine receptors and myocardial protection: an updated overview. Cardiovasc Res 2001;52:25-39.
19. Zaugg M, Lucchinetti E, Spahn DR, Pasch T, Schaub MC. Volatile anesthetics mimic cardiac preconditioning by priming the activation of mitochondrial KATP channels via multiple signaling pathway. Anesthesiology 2002;97:4-14.
20. Peralta C, Closa D, Hotter G, Gelpi E, Prats N, Rosellò-Catafau J. Liver ischemic preconditioning is mediated by the inhibitory action of nitric oxide on endothelin. Biochem Biophys Res Commun 1996;229:264-270.
21. Peralta C, Hotter G, Closa D, Gelpi E, Bulbena O, Rossellò -Catafau J. Protective effect of preconditioning on the injury associated to hepatic ischemia-reperfusion in the rat: role of nitric oxide and adenosine. Hepatology 1997;25:934-937.
22. Yoshizumi T, Yanaga K, Soejima Y, Maeda T, Uchiyama H, Sugimachi K. Amelioration of the liver injury by ischaemic preconditioning. Br J Surg 1998;85:1636-1640.
23. Teoh N, Pena AD, Farrell G. Hepatic ischemic preconditioning in mice is associated with activation of NFκB, p38 kinase and cycle entry. Hepatology 2002;36:94-102.
24. Yadav S, Sindram D, Perry DK, Clavien PA. Ischemic preconditioning protects the mouse liver by inhibition of apoptosis through a caspase-dependent pathway. Hepatology 1999;130:1223-1231.
25. Serafin A, Rossellò-Catafau J, Prats N, Xaus C, Gelpi E, Peralta C. Ischemic preconditioning increases the tolerance of fatty liver to hepatic ischemia-reperfusion injury in the rat. Am J Pathol 2002;161:587-601.
26. Ricciardi R, Meyers WC, Schaffer BF, Kim RD, Shah SA, Wheeler SM, Donohue SE, Sheth KR, Callery MP, Chari RS. Protein kinase C inhibition abrogates hepatic ischemic preconditioning response. J Surg Res 2001;97:144-149.
27. Shultz R, Walz MK, Behrends M, Neumann T, Gerken G, Heusch G. Minimal protection of the liver by ischemic preconditioning in pigs. Am J Physiol 2001;280:H198-H207.
28. + accumulation and cell killing in isolated rat hepatocytes exposed to hypoxia. Hepatology 2000;31:166-172.
29. Peralta C, Closa D, Xaus C, Gelpi E, Rossellò-Catafau J, Hotter G. Hepatic preconditioning in rats is defined by the balance of adenosine and xanthine. Hepatology 1998;28:768-773.
30. Yamagami K, Yamamoto Y, Kume M, Kimoto S, Yamamoto H, Ozaki M, Yamamoto M. Heat shock preconditioning ameliorates liver injury following normothermic ischemia-reperfusion in steatotic rat livers. J Surg Res 1998;79:47-53.
31. Terajima H, Enders G, Thiaener A, Hammer C, Kondo T, Thiery J, Yamamoto Y, Yamaoka Y, Messmer K. Impact of hyperthermic preconditioning on postischemic hepatic microcirculatory disturbances in an isolated perfusion model of rat liver. Hepatology 2000;31;407-415.
32. Ito K, Ozasa H, Sanada K, Horikawa S. Doxorubicin preconditioning: a protection against rat hepatic ischemia-reperfusion injury. Hepatology 2000;31:416-419.
33. Arai M, Thurman M, Lemaster JJ, Contribution of adenosine A2 receptors and cyclic adenosine monophosphate to protective ischemic preconditioning of sinusoidal endothelial cells against storage/reperfusion injury in rat liver. Hepatology 2000;32:297-302.
34. Yin DP, Sankari HM, Chong ASF, Ma LL, Shen J, Foster P, Williams JW. Protective effect of ischemic preconditioning on liver preservation-reperfusion injury in rats. Transplantation 1998;66:152-157.
35. Arai M, Thurman RG, Lemaster JJ. Ischemic preconditioning of rat livers against cold storage-reperfusion injury: role of nonparenchymal cells and the phenomenon of heterologous preconditioning. Liver Transpl 2001;7:292-299.
36. 2 receptors. Hepatology 1999;29:126-132.
37. 2 receptor supplants ischemic preconditioning in providing ischemic tolerance in rat livers. Surgery 1999;126:945-954.
38. Dixon AK, Gubitz AK, Sirinathsinghji DJ, Richardson PJ, Freeman TC. Tissue distribution of adenosine receptors mRNAs in the rat. Br J Pharmacol 1996;118:1461-1468.
39. Ralevic V, Burnstock G. Receptors for purines and pyrimidines. Pharmacol Rev 1998;50:413-492.
40. Carini R, De Cesaris MG, Splendore R, Vay D, Domenicotti C, Nitti MP, Paola D, Pronzato MA, Albano E. Signal pathway involved in the development of hypoxic preconditioning in rat hepatocytes. Hepatology 2001;33:131-139.
41. Carini R, Nitti MP, De Cesaris MG, Splendore R, Domenicotti C, Pronzato MA, Albano E. Role of phosphatidylinositol-3-kinase in the signaling of hepatic ischemic preconditioning. (abstr) Hepatology 2002;36:200A.
42. Peralta C, Rull R, Rimola A, Deulofeu R, Rosellò-Catafau J, Gelpi E, Rodes J. Endogenous nitric oxide supplementation in hepatic ischemia-reperfusion injury in the rat. Transplantation 2001;71: 529-536.
43. Kotf RS, Seifalian AM, McBride A, Yang W, Davidson BR. The relationship of hepatic tissue oxygenation with nitric oxide metabolism in ischemic preconditioning of the liver. FASEB J 2002;16:1654-1656.
44. Serracino-Inglott F, Virlos IT, Habib NA, Williamson RCN, Mathie RT. Adenosine preconditioning attenuates hepatic reperfusion injury in rat by preserving the down-regulation of endothelial nitric oxide synthase. BMC Gastroenterol 2002;2:22.
45. Carini R, De Cesaris MG, Splendore R, Domenicotti C, Nitti MP, Pronzato MA, Albano E. Signal pathway responsible for hepatocyte preconditioning by nitric oxide. Free Radic Biol Med 2003;34:1047-1055.
46. Nandagopal K, Dawson TM, Dawson VL. Critical role of nitric oxide signaling in cardiac and neuronal ischemic preconditioning and tolerance. J Pharmacol Exp Ther 2001;297:474-478.
47. Li J, Billar TR. Nitric oxide IV. Determinants of nitric oxide protection and toxicity. Am J Physiol 1999;276:G1069-G1073.
48. Ajamieh H, Merino N, Candelario-Jalil E, Menéndez S, Martinez-Sancez G, Re L, Giuliani A, Leon OS. Similar protective effects of ischemic preconditioning and oxone oxidative preconditioning in liver ischemia/reperfusion injury. Pharmacol Res 2002;45: 333-339.
49. Sindram D, Rüdiger HA, Upadhya AG, Strasberg SM, Clavien PA. Ischemic preconditioning protects against cold ischemic injury through an oxidative stress dependent mechanism. J Hepatol 2002;36;78-84.
50. Bilzer M, Witthaut R, Paumgartner G, Gerbes AL. Prevention of ischemia/reperfusion injury in the rat liver by atrial natriuretic peptide. Gastroenterology 1994;106:143-151.
51. Gerbes AL, Vollmar AM, Kiemer AK, Bilzer M. The guanylate cyclase-coupled natriuretic peptide receptor: a new target for prevention of cold ischemia-reperfusion damage of the rat liver. Hepatology 1998;28:1309-1317.
52. Bilzer M, Jaeschke H, Vollmar AM, Paumgartner G, Gerbes AL. Prevention of Kupffer cell-induced oxidant injury in rat liver by atrial natriuretic peptide. Am J Physiol 1999;276:G1137-G1144.
53. Kiemer AK, Vollmar AM, Bilzer M, Gerwing T, Gerbes AL. Atrial natriuretic peptide reduces expression of TNF-α mRNA during reperfusion of the rat liver upon decreased activation of NF-κB and AP-1. J Hepatol 2000;33:236-246.
