肝硬化是臺灣常見的慢性病，急性寡尿性腎衰竭（肝腎症候群, HRS）則是末期肝硬化常見的致命併發症，目前仍然缺乏有效的治療。儘管肝硬化與門脈高壓的動物模式及相關研究已經十分成熟，併發急性腎臟損傷的詳細機制卻仍然不明，相關之預防與治療的研究當然更無法進展，主要關鍵在於缺乏理想的研究動物模式能模擬此一致命疾病的複雜面貌。
過去的臨床觀察結果顯示，嚴重肝硬化併發急性腎臟損傷的病患通常僅有腎功能異常的表現，卻沒有腎臟組織損傷的現象，因此，其腎臟可以捐贈並成功移植於尿毒病患身上；另一方面，一旦患者成功接受肝臟移植治療，腎功能異常也會復原。數十年來，肝腎症候群廣被醫學界接受的病生理機轉是肝硬化造成全身血管擴張、全身血管阻力減少、及平均動脈壓下降，使血管內有效血容量不足後，刺激內生性血管收縮劑分泌，使腎臟血管代償性收縮，導致腎臟血流不足及腎功能異常。然而，近年來的許多研究結果卻顯示，門脈高壓以及代償性肝硬化大白鼠的腎臟灌流壓低於正常鼠，且腎臟血管對血管收縮劑的反應性不佳（意即血管擴張）。為了解釋在肝硬化疾病進展過程中，腎臟血管先擴張而後嚴重收縮的變化原因，雙重打擊假說(2-hit hypothesis)應運而生並成為最合理的理論。也就是門脈高壓或肝硬化都只是背景因子（first hit），病患雖然會因為一氧化氮（nitric oxide, NO）的製造增加造成全身血管擴張使血管內有效血容量不足，但其心、腎仍然能藉著增加心跳及鹽份、水份的回收來提昇心輸出量以代償；一旦併發其它惡化因子，如利尿劑過度使用、大量放腹水、腸胃道出血、心肌病變、或自發性腹膜炎等“second hit”，血管內有效血容量不足的情形超越身體的調節及代償能力時，身體製造的內生性血管收縮劑將使腎臟血管嚴重收縮，腎臟將因灌流不足而導致功能衰竭。在“2-hit”假說內容中，門脈高壓以及代償性肝硬化的腎臟血管擴張現象已經由許多人體及動物實驗證實，然而，從門脈高壓或代償性肝硬化進展至失償性肝硬化的腎臟血管反應性變化及相關機制仍有待探討。
利用部份門靜脈結紮（partial portal vein ligation, PVL）誘導大白鼠產生門脈高壓狀態，是一種廣被接受的門脈高壓研究動物模式；而離體腎臟灌流模式（isolated perfused kidney model）則廣泛被用於腎臟病生理及藥理學動物研究，結合這兩種已經十分成熟的研究動物模式，進行門脈高壓大白鼠的腎臟血管反應性研究，希望可以對肝病患者的急性腎臟損傷機制有進一步的了解。實驗設計首先嘗試在部份門靜脈結紮的門脈高壓大白鼠執行準確而穩定的離體腎臟灌流實驗，建立一系列血流動力學的資料庫，證實在手術七天後，門脈高壓大白鼠的腎臟血管擴張且對內皮素（endothelin-1, ET-1）的反應性也變差，腎動脈的內皮型一氧化氮合成酶（endothelial nitric oxide synthase, eNOS）的表現增加可能扮演關鍵性角色。其次，再將門脈高壓大白鼠腹腔內注射內毒素（lipopolysaccharide, LPS）來模擬“2-hit”假說中的“second hit”（腹膜炎），這是失償性肝硬化患者常見的臨床情境。結果證實大白鼠在細菌感染時，血中內皮素分泌量會顯著增加，相異於正常大白鼠在細菌感染時的腎臟血管反應性下降（腎臟血管擴張），門脈高壓大白鼠在細菌感染時，原先對血管收縮劑反應不佳的腎臟血管對內皮素的反應性卻顯著增強(腎臟血管強烈收縮)，且腎臟組織中第一型內皮素接受器（endothelin receptor type A, ETA）的表現增加，這可能是失償性肝硬化患者併發腎功能異常的重要機制。
這些實驗結果顯示門脈高壓大白鼠面對細菌感染時，腎臟血管反應性及腎功能變化的可能病生理機轉，有助於印證“2-hit”假說內容中，隨著肝病患者疾病嚴重度的進展，腎臟血管先擴張而後嚴重收縮的變化，同時，可作為肝腎症候群研究的試金石，可藉此進一步找尋具有潛力的治療藥物。

Liver cirrhosis is a common disease in Taiwan, which may lead to a severe complication of oliguric acute renal failure, so called “hepatorenal syndrome” (HRS), without effective treatment. Although a great advance in the researches of portal hypertension and liver cirrhosis has been achieved with highly reproducible animal models, the mechanisms leading to altered renal blood flow and renal dysfunction in advanced liver cirrhosis are not entirely clear yet. The critical impediment lies mainly in the paucity of an ideal animal model to correctly mimic human disease and fulfill these complex manifestations of HRS.
