Bilzer, Manfred

Gerbes, Alexander L.

Gülberg, Veit

English

Universität München: Elektronischen Publikationen

Endothelin and other mediators in the pathophysiology of portal hypertension

Alexander Gerbes

Veit Gülberg

Manfred Bilzer

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Endothelin and Other Mediators in the Pathophysiology of Portal Hypertension

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Pathophysiology of Bleeding and Hepatorenal SyndromeDigestion 1998;59(suppl 2):8–10Alexander L. GerbesVeit Gu¨lbergManfred BilzerDepartment of Medicine II,Klinikum Grosshadern,University of Munich, GermanyEndothelin and Other Mediatorsin the Pathophysiology ofPortal Hypertension...........................................................................................................Key WordsLiver cirrhosis · Portal pressure · Hepatic stellate cells ·Sinusoidal endothelial cells · Kupffer cells.......................Hyperdynamic circulation as well as increased hepatic larly regarding portal pressure, has not been fully elucid-ated yet. Therefore, mainly ET-1 will be covered in theresistance contribute to portal hypertension in cirrhosisof the liver [1]. Hyperdynamic circulation with increased following text.cardiac output, heart rate and plasma volume and de-creased arterial blood pressure and systemic vasodila-tation is pivotal for the hyperdynamic circulation. This ET Plasma Concentration and Hepatic Release inCirrhosishas prompted intense research of a number of endogenousneurohumoral mediators with vasodilating properties(NO, natriuretic peptides, glucagon, etc.) [2, 3]. In patients with cirrhosis of the liver, elevated arterialand venous plasma concentrations of ET-1 and ET-3In recent years, however, mechanisms augmenting in-trahepatic vascular resistance and thus contributing to have been described [2, 10–16]. Interestingly, there is anincreased hepatosplanchnic release of ET in these patientsportal hypertension have received increasing attention. Inthis respect, endothelins (ET) are of particular interest (fig. 1). Release of ET-1 as well as arterial and venousplasma concentrations were found to correlate to the[4–8].ET are a family of 21-amino acid polypeptides with hepatic-venous-pressure gradient [13, 14]. In the liver ofcirrhotic rats, increased concentrations of ET-1 and anpotent vasoactive properties. ET-1 was first isolated inthe supernatant of vascular endothelial cells [8] but later increased ET receptor density have been described [17].Furthermore, release of ET from isolated perfused liversynthesis of both circulating isopeptides ET-1 and ET-3was shown in other organs such as the gastrointestinal as well as from sinusoidal endothelial cells upon stimu-lation by TGF-b have been observed [18, 19]. These find-tract [9]. ET-1 has mainly vasoconstrictive propertiesby acting on the ETA receptor on smooth muscle cells. ings raise the question which cells of the liver synthesizeET and whether this is stimulated in liver damage orET-1 binds with lower affinity also to the ETB receptoron endothelial cells inducing a vasodilatation by the re- cirrhosis.lease of NO and prostacyclins. ET-1 exhibits a muchhigher affinity to the ETA receptor than ET-3 whereas theETB receptor exhibits similar affinity for both isopeptides. ET Synthesis in Various Cell Types of the LiverVascular response to ET thus depends on the ratio ofdifferent receptors which seems to vary in different vascu- Expression of ET-1 in isolated liver cells was detectedmainly in sinusoidal endothelial cells and stellate cellslar regions [for reviews, see 5–8]. The role of ET-3, particu-Ó1998 S. Karger AG, Basel Alexander L. Gerbes0012–2823/98/0598–0008$15.00/0 Klinikum Grosshadern, Medizinische Klinik und Poliklinik IIFax+41 61 306 12 34 Marchioninistrasse 15, D–81366 Munich (Germany)E-Mail karger@karger.ch Tel. +49 089 7095 2292, Fax +49 089 7095 2392,www.karger.com E-Mail gerbes@med2.med.uni-muenchen.de]]Fig. 1. ET-1 plasma concentrations inhepatic venous samples (a) and in femoralartery (data not shown) of patients withcirrhosis were significantly (p=0.0001)higher than in control sujects. In the samepatients, hepatosplanchnic release of ET-1was increased (p=0.01) compared tocontrols (b) [Data adapted from 14].a bTable 1. Synthesis of and receptors for ET-1 in nonparenchymal administration of an ET receptor antagonist [24]. Theseand parenchymal cells of the liver data suggest a role of ET in modulating portal pressureparticularly in portal hypertension.SynthesisEndothelial cells ? Stellate cells 9 Kupffer cells, HepatocytesReceptorsET Effects on Various Cells of the LiverStellate cells ? Endothelial cells, Kupffer cells, HepatocytesET receptors have been found mainly on stellate cellsand sinusoidal endothelial cells but also on Kupffer cellsand hepatocytes (table 1) [25–27]. As shown recently, ET-and to a lesser extent in Kupffer cells (table 1); followinginduced decrease of the hepatic microvascular blood flowliver injury by bile duct ligation prepro-ET-1 mRNA in-is predominantly mediated by the contraction of stellatecreased mainly in stellate cells and to a lesser extent incells [26, 28–30]. Therefore, an autocrine effect of ETendothelial cells [20]. These data support the finding ofappears as an interesting pathomechanism of portal hy-ET-1 overexpression in stellate cells and sinusoidal endo-pertension: in liver damage, increased ET synthesis fromthelial cells of human cirrhotic liver [21]. Hepatic stellatestellate cells may induce an increase of portal pressure bycells are located in the space of Disse and surround thecontraction of these cells. Furthermore, recent evidencesinusoidal capillary composed of endothelial cells andsuggests an effect of ET on hepatic microvascular ex-Kupffer cells. This anatomic location suggests a role ofchange in cirrhosis, possibly by affecting the fenestrationstellate cells in the regulation of the diameter of liverof sinusoidal endothelial cells [31]. This might be anothersinusoids and thus of portal pressure. The data on in-mechanism contributing to a decrease of hepatic functioncreased hepatic synthesis of ET in liver damage raise thein cirrhosis. Finally, the increase of portal pressure uponissue of how ET affects portal pressure and whether thereKupffer cell stimulation seems to be partly mediated bymight be endocrine or paracrine effects involved.ET as was recently shown in isolated perfused rat liver[32].In summary: In conclusion, plasma concentrations ofET and Portal PressureET are increased in cirrhosis which may be due toincreased hepatosplanchnic release. This could reflectET causes an increase of portal pressure in vivo asincreased hepatic synthesis of ET-1, mainly by stellatewell as in isolated perfused liver [22, 23]. In cirrhoticand sinusoidal endothelial cells. ET increases portal pres-liver, but not in controls, portal pressure decreases uponEndothelin and Other Mediators in thePathophysiology of Portal HypertensionDigestion 1998;59(suppl 2):8–10 9sure with sinusoidal constriction by stellate cells playing Acknowledgmentsan important role. Thus, ET modulates portal pressureSupported in part by the Deutsche Forschungsgemeinschaft (DFGand is involved in the pathophysiology of portal hyper-Ge576/13-1) and by the Friedrich Baur Stiftung. K. Simon is thankedtension.for the preparation of the manuscript..................................................................................................................................................................References1 Gerbes AL, Fischer G, Holl J, PaumgartnerG: Therapie der Varizenblutung. Dtsch MedWochenschr 1996;121:416–423.2 Bernardi M, Gu¨lberg V, Colantoni A, TrevisaniF, Gasbarrini A, Gerbes AL: Plasma endoth-elin-1 and -3 in cirrhosis: Relationship with sys-temic hemodynamics, renal function and neu-rohumoral systems. J Hepatol 1996;24:161–168.3 Gerbes AL, Arendt RM, Ritter D, Ju¨ngst D,Za¨hringer J, Paumgartner G: Plasma atrial na-triuretic factor in patients with cirrhosis. 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Endothelin and other mediators in the pathophysiology of portal hypertension

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