54. Carini R, De Cesaris MG, Splendore R, Domenicotti C, Nitti MP, Pronzato MA, Albano E. Mechanism of hepatocyte protection against hypoxic injury by atrial natriuretic peptide. Hepatology 2003;37:277-285.
55. Nakano A, Baines CP, Kim SO, Pelech SL, Downey JM, Cohen MV, Critz SD. Ischemic preconditioning activates MAPKAPK2 in the isolated rabbit heart: evidence for the involvement of p38 MAPK. Circ Res 2000;86:144-151.
56. One K, Han J. The p38 signal transduction pathway. Activation and function. Cell Signal 2000;12:1-13.
57. Glanemann M, Vollmar B, Nussler AK, Schaefer T, Neuhaus P, Menger MD. Ischemic preconditioning protects from hepatic ischemia/reperfusion-injury by preservation of microcirculation and mitochondrial redox-state. J Hepatol 2003;38:59-66.
58. Peralta C, Bartrons R, Serafin A, Blazquez C, Guzman M, Prats N, Xaus C, Cutillas B, Gelpi E, Rosellò-Catafau J. Adenosine monophosphate-activated protein kinase mediates the protective effects of ischemic preconditioning on hepatic ischemia-reperfusion injury in the rats. Hepatology 2001;34:1164-1173.
59. Peralta C, Bartrons R, Riera L, Manzano A, Xaus C, Gelpi E, Rosellò-Catafau J. Hepatic preconditioning preserves energy metabolism during sustained ischemia. Am J Physiol 2000;279: G163-G171.
60. ATP channels; role in cardioprotection. Cardiovasc Res 2002; 55:429-437.
61. + homeostasis as a critical step in the development of irreversible hepatocyte injury after adenosine triphosphate depletion. Hepatology 1995;21:1089-1098.
62. Rehring TF, Shapiro JI, Cain BS, Meldrum DR, Cleveland JC, Harken AH, Benerjee A. Mechanisms of pH preservation during global ischemia in preconditioned rat heart: role of PKC and NHE. Am J Physiol 1998;275:H805-H813.
63. Gottlieb RA, Gruol DL, Zhu JY, Engler RL. Preconditioning in rabbit cardiomyocytes: role of pH, vacuolar proton ATPase and apoptosis. J Clin Invest 1996;97:2391-2398.
64. +-ATPase from rat liver lysosomes. J Biol Chem 1993; 268:5649-5660.
65. + overload in preconditioned hepatocytes. FEBS Lett 2001;491:180-183.
66. + accumulation and hepatocyte injury during cold storage. Transplantation 1999;68:249-319.
67. + homeostasis in hepatocyte reoxygenation injury. Biochim Biophys Acta 2000;1500:297-305.
68. 2+ chelation. Biochem Biophys Res Commun 1997;232:107-110.
69. Cavalieri B, Perrelli MG, Aragno M, Mastrocola R, Corvetti G, Durazzo M, Poli G, Cutrin JC. Ischemic preconditioning attenuates the oxidant-dependent mechanisms of reperfusion cell damage and death in rat liver. Liver Transpl 2002;8:990-999.
70. Peralta C, Bulbena O, Xaus C, Prats N, Cutrin JC, Poli G, Gelpi E, Rosellò-Catafau J. Ischemic preconditioning: a defence mechanism against the reactive oxygen species generated after hepatic ischemic reperfusion. Transplantation 2002;73:1203-1211.
71. Shauer RJ, Gerbes AL, Vonier D, den Winkel M, Fraunberger P, Bilzer M. Induction of cellular resistance against Kupffer cell-derived oxidant stress: a novel concept of hepatoprotection by ischemic preconditioning. Hepatology 2003;37:286-295.
72. Fernandez L, Heredia N, Grande L, Gomez G, Rimola A, Marco A, Gelpi E, Rosello-Catafau J, Peralta C. Preconditioning protects liver and lung damage in rat liver transplant: role of xanthine/xanthine oxidase. Hepatology 2002;36:562-572.
73. Brazil DP, Park J, Hemmings BA. PKB binding proteins: getting on Akt. Cell 2002;111:293-303.
74. Liu H, Lo CR, Czaja MJ. NF-kappaB inhibition sensitizes hepatocytes to TNF-induced apoptosis through a sustained activation of JNK and c-Jun. Hepatology 2002;35:772-778.