Usually, acute kidney injury secondary to liver dysfunction occurred in the absence of significant alterations in renal histology. The functional nature of renal dysfunction in advanced liver disease was confirmed by the successful transplantation of cadaveric kidneys from patients with HRS as well as the normalization of renal dysfunction after liver transplantation. For decades, traditional consensus defined the HRS as hypo-perfusion of the kidneys resulting from combined intense renal vasoconstriction and decreased renal blood flow in response to generalized systemic arterial vasodilatation. However, cumulative studies demonstrated that the renal vasculature of portal hypertensive and compensated cirrhotic rats had lower perfusion pressure and hypo-responsiveness to endogenous vasoconstrictors, implying renal vasodilatation. In order to illustrate the evolution of renal vascular reactivity during disease progression of liver cirrhosis, the “2-hit” hypothesis seems to be the best accepted theory. Usually, the liver dysfunction appears to be an important background factor or “first hit” when the vasodilatation related hypovolemia can be compensated by the development of hyperdynamic circulation, such as increased heart rate, avid renal sodium and water retention, and higher cardiac output. Once the auto-regulatory mechanisms are overwhelmed by the precipitating event or “second hit”, extreme effective arterial underfilling will initiate extreme intra-renal vasoconstriction and subsequent renal impairment. Such events may include the overzealous use of diuretics, large volume paracentesis, gastrointestinal bleeding, cardiomyopathy, or development of spontaneous bacterial peritonitis in ascitic patients.
Partial portal vein ligation (PVL) rat is a well-established and reproducible animal model for studies in the field of portal hypertension. For decades, the isolated perfused kidney model has been established as a valid tool for the investigations of renal physiology and pathophysiology. The combination of both mature animal models might enable us to explore the potential mechanisms of renal dysfunction in advanced liver cirrhosis. At first, the technique of isolated kidney perfusion was established and successfully demonstrated poor renal vascular responsiveness to endothelin-1 (ET-1) in the PVL rats since the 7th post-operative day. Up-regulated endothelial nitric oxide synthase (eNOS) of renal arteries may play the major role in modulating the renal vascular hypo-reactivity of PVL rats. Furthermore, endotoxemia was, a common complication of cirrhotic patients, induced by intra-peritoneal injection of lipopolysaccharide (LPS) in the PVL rats to mimic the clinical condition of “2-hit” hypothesis. There was significantly higher serum level of ET-1 developed at 5 hours following LPS injection in both SHAM and PVL rats. In contrast with vascular hypo-reactivity and down-regulated renal endothelin receptor type A (ETA) in the LPS-injected SHAM rats, LPS-injected PVL rats demonstrated significantly increased renal vascular responsiveness to ET-1 and up-regulated renal ETA expression, which might contribute to the pathogenesis of renal dysfunction in portal hypertensive patients during endotoxemia.
These findings may help improve our understanding of the pathophysiology of renal dysfunction in advanced liver cirrhosis and lead to the development of useful therapeutic strategies.

CONTENTS

page
English Abstract 1
Chinese Abstract 3
List of Abbreviations 5
Introduction 7
Materials and Methods 17
Result 27
Discussion 33
Conclusion 42
Perspectives 44
References 46
Figures and Tables 59
Publications 80

1. Gines A, Escorsell A, Gines P, Salo J, Jimenez W, Inglada L, et al. Incidence, predictive factors, and prognosis of hepatorenal syndrome in cirrhosis. Gastroenterology 1993; 105: 229-236.
2. Hecker R, Sherlock S. Electrolyte and circulatory changes in terminal liver failure. Lancet 1956; 271: 1121–1125.
3. Arroyo V, Terra C, Ginès P. Advances in the pathogenesis and treatment of type-1 and type-2 hepatorenal syndrome. J Hepatol 2007; 46: 935-946.
4. Epstein M, Berk DP, Hollenberg NK, Adams DF, Chalmers TC, Abrams HL, et al. Renal failure in the patient with cirrhosis. The role of active vasoconstriction. Am J Med 1970; 49: 175–185.
5. Koppel MH, Coburn JW, Mims MM, Goldstein H, Boyle JD, Rubini ME. Transplantation of cadaveric kidneys from patients with hepatorenal syndrome. Evidence for the functional nature of renal failure in advanced liver disease. N Engl J Med 1969; 280: 1367–1371.
6. Iwatsuki S, Popovtzer MM, Corman JL, Ishikawa M, Putnam CW, Katz FH, et al. Recovery from “hepatorenal syndrome” after orthotopic liver transplantation. N Engl J Med 1973; 289: 1155–1159.
7. Gonwa TA, Morris CA, Goldstein RM, Husberg BS, Klintmalm GB. Long-term survival and renal function following liver transplantation in patients with and without hepatorenal syndrome: experience in 300 patients. Transplantation 1991; 51: 428– 430.
8. Gonwa TA, Klintmalm GB, Levy M, Jennings LS, Goldstein RM, Husberg BS. Impact of pretransplant renal function on survival after liver transplantation. Transplantation 1995; 59: 361–365.
9. Arroyo V, Gines P, Gerbes AL, Dudley FJ, Gentilini P, Laffi G, et al. Definition and diagnostic criteria of refractory ascites and hepatorenal syndrome in cirrhosis. Hepatology 1996; 23: 164–176.
10. Chojkier M, Groszmann RJ. Measurement of the portal-systemic shunting in the rat by using γ-labeled microspheres. Am J Physiol 1981; 240: G371-G375.
11. Bosch J, Enriquez R, Groszmann RJ, Storer EH. Chronic bile duct ligation in the dog: hemodynamic characterization of a portal hypertensive model. Hepatology 1983; 3: 1002–1007.
12. Vorobioff J, Bredfeldt JE, Groszmann RJ. Increased blood flow through the portal system in cirrhotic rats. Gastroenterology 1984; 87: 1120–1126.
13. Green J, Better OS. Systemic hypotension and renal failure in obstructive jaundice-mechanistic and therapeutic aspects. J Am Soc Nephrol 1995; 5: 1853-1871
14. Betjes MG, Bajema I. The pathology of jaundice-related renal insufficiency: cholemic nephrosis revisited. J Nephrol 2006; 19: 229-233.
15. Fickert P, Krones E, Pollheimer MJ, Thueringer A, Moustafa T, Silbert D, et al. Bile acids trigger cholemic nephropathy in common bile-duct-ligated mice. Hepatology 2013; 58: 2056-2069
16. Rodrigo R, Avalos N, Orellana M, Bosco C, Thielemann L. Renal effects of experimental obstructive jaundice: morphological and functional assessment. Arch Med Res 1999; 30: 275-285
17. Kramer HJ, Schwarting K, Backer A, Meyer-Lehnert H. Renal endothelin system in obstructive jaundice: its role in impaired renal function of bile-duct ligated rats. Clin Sci (Lond) 1997; 92: 579-585
18. Sinicrope RA, Gordon JA, Little JR, Schoolwerth AC. Carbon tetrachloride nephrotoxicity: a reassessment of pathophysiology based upon the urinary diagnostic indices. Am J Kidney Dis 1984; 3: 362-365.
19. Rincón AR, Covarrubias A, Pedraza-Chaverrí J, Poo JL, Armendáriz-Borunda J, Panduro A. Differential effect of CCl4 on renal function in cirrhotic and non-cirrhotic rats. Exp Toxicol Pathol 1999; 51: 199-205.
20. Natarajan SK, Thomas S, Ramamoorthy P, Basivireddy J, Pulimood AB, Ramachandran A, et al. Oxidative stress in the development of liver cirrhosis: a comparison of two different experimental models. J Gastroenterol Hepatol 2006; 21: 947-957.
21. Natarajan SK, Basivireddy J, Ramachandran A, Thomas S, Ramamoorthy P, Pulimood AB, et al. Renal damage in experimentally-induced cirrhosis in rats: Role of oxygen free radicals. Hepatology 2006; 43: 1248-1256.
