Effect of Losartan, An Angiotensin Ii Receptor Antagonist, on Portal Pressure in Cirrhosis

Abstract

The primary objective of drug therapy in portal hypertension is the prevention of variceal bleeding. The use of nonselective ␤-blockers that reduce portal pressure by lowering splanchnic blood inflow 1 has proved effective in this indication. Treatment with propranolol or nadolol reduces the risk of first hemorrhage 2 as well as that of further bleeding episodes in patients with a history of variceal bleeding. 3 However, the average reduction in portal pressure by 15% achieved with ␤-blockers is moderate, 4 and no relevant decrease is observed in more than 30% of patients despite adequate dosage. 5 To enhance the pressure-lowering effect on portal hypertension, ␤-blockers are combined with isosorbide-5 mononitrate, 6 an agent that reduces portal pressure in cirrhosis because of its vasodilator properties. 7 One study demonstrated a mean reduction in portal pressure of 19% during therapy with the combination of propranolol and isosorbide-5 mononitrate. 6 In patients with sodium retention and ascites, however, serious deterioration of renal function was observed with the combination of ␤-blockers and nitrates. 8 The limited effect on portal pressure, the incidence of adverse effects-15% for nonselective ␤-blockers alone, 9 16% for nadolol plus isosorbide-5 mononitrate 10 -and the timeconsuming dose-finding are a stimulant for the search for new antihypertensive substances.Angiotensin II is considered a potential mediator of intrahepatic portal hypertension, because its plasma level is elevated in cirrhosis 11 and its administration induces a rise in portal pressure. 12 Enhancement of the adrenergic vasoconstrictor influence on the portal systems, 13 direct contractile influence on stellate cells, 14 which serve as regulators of the sinusoidal blood flow, 15,16 and sodium and fluid retention induced by the stimulation of aldosterone secretion 17 may be mechanisms that contribute to the portal hypertensive effect of angiotensin II. Losartan is an angiotensin II receptor antagonist with dilatory effects on arteries and veins. 18 The substance has recently been approved for the treatment of arterial hypertension. As yet, its influence on portal hypertension has not been investigated. The aim of this study was to determine the antihypertensive effects of losartan on portal pressure with particular attention paid to potential side effects. PATIENTS AND METHODSPatients. In patients with cirrhosis and esophageal varices, portal hypertension was evaluated by the determination of hepatic venous pressure gradient (HVPG). Thirty consecutive patients with HVPG Ն 20 mm Hg (severe portal hypertension) were assigned to losartan treatment according to the below-mentioned protocol. In accordance with Armonis et al., 19 our preliminary investigations had shown a variability of Ϯ 1 mm Hg in the measurement of HVPG independent from the height of the values. Therefore, this initial selection of patients with high HVPG values was performed to reduce the influence of variability on the percentage change in HVPG caused by losartan. Later,...

International Union of Basic and Clinical Pharmacology. XCIX. Angiotensin Receptors: Interpreters of Pathophysiological Angiotensinergic Stimuli

“…In rats, experimental models of liver fibrosis induced by bile duct ligation or carbon tetrachloride or choline deficiency, administration of irbesartan, olmesartan, telmisartan, candesartan, or losartan inhibited expression of collagens and TGFb in stellate cells and reduced established liver fibrosis (Kurikawa et al, 2003;Ueki et al, 2006;Hirose et al, 2007;Yoshiji et al, 2009;Moreno et al, 2010;Kato et al, 2012). In clinical practice, however, the usefulness of treating liver fibrosis with ARBs remains contradictory (Schneider et al, 1999;Gonzalez-Abraldes et al, 2001;Lee, 2014). A handful of randomized controlled trials suggest that ARB treatment is a potentially useful therapeutic approach in patients with nonalcoholic fatty liver disease (Paschos and Tziomalos, 2012).…”

NF‐κB in liver diseases: a target for drug therapy

“…Captopril, an ACE inhibitor, has been well studied and reported to suppress rat hepatic fibrosis induced by pig serum (Ohishi et al, 2001). Similarly, angiotensin receptor 1 antagonists reduce the portal pressure in hepatic cirrhosis (Schneider et al, 1999). The transforming growth factor-β (TGF-β ) plays a dominant role in the development of fibrosis (Muriel, 2007b) and this factor may be enhanced by AT-II (Jonsson et al, 2001).…”

Vascular mediators in the injured liver

“…Given data indicating that angiotensin II induces stellate cell (and smooth muscle cell) contractility, the RAAS is an attractive therapeutic target in intrahepatic portal hypertension. However, studies in humans with cirrhosis in which angiotensin II signaling has been blocked have been met with mixed results [83][84][85] ; in particular, angiotensin II receptor antagonists adversely affected glomerular filtration rate and caused systemic hypotension in cirrhotic patients 85 ; therefore, caution is required with these agents. Indeed, because of potential systemic adverse effects, some have suggested that cirrhotic patients not be treated with these compounds.…”