75. Hatano E, Brenner DA. Akt protects mouse hepatocytes from TNF-α- and Fas-mediated apoptosis through NF-κB activation. Am J Physiol 2002;282:G1357-G1368.
76. Moncada S, Erusalimsky JD. Does nitric oxide modulate energy generation and apoptosis? Nat Rev Mol Cell Biol 2002;3:214-220.
77. 2A receptor agonists reduce ischemia/reperfusion injury of rat liver mainly by inhibiting leukocyte activation. J Pharmacol Exp Res 2000;294:1034-1042.
78. Howel JG, Zibari GB, Brown MF, Burney DL, Sawaya DE, Olinde JG, Granger DN, McDonald JC. Both ischemic and pharmacological preconditioning decrease hepatic leukocyte/endothelial cell interactions. Transplantation 2000;69:300-314.
79. Peralta C, Prats N, Xaus C, Gelpi E, Rosellò-Catafau J. Protective effect of ischemic preconditioning on liver and lung injury induced by hepatic ischemia-reperfusion in the rat. Hepatology 1999;30:1481-1489.
80. Peralta C, Bulbena O, Bargallo R, Prats N, Gelpi E, Rosellò -Catafau J. Strategies to modulate the deleterious effects of endothelin in hepatic ischemia-reperfusion. Transplantation 2000;70:1761-1770.
81. Cutrin JC, Perrelli MA, Cavalieri B, Peralta C, Rosellò-Catafau J, Poli G. Microvascular dysfunction induced by reperfusion injury and protective effect of ischemic preconditioning. Free Radic Biol Med 2002;33:1200-1208.
82. Peralta C, Fernandez L, Panes J, Prats N, Sans M, Piqué JM, Gelpi E, Rosellò-Catafau J. Preconditioning protects against systemic disorders associated with hepatic ischemia-reperfusion through blockade of tumor necrosis factor-induced P selectin up-regulation in the rat. Hepatology 2001;33:100-113.
83. Teoh N, Leclercq I, Dela Pena A, Farrell G. Low-dose TNF-α protects against hepatic ischemia-reperfusion injury in mice: implications for preconditioning. Hepatology 2003;37:118-128.
84. Funaki H, Shimizu K, Harada SI, Tsuyama H, Fushida S, Tani T, Miwa K. Essential role for nuclear factor kB in ischemic preconditioning for ischemia-reperfusion injury of the mouse liver. Transplantation 2002;74:551-556.
85. Kume M, Yamamoto Y, Saad S, Gomi T, Kimoto S, Shimabukuro T, Yagi T, Nakagami M, Takada Y, Morimoto T, Yamaoka Y. Ischemic preconditioning of the liver in rats: Implications of heat protein induction to increase tolerance of ischemia-reperfusion injury. J Lab Clin Med 1996;128:251-258.
86. Yamagami K, Yamamoto Y, Toyokuni S, Hata K, Yamaoka Y. Heat shock preconditioning reduces the formation of 8-hydroxy-2′-deoxyguanosine and 4-hydroxy-2-nonenal modified proteins in ischemia-reperfused liver of rats. Free Radic Res 2002;36: 169-176.
87. Kiemer AK, Gerbes AL, Bilzer M, Vollmar AM. The atrial natriuretic peptide and cGMP: novel activators of the heat shock response in rat livers. Hepatology 2002;35:88-94.
88. Ishikawa Y, Yamamoto Y, Kune K, Yamagami K, Yamamoto H, Kimoto S, Sakai Y, Yamamoto M, Yamaoka Y. Heat shock preconditioning on mitochondria during warm ischemia in rat livers. J Surg Res 1999;87:178-184.
89. Xanthoudakis S, Nicholson DW. Heat-shock proteins as death determinants. Nat Cell Biol 2000;2:E163-E165.
90. Garrido C, Gurbuxani S, Ravagnan L, Kroemer G. Heat shock proteins: endogenous modulators of apoptotic cell death. Biochem Biophys Res Commun 2001;286:433-442.