22. Anand R, Harry D, Holt S, Milner P, Dashwood M, Goodier D, et al. Endothelin is an important determinant of renal function in a rat model of acute liver and renal failure. Gut 2002; 50: 111-117.
23. Keppler D, Lesch R, Reutter W, Decker K. Experimental hepatitis induced by D-galactosamine. Exp Mol Patho 1968; 9: 279-290.
24. Diaz-Buxo JA, Blumenthal S, Hayes D, Gores P, Gordon B. Galactosamine-induced fulminant hepatic necrosis in unanesthetized canines. Hepatology 1997; 25: 950-957.
25. Watanabe A, Higashi T, Nagashima H. An animal model of fulminant hepatic failure in the rat. Acta Med Okayama. 1979; 33: 443-450.
26. Dixit V, Chang TM. Brain edema and the blood brain barrier in galactosamine-induced fulminant hepatic failure rats. An animal model for evaluation of liver support systems. ASAIO Trans 1990; 36: 21-27.
27. Sielaff TD, Hu MY, Rollins MD, Bloomer JR, Amiot B, Hu WS, et al. An anesthetized model of lethal canine galactosamine fulminant hepatic failure. Hepatology 1995; 21: 796-804.
28. Schrier RW, Arroyo V, Bernardi M, Epstein M, Henriksen JH, Rodes J. Peripheral arterial vasodilation hypothesis: A proposal for the initiation of renal sodium and water retention in cirrhosis. Hepatology 1988; 8: 1151–1157.
29. Lee FY, Albillos A, Colombato LA, Groszmann RJ. The role of nitric oxide in the vascular hyporesponsiveness to methoxamine in portal hypertensive rats. Hepatology 1992; 16: 1043–1048.
30. Martin PY, Gines P, Schrier RW. Nitric oxide as a mediator of hemodynamic abnormalities and sodium and water retention in cirrhosis. N Engl J Med 1998; 339: 533– 541.
31. Bichet DG, Van Putten VJ, Schrier RW. Potential role of increased sympathetic activity in impaired sodium and water excretion in cirrhosis. N Engl J Med 1982; 307: 1552–1557.
32. Bosch J, Arroyo V, Betriu A, Mas A, Carrilho F, Rivera F, et al. Hepatic hemodynamics and the renin–angiotensin–aldosterone system in cirrhosis. Gastroenterology 1980; 78: 92–99.
33. Bichet D, Szatalowicz V, Chaimovitz C, Schrier RW. Role of vasopressin in abnormal water excretion in cirrhotic patients. Ann Intern Med 1982; 96: 413–417.
34. Uriz J, Gines P, Cardenas A, Sort P, Jimenez W, Salmeron JM, et al. Terlipressin plus albumin infusion: An effective and safe therapy of hepatorenal syndrome. J Hepatol 2000; 33: 43–48.
35. Ortega R, Gines P, Uriz J, Cardenas A, Calahorra B, De Las Heras D, et al. Terlipressin therapy with and without albumin for patients with hepatorenal syndrome: Results of a prospective, nonrandomized study. Hepatology 2002; 36: 941–948.
36. Fernandez-Seara J, Prieto J, Quiroga J, Zozaya JM, Cobos MA, Rodriguez-Eire JL, et al. Systemic and regional hemodynamics in patients with liver cirrhosis and ascites with and without functional renal failure. Gastroenterology 1989; 97: 1304–1312.
37. Sato S, Ohnishi K, Sugita S, Okuda K. Splenic artery and superior mesenteric artery blood flow. Nonsurgical Doppler US measurement in healthy subjects and patients with chronic liver disease. Radiology 1987; 164: 347–352.
38. Murray JF, Dawson AM, Sherlock S. Circulatory changes in chronic liver disease. Am J Med 1958; 24: 358–367.
39. Kowalski HJ, Abelmann WH. The cardiac output at rest in Laennec’s cirrhosis. J Clin Invest 1953; 32: 1025–1033.
40. García-Estañ J, Atucha NM, Groszmann RJ. Renal response to methoxamine in portal hypertensive rats: role of prostaglandins and nitric oxide. J Hepatol 1996; 25: 206-211.
41. Ortiz MC, Manriquez MC, Nath KA, Lager DJ, Romero JC, Juncos LA. Vitamin E prevents renal dysfunction induced by experimental chronic bile duct ligation. Kidney Int 2003; 64: 950-961.
42. Stadlbauer V, Wright GA, Banaji M, Mukhopadhya A, Mookerjee RP, Moore K, et al. Relationship between activation of the sympathetic nervous system and renal blood flow autoregulation in cirrhosis. Gastroenterology 2008; 134: 111-119.
43. Wong F, Blendis L. New challenge of hepatorenal syndrome: prevention and treatment. Hepatology 2001; 346: 1242-1251.
44. Rasool A, Palevsky PM. Treatment of edematous disorders with diuretics. Am J Med Sci 2000; 319: 25-37.
45. Ruiz-del-Arbol L, Monescillo A, Jimenez W, Garcia-Plaza A, Arroyo V, Rodés J. Paracentesis-induced circulatory dysfunction: mechanism and the effect on hepatic hemodynamics in cirrhosis. Gastroenterology 1997; 113: 579-586.
46. Cardenas A, Gines P, Uriz J, Bessa X, Salmerón JM, Mas A, et al. Renal failure after upper gastrointestinal bleeding in cirrhosis: incidence, clinical course, predictive factors, and short-term prognosis. Hepatology 2001; 34: 671-676.
47. Pozzi M, Carugo S, Boari G, Pecci V, de Ceglia S, Maggiolini S, et al. Evidence of functional and structural cardiac abnormalities in cirrhotic patients with and without ascites. Hepatology 1997; 26: 1131–1137.
48. Follo A, Llovet JM, Navasa M, Planas R, Forns X, Francitorra A, et al. Renal impairment after spontaneous bacterial peritonitis in cirrhosis: incidence, clinical course, predictive factors and prognosis. Hepatology 1994; 20: 1495-1501.
49. Vorobioff J, Bredfeldt JE, Groszmann RJ. Hyperdynamic circulation in portal-hypertensive rat model: a primary factor for maintenance of chronic portal hypertension. Am J Physiol 1983; 244: G52-G57
50. Sikuler E, Kravetz D, and Groszmann RJ. Evolution of portal hypertension and mechanisms involved in its maintenance in a rat model. Am J Physiol 1985; 248: G618-G625.
51. Alcaraz A, Iyú D, Atucha NM, García-Estañ J, Ortiz MC. Vitamin E. Supplementation reverses renal altered vascular reactivity in chronic bile duct-ligated rats. Am J Physiol Regul Integr Comp Physiol. 2007; 292: R1486-R1493.
52. Alcaraz A, Hernández D, Iyú D, Mota R, Atucha NM, Ortiz AJ, et al. Effects of chronic L-NAME on nitrotyrosine expression and renal vascular reactivity in rats with chronic bile-duct ligation. Clin Sci (Lond). 2008; 115: 57-68.
53. Bauman AW, Clarkson TW, Miles EM. Functional evaluation of isolated perfused rat kidney. J Appl Physiol. 1963; 18: 1239-1246.
54. Nishiitsutsuji-Uwo JM, Ross BD, Krebs HA. Metabolic activities of the isolated perfused rat kidney. Biochem J 1967; 103: 852-862.
55. Bakhle YS, Reynard AM, Vane JR. Metabolism of the angiotensins in isolated perfused tissues. Nature 1969; 222: 956-959.
56. Hems DA, Gaja G. Carbohydrate metabolism in the isolated perfused rat kidney. Biochem J 1972; 128: 421-426.
57. Ciarimboli G, Hjalmarsson C, Bökenkamp A, Schurek HJ, Haraldsson B. Dynamic alterations of glomerular charge density in fixed rat kidneys suggest involvement of endothelial cell coat. Am J Physiol Renal Physiol 2003; 285: F722-F730,
58. Hamilton RL, Berry MN, Williams MC, Severinghaus EM. A simple and inexpensive membrane “lung” for small organ perfusions. J Lipid Res 1974; 15: 182-186.
59. Lee FY, Colombato LA, Albillos A, Groszmann RJ. Administration of Nω-nitro-L- arginine ameliorates portal-systemic shunting in portal-hypertensive rats. Gastroenterology 1993; 105: 1464-1470.
60. Gadano AC, Sogni P, Yang S, Cailmail S, Moreau R, Nepveux P, et al. Endothelial calcium-calmodulin dependent nitric oxide synthase in the in vitro vascular hyporeactivity of portal hypertensive rats. J Hepatol 1997; 26: 678-686.
