Chronic administration of losartan, an angiotensin II receptor antagonist, is not effective in reducing portal pressure in patients with preascitic cirrhosis

OBJECTIVES: Plasma angiotensin II (ANG II) concentrations are elevated in cirrhosis and have been implicated as a cause of portal hypertension. We aimed to study both the systemic and portal hemodynamics, and tolerability after chronic administration of losartan, an ANG II receptor antagonist. METHODS: Twelve patients with preascitic cirrhosis were studied: mean age of 53.8 +/- 3.3 yr; average Child-Pugh score of 5.8 +/- 0.3; alcohol etiology (5), hepatitis B/C (1/3), primary biliary cirrhosis (3). No patients were on diuretics or vasoactive medication. Hemodynamic measurements were performed at baseline and 4 weeks after daily administration of 25 mg losartan. RESULTS: There was no significant change in the hepatic venous pressure gradient (15.4 +/- 1.5 to 13.6 +/- 1.6 mmHg, -11.7%, p = NS), despite a significant reduction in the wedge hepatic venous pressure (20.3 +/- 1.8 to 17.3 +/- 1.8 mmHg, -14.8%, p < 0.05). Cardiac output, hepatic blood flow, systemic vascular resistance, creatinine clearance, and natriuresis were unaffected. The plasma renin activity increased significantly from 2.7 +/- 0.4 to 5.2 +/- 1.1 ng/ml/h (p < 0.05). There was a significant reduction in the mean arterial pressure from 96.9 +/- 3.3 to 89.3 +/- 3.5 mmHg, -7.8 +/- 3.0% (p = 0.02), with 1 patient experiencing symptomatic hypotension. CONCLUSIONS: Chronic administration of low-dose losartan does not lead to a significant reduction in the portal pressure gradient. Losartan is unlikely to be useful in the management of patients with early cirrhosis, who are at risk of variceal bleeding.     

Irbesartan plus low-dose propranolol versus low-dose propranolol alone in cirrhosis: a placebo-controlled, double-blind study

OBJECTIVES:  Angiotensin II receptor antagonists have been shown to moderately lower portal pressure in some patients with cirrhosis but may have adverse effects on kidney function. This study aimed at comparing the effects of a combined treatment using irbesartan plus propranolol with propranolol monotherapy on portal pressure and kidney function in patients with cirrhosis.
METHODS:  Thirty-two patients were included (Child A/B/C: 13/18/1, etiology: 16 alcohol, 13 viral, 3 other; bilirubin 1.4 ± 1.1 mg/dL, creatinine 0.86 ± 0.20 mg/dL, baseline hepatic venous pressure gradient 18.7 ± 5.3 mmHg). All patients received 20 mg propranolol b.i.d. Additionally, they randomly received either placebo (N = 15) or irbesartan (step-up dosage titration up to 300 mg/d, N = 17). Patients were followed at weekly intervals, re-evaluation of hepatic venous pressure gradient (HVPG) was performed after 8 wk.
RESULTS:  One patient in the propranolol/irbesartan group was excluded due to variceal bleeding. No other adverse events occurred. Portal pressure declined in both groups (propranolol/irbesartan group 19.6 ± 1.5 mmHg to 16.6 ± 1.2 mmHg, P = 0.037, propranolol/placebo group 17.8 ± 1.1 mmHg to 15.1 ± 1.2 mmHg, P = 0.019). Sodium excretion significantly increased in the propranolol/irbesartan group (from 122 ± 20 mmol/d to 230 ± 23 mmol/d, P = 0.045), but not in the propranolol/placebo group.
CONCLUSIONS:  Combination treatment of propranolol plus irbesartan is well tolerated in cirrhotic patients when titrating the angiotensin II antagonist in a step-up manner, and it increases sodium excretion in patients with compensated or moderately decompensated cirrhosis. Addition of irbesartan has no effect on portal pressure.     

Effect of V1-vasopressin receptor blockade on arterial pressure in conscious rats with cirrhosis and ascites.