91. Huot J, Houle F, Spitz DR, Landry J. HPS27 phosphorylation-mediated resistance against actin fragmentation and cell death induced by oxidative stress. Cancer Res 1996;56:273-279.
92. Redaelli CA, Tian YH, Schaffner T, Ledermann M, Bauer HU, Dufour JF. Extended preservation of rat liver graft by induction of heme oxygenase-1. Hepatology 2002;35:1082-1092.
93. Katori M, Busuttil RW, Kupiec-Weglinski JW. Heme oxygenase-1 system in organ transplantation. Transplantation 2002;74:905-912.
94. Amersi F, Shen XD, Anselmo D, Melinek J, Iyer S, Suthard DJ, Katori M, Volk HD, Busuttil RW, Buelow R, Kupiec-Weglinski JW. Ex vivo exposure to carbon monoxide prevents hepatic ischemia/reperfusion injury through p38 MAP kinase pathway. Hepatology 2002;35:815-823.
95. Pirkkala L, Nykänen P, Sistonen L. Roles of the heat shock transcription factors in regulation of the heat shock response and beyond. FASEB J 2001;15:1118-1131.
96. Choi BM, Pae HO, Kim YM, Chung HT. Nitric oxide-mediated cytoprotection of hepatocytes from glucose deprivation-induced cytotoxicity: involvement of heme oxygenase-1. Hepatology 2003;37:810-823.
97. Hoshida S, Yamashita N, Otsu K, Hori M. The importance of manganese superoxide dismutase in delayed preconditioning: involvement of reactive oxygen species and cytokines. Cardiovasc Res 2002;55:495-505.
98. Bolli R, Shinmura K, Tang XL, Kodani E, Xuan YT, Guo Y, Dawn B. Discovery of a new function of cyclooxygenase (COX)-2: COX-2 is a cardioprotective protein that alleviates ischemia/reperfusion injury and mediates the late phase of preconditioning. Cardiovasc Res 2002;55:506-519.
99. Uckinami H, Yamamoto Y, Kume M, Yonezawa K, Ishikawa Y, Taura K, Nakajima A, Hata K, Yamaoka Y. Effect of heat shock preconditioning of NF-kB/1-kB pathway during I/R injury of the rat liver. Am J Physiol 2002;282:G962-G971.
100. Clavien PA, Yadav S, Sindram D, Bentley RC. Protective effects of ischemic preconditioning for liver resection performed under inflow occlusion in humans. Ann Surg 2000;232:155-162.
101. Totsuka E, Fung JJ, Urakami A, Moras N, Ishii T, Takahashi K, Narumi S, Hakamada K, Sasaki M. Influence of donor cardiopulmonary arrest in human liver transplantation: possible role of ischemic preconditioning. Hepatology 2000;31:577-580.
102. 2 receptors on rat Kupffer cells. Hepatology 1994;19:1445-1452.
103. Leesar MA, Stoddard M, Ahmed M, Broadbent J, Bolli R. Preconditioning of human myocardium with adenosine during coronary angioplasty. Circulation 1997;95:2500-2507.
104. Fiorucci S, Santucci L, Antonelli E, Distrutti A, Del Sero G, Morelli O, Romani L, Federici B, Del Soldato P, Morelli A. NO-aspirin protects from T cell-mediated liver injury by inhibiting caspase-dependent processing of Th1like cytokines. Gastroenterology 2000;118:404-421.
105. Fiorucci S, Mencarelli A, Palazzetti B, Del Soldato P, Morelli A, Ignarro LJ. An NO derivative of ursodeoxycholic acid protects against Fas-mediated liver injury by inhibiting caspase activity. Proc Natl Acad Sci U S A 2001;98:2652-2657.
106. Leesar MA, Stoddard M, Dawn B, Jasti VG, Masden R, Bolli R. Delayed preconditioning-mimetic action of nitroglycerin in patients undergoing coronary angioplasty. Circulation 2001;103:2935-2941.
107. Brenner BM, Ballermann BJ, Gunning ME, Zeidel ML. Diverse biological actions of atrial natriuretic peptide. Physiol Rev 1990;70:665-699.
108. Sagnella GA. Atrial natriuretic peptide mimetics and vasopeptidase inhibitors. Cardiovasc Res 2001;51:416-428.