61. Sieber CC, Groszmann RJ. Nitric oxide mediates hyporeactivity to vasopressors in mesenteric vessels of portal hypertensive rats. Gastroenterology 1992; 103: 235–239.
62. Langer DA, Shah VJ. Nitric oxide and portal hypertension: Interface of vasoreactivity and angiogenesis. J Hepatol 2006; 44: 209-216.
63. Cahill PA, Redmond EM, Hodges R, Zhang S, Sitzmann JV. Increased endothelial nitric oxide synthase activity in the hyperemic vessels of portal hypertensive rats. J Hepatol 1996; 25: 370–378.
64. Pateron D, Tazi KA, Sogni P, Heller J, Chagneau C, Poirel O, et al. Role of aortic nitric oxide synthase 3 (eNOS) in the systemic vasodilation of portal hypertension. Gastroenterology 2000; 119: 196-200
65. Iwakiri Y, Cadelina G, Sessa WC, Groszmann RJ. Mice with targeted deletion of eNOS develop hyperdynamic circulation associated with portal hypertension. Am J Physiol Gastrointest Liver Physiol 2002; 283: G1074-G1081.
66. Niederberger M, Gines P, Martin P, Tsai P, Morris K, McMurtry I, et al. Comparison of vascular nitric oxide production and systemic hemodynamics in cirrhosis versus prehepatic portal hypertension in rats. Hepatology 1996; 24: 947–951.
67. Gadano AC, Sogni P, Heher J, Moreau R, Bories PN, Lebrec D. Vascular nitric oxide production during the development of two experimental models of portal hypertension. J Hepatol 1999; 30: 896-903.
68. Theodorakis NG, Wang YN, Skill NJ, Metz MA, Cahill PA, Redmond EM, et al. The role of nitric oxide synthase isoforms in extrahepatic portal hypertension: studies in gene-knockout mice. Gastroenterology 2003; 124: 1500-1508.
69. Bexis S, Vandeputte C, McCormick PA, Docherty JR. Deletion of inducible nitric oxide synthase decreases mesenteric vascular responsiveness in portal hypertensive mice. Eur J Pharmacol 2004; 499: 325-333.
70. Mizumoto M, Arii S, Furutani M, Nakamura T, Ishigami S, Monden K, et al. NO as an indicator of portal hemodynamics and the role of iNOS in increased NO production in CCl4-induced liver cirrhosis. J Surg Res 1997; 70: 124–133.
71. Ferguson JW, Dover AR, Chia S, Cruden NL, Hayes PC, Newby DE. Inducible nitric oxide synthase activity contributes to the regulation of peripheral vascular tone in patients with cirrhosis and ascites. Gut 2006; 55: 542–546.
72. Lumsden AB, Henderson JM, Kutner MH. Endotoxin levels measured by a chromogenic assay in portal, hepatic and peripheral venous blood in patients with cirrhosis. Hepatology 1988; 8: 232–236.
73. Vallance P, Moncada S. Hyperdynamic circulation in cirrhosis: a role for nitric oxide? Lancet 1991; 337: 776–778.
74. Swierkosz TA, Mitchell JA, Warner TD, Botting RM, Vane JR. Co-induction of nitric oxide synthase and cyclo-oxygenase: interactions between nitric oxide and prostanoids. Br J Pharmacol 1995; 114: 1335-1342.
75. Kajita M, Murata T, Horiguchi K, Iizuka M, Hori M, Ozaki H. iNOS expression in vascular resident macrophages contributes to circulatory dysfunction of splanchnic vascular smooth muscle contractions in portal hypertensive rats. Am J Physiol Heart Circ Physiol 2011; 300: H1021-H1031
76. Wu Y, Burns RC, Sitzmann JV. Effects of nitric oxide and cyclooxygenase inhibition on splanchnic hemodynamic in portal hypertension. Hepatology 1993; 18: 1416-1421.
77. Hou MC, Cahill PA, Zhang S, Wang YN, Hendrickson RJ, Redmond EM, et al. Enhanced cyclooxygenase-1 expression within the superior mesenteric artery of portal hypertensive rats: role in the hyperdynamic circulation. Hepatology 1998; 27: 20-27.
78. Potenza MA, Botrugno OA, De Salvia MA, Lerro G, Nacci C, Marasciulo FL, et al. Endothelial COX-1 and -2 differentially affect reactivity of MVB in portal hypertensive rats. Am J Physiol Gastrointest Liver Physiol 2002; 283: G587-G594.