Angiotensin II blockade with saralasin in human cirrhosis with ascites is associated with a significant reduction in arterial pressure, indicating that endogenous angiotensin II plays an important role in the maintenance of systemic hemodynamics in this condition. The aim of the current study was to investigate whether vasopressin also contributes to the maintenance of arterial pressure in cirrhosis with ascites. The study was performed using three groups of cirrhotic rats with ascites and three groups of control animals. The administration of d(CH2)5Tyr(Me)AVP, a selective antagonist of the vascular effect of vasopressin, to 10 cirrhotic rats induced a significant reduction in mean arterial pressure (from 94 +/- 4 to 85 +/- 4 mm Hg; P less than 0.001) and a significant increase in plasma renin activity (from 24.3 +/- 4.9 to 34.3 +/- 5.9 ng/mL.h; P less than 0.02) and plasma norepinephrine concentration (from 1474 +/- 133 to 2433 +/- 253 pg/mL; P less than 0.01). Similar results were observed following saralasin administration in a second group of 5 cirrhotic rats [mean arterial pressure decreased from 97 +/- 4 to 85 +/- 5 mm Hg (P less than 0.0001); and plasma renin activity and norepinephrine concentration increased from 18.4 +/- 5.8 to 40.3 +/- 5.7 ng/mL.h (P less than 0.02) and from 1383 +/- 70 to 2312 +/- 334 pg/mL (P less than 0.05), respectively]. The simultaneous blockade of angiotensin II and vasopressin in a third group of cirrhotic rats resulted in a significantly greater reduction of mean arterial pressure (from 97 +/- 6 to 74 +/- 6 mm Hg; P less than 0.05). No changes in arterial pressure were observed in the three groups of control rats. These findings indicate that endogenous vasopressin is as important as angiotensin II in the maintenance of arterial pressure in cirrhotic rats with ascites and support the contention that arterial hypotension is the initial event leading to the stimulation of the renin-angiotensin system and vasopressin in this animal model of cirrhosis.     

Efficacy of an angiotensin II receptor antagonist in managing hyperaldosteronism

OBJECTIVE: To determine whether an angiotensin II receptor antagonist decreases blood pressure in patients with hyperaldosteronism and hypertension who are taking other antihypertensive agents. DESIGN: A double-blind randomized placebo-controlled crossover study. PATIENTS AND METHODS: Blood pressure and hormonal responses to 2-week courses of placebo/irbesartan (150 mg/day given by mouth at 08.05 h) were assessed in 10 patients with hyperaldosteronism. Clinic blood pressure was measured by sphygmomanometer, and plasma concentrations of aldosterone, cortisol, angiotensin II, electrolytes and renin activity (PRA) were determined weekly. Automated 24 h ambulatory blood pressure recordings were made at the end of the active and placebo phases. RESULTS: Irbesartan caused a post-dose decrease in ambulatory blood pressure (systolic, P = 0.02; diastolic, P = 0.05) in the period from 10.00 h to 20.00 h. Clinic blood pressure, measured at trough, was not significantly decreased. Plasma aldosterone decreased (P < 0.03) and PRA increased (P < 0.04) in the first week of active treatment with irbesartan, but differences between the placebo and active-treatment groups were not significant in the second week. There were no significant changes in plasma concentrations of angiotensin II, cortisol or potassium in either week. In the second week of irbesartan treatment, there were associations between change in plasma aldosterone and maximal change in ambulatory blood pressure (systolic and diastolic). CONCLUSION: Irbesartan has a role in combination antihypertensive treatment of patients with hyperaldosteronism.     

Vascular,hemodynamic and renal effects of low‐dose losartan in rats with secondary biliary cirrhosis

Background: In cirrhosis, splanchnic and systemic vasodilatation induce a hyperdynamic circulatory dysfunction, portal hypertension and renal sodium retention. This vasodilatation is in part because of an impaired vascular response to α1‐adrenoceptor agonists. Recently, the angiotensin II type 1‐receptor antagonist losartan has been shown to attenuate portal hypertension. We hypothesized that losartan decreases portal pressure by counteracting the impaired vascular responsive to α1‐adrenoceptor agonists. Methods: We studied, in rats with secondary biliary cirrhosis and sham‐operated rats, the effect of 0.5 and 10 mg losartan/kg × day on aortic responsiveness to α1‐adrenoceptor stimulation with methoxamine and angiotensin II (myograph), splanchnic and systemic hemodynamics (colored microspheres), plasma noradrenaline levels and kidney function. Results: In cirrhotic rats, 10 mg losartan/kg × day completely inhibited aortic contractility to angiotensin II, decreased vascular resistance and arterial pressure and induced renal failure. In contrast, 0.5 mg losartan/kg × day only partially inhibited aortic contractility to angiotensin II, but improved aortic contractility to methoxamine, increased splanchnic and systemic vascular resistance, decreased portal pressure, decreