Effect of angiotensin‐ll blockade on systemic and hepatic haemodynamics and on the renin‐angiotensin‐aldosterone system in cirrhosis with ascites

Arroyo, Vicente; Bosch, Jaume; Mauri, M; Ribera, Francisca; Navarro-López, F; Rodés, Joan

doi:10.1111/j.1365-2362.1981.tb01844.x

Cited by 140 publications

(46 citation statements)

References 34 publications

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“…24 The significant decrease in total bilirubin that occurred during losartan treatment in the group with severe portal hypertension cannot be explained from our data and requires further investigation.…”

Section: Discussionmentioning

confidence: 69%

“…[14][15][16]23 In the early 1980s, it was demonstrated that intravenous administration of saralasin, a competitive peptide angiotensin II antagonist with intrinsic agonist activity, reduces elevated portal pressure in cirrhosis. 24 However, because of its short duration of action and poor oral bioavailability, saralasin is not suitable for long-term treatment.…”

Section: Discussionmentioning

confidence: 99%

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

1999

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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,...

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Section: Discussionmentioning

confidence: 69%

Section: Discussionmentioning

confidence: 99%

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

1999

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“…Cirrhotic patients have a cardiovascular disturbance characterized by low arterial pressure, high cardiac output, and increased plasma volume (1)(2)(3)(4). Besides arteriolar vasodilation and arteriovenous shunting, these patients exhibit a diminished sensitivity to pressor hormones and impaired hypoxic vasoconstriction (5)(6)(7).…”

Section: Introductionmentioning

confidence: 99%

Liver cirrhosis induces renal and liver phospholipase A2 activity in rats.

Vishwanath¹,

Frey²,

Escher³

et al. 1996

J. Clin. Invest.

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Maintenance of renal function in liver cirrhosis requires increased synthesis of arachidonic acid derived prostaglandin metabolites. Arachidonate metabolites have been reported to be involved in modulation of liver damage. The purpose of the present study was to establish whether the first enzyme of the prostaglandin cascade synthesis, the phospholipase A 2 (PLA 2 ) is altered in liver cirrhosis induced by bile duct excision. the mRNA of PLA 2 (group I and II) and annexin-I a presumptive inhibitor of PLA 2 enzyme was measured by PCR using glyceraldehyde 3-phosphate dehydrogenase (GAPDH) as an internal standard. The mean mRNA ratio of group II PLA 2 /GAPDH was increased in liver tissue by 126% ( P Ͻ 0.001) and in kidney tissue by 263% ( P Ͻ 0.006) following induction of liver cirrhosis. The increase in group II PLA 2 mRNA in cirrhotic animals was reflected by an increase in PLA 2 protein and enzyme activity in both liver and kidney tissues. Since the mRNA of group I PLA 2 was not detectable and Group IV PLA 2 activity measured in liver and kidney tissue samples was very low and not changed following induction of cirrhosis, it is likely that the major PLA 2 activity measured in liver and kidney corresponds to group II PLA 2 enzyme. The mean mRNA ratio of annexin-I/GAPDH was increased in liver tissue by 115% ( P Ͻ 0.05) but unchanged in kidney tissue following induction of cirrhosis. The protein content of annexin-I and -V were not affected by bile duct excision in liver and kidney tissue indicating that upregulation of group II PLA 2 activity was not due to downregulation of annexin-I or -V. Group II PLA 2 activity of glomerular mesangial cells stimulated by interleukin-1 ␤ was enhanced by bile juice and various bile salts. In conclusion, activity of group II PLA 2 is upregulated partly due to enhanced transcription and translation in cirrhosis and is furthermore augmented by elevated levels of bile salts. ( J. Clin. Invest. 1996. 98:365-371.)

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“…Approximately 30% of patients with cirrhosis and ascites have normal levels of plasma renin activity and aldosterone. These patients have a better survival compared to patients with abnormal values of these parameters [5,9,13]. Patients with increased plasma renin activity and increased aldosterone and norepinephrine levels also have a high probability of developing HRS [14,15].…”

Section: Circulatory Functionmentioning

confidence: 97%

“…The severities of renal and circulatory dysfunction are well established prognostic factors in patients with cirrhosis and ascites. In fact sodium retention, a highly prevalent renal function abnormality of cirrhosis, is associated with reduced survival [13]. Sodium excretion should ideally be measured in patients on a low-sodium diet of 70-90 mEq/day during 5-7 days and off diuretics.…”

Section: Renal Functionmentioning

confidence: 99%