79. Roig F, Llinas MT, Lopez R, Salazar FJ. Role of cyclooxygenase-2 in the prolonged regulation of renal function. Hypertension 2002; 40: 721–728.
80. Wu F, Park F, Cowley AW Jr, Mattson DL. Quantification of nitric oxide synthase activity in microdissected segments of the rat kidney. Am J Physiol 1999; 276: F874–F881,
81. Zou AP, Wu F, Cowley AW. Protective Effect of angiotensin II-induced increase in nitric oxide in the renal medullary circulation. Hypertension 1998; 31; 271-276
82. Patzak A, Mrowka R, Storch E, Hocher B, Persson PB. Interaction of angiotensin II and nitric oxide in isolated perfused afferent arterioles of mice. J Am Soc Nephrol 2001; 12: 1122–1127
83. Harris RC, Breyer MD. Physiological regulation of cyclooxygenase-2 in the kidney. Am J Physiol Renal Physiol 2001; 281: F1–F11.
84. Chen J, Zhao M, He W, Milne GL, Howard JR, Morrow J, et al. Increased dietary NaCl induces renal medullary PGE2 production and natriuresis via the EP2 receptor. Am J Physiol Renal Physiol 2008; 295: F818-F825.
85. Yang T, Singh I, Pham H, Sun D, Smart A, Schnermann JB, et al. Regulation of cyclooxygenase expression in the kidney by dietary salt intake. Am J Physiol 1998; 274: F481–F489.
86. Yang T, Sun D, Huang YG, Smart A, Briggs JP, Schnermann JB. Differential regulation of COX-2 expression in the kidney by lipopolysaccharide: role of CD14. Am J Physiol Renal Physiol 1999; 277: F10–F16.
87. Cheng HF, Wang JL, Zhang MZ, Miyazaki Y, Ichikawa I, McKanna JA, et al. Angiotensin II attenuates renal cortical cyclooxygenase-2 expression. J Clin Invest 1999; 103: 953-961.
88. Wolf K, Castrop H, Hartner A, Goppelt-Strübe M, Hilgers KF, Kurtz A. Inhibition of the renin-angiotensin system upregulates cyclooxygenase-2 expression in the macula densa. Hypertension 1999; 34: 503-507.
89. Theimermann C. Nitric oxide and septic shock. Gen Pharmacol 1997; 29: 159-166.
90. Sjövall F, Morota S, Asander Frostner E, Hansson MJ, Elmér E. Cytokine and nitric oxide levels in patients with sepsis - temporal evolvement and relation to platelet mitochondrial respiratory function. PLoS One. 2014; 9: e97673.
91. Sugiura M, Inagami T, Kon V. Endotoxin stimulates endothelin-release in vivo and in vitro as determined by radioimmunoassay. Biochem Biophys Res Commun 1989; 161: 1220-1227.
92. Voerman HJ, Stehouwer CD, van Kamp GJ, Strack van Schijndel RJ, Groeneveld AB, Thijs LG. Plasma endothelin levels are increased during septic shock. Crit Care Med 1992; 20: 1097-1101.
93. Szabo C, Salzmann AL, Ischiropoulos H. Endotoxin triggers the expression of an inducible nitric oxide synthase and the formation of peroxynitrite in the rat aorta in vivo. FEBS Lett 1995; 363: 235-238.
94. MacMicking JD, Nathan C, Hom G, Chartrain N, Fletcher DS, Trumbauer M, et al. Altered response to bacterial infection and endotoxic shock in mice lacking inducible nitric oxide synthase. Cell 1995; 81: 641–650.
95. Cohen RI, Hassell AM, Marzouk K, Marini C, Liu SF, Scharf SM. Renal effects of nitric oxide in endotoxemia. Am J Respir Crit Care Med 2001; 164: 1890-1895.
96. Di Giantomasso D, May CN, Bellomo R. Vital organ blood flow during hyperdynamic sepsis. Chest 2003; 124: 1053-1059.
97. Yanagisawa M, Kurihara H, Kimura S, Tomobe Y, Kobayashi M, Mitsui Y, et al. A novel potent vasoconstrictor peptide produced by vascular endothelial cells. Nature 1988; 332: 411–415.
98. Pittet JF, Morel DR, Hemsen A, Gunning K, Lacroix JS, Suter PM, et al. Elevated plasma endothelin-1 concentrations are associated with the severity of illness in patients with sepsis. Ann Surg 1991; 213: 261 - 264.
99. Takakuwa T, Endo S, Nakae H, Kikichi M, Suzuki T, Inada K, et al. . Plasma levels of TNF-alpha, endothelin-1 and thrombomodulin in patients with sepsis. Res Commun Chem Pathol Pharmacol 1994; 84: 261-269.
100. Denton KM, Shweta A, Finkelstein L, Flower RL, Evans RG. Effect of endothelin-1 on regional kidney blood flow and renal arteriole calibre in rabbits. Clin Exp Pharmacol Physiol 2004; 31: 494–501.
101. Filep JG. Role for endogenous endothelin in the regulation of plasma volume and albumin escape during endotoxin shock in conscious rats. Br J Pharmacol 2000; 129: 975-983.
102. de Nucci G, Thomas R, D’Orleans-Juste P, Antunes E, Walder C, Warner TD, et al. Pressor effects of circulating endothelin are limited by its removal in the pulmonary circulation and by the release of prostacyclin and endothelium-derived relaxing factor. Proc Natl Acad Sci U S A 1988; 85: 9797–9800.
103. Seo B, Oemar BS, Siebenmann R, von Segesser L, Luscher TF. Both ETA and ETB receptors mediate contraction to endothelin-1 in human blood vessels. Circulation 1994; 89: 1203–1208.
104. Gurbanov K, Rubinstein I, Hoffman A, Abassi Z, Better OS, Winaver J. Differential regulation of renal regional blood flow by endothelin-1. Am J Physiol Renal Physiol 1996; 271: F1166-F1172.
105. Fenhammar J, Andersson A, Forestier J, Weitzberg E, Sollevi A, Hjelmqvist H, et al. Endothelin receptor A antagonism attenuates renal medullary blood flow impairment in endotoxemic pigs. PLoS One 2011; 6: e21534.
106. Albertini M, Clement MG, Hussain SN. Role of endothelin ETA receptors in sepsis-induced mortality, vascular leakage, and tissue injury in rats. Eur J Pharmacol 2003; 474: 129-135.
107. Aramori I, Nakanishi S. Coupling of two endothelin receptor subtypes to differing signal transduction in transfected Chinese hamster ovary cells. J Biol Chem 1992; 267: 12468–12474.
108. Henriksson M, Stenman E, Vikman P, Edvinsson L. MEK1/2 inhibition attenuates vascular ETA and ETB receptor alterations after cerebral ischemia. Exp Brain Res 2007; 178: 470–476.
109. Ruiz-del-Arbol L, Urman J, Fernandez J, Gonzalez M, Navasa M, Monescillo A, et al. Systemic, renal, and hepatic hemodynamic derangement in cirrhotic patients with spontaneous bacterial peritonitis. Hepatology 2003; 38: 1210–1218.
110. Ruiz-del-Arbol L, Monescillo A, Arocena C, Valer P, Ginès P, Moreira V, et al. Circulatory function and hepatorenal syndrome in cirrhosis. Hepatology 2005; 42: 439–447.
111. Guevara M, Gines P, Fernandez-Esparrach G, Sort P, Salmerón JM, Jiménez W, et al. Reversibility of hepatorenal syndrome by prolonged administration of ornipressin and plasma volume expansion. Hepatology 1998; 27: 35–41.
112. Angeli P, Volpin R, Gerunda G, Craighero R, Roner P, Merenda R, et al. Reversal of type 1 hepatorenal syndrome with the administration of midodrine and octreotide. Hepatology 1999; 29: 1690-1697.
113. Soper CP, Latif AB, Bending MR. Amelioration of hepatorenal syndrome with selective endothelin-A antagonist. Lancet 1996; 347: 1842-1843.
114. Kramer HJ, Schwarting K, Bäcker A, Meyer-Lehnert H. Renal endothelin system in obstructive jaundice: its role in impaired renal function of bile-duct ligated rats. Clin Sci (Lond) 1997; 92: 579-585.
115. Wong F, Moore K, Dingemanse J, Jalan R. Lack of renal improvement with nonselective endothelin antagonism with tezosentan in type 2 hepatorenal syndrome. Hepatology 2008; 47: 160-168.
116. Izzedine H, Kheder-Elfekih R, Deray G, Thabut D. Endothelin-receptor antagonist/N-acetylcysteine combination in type 1 hepatorenal syndrome. J Hepatol 2009; 50: 1055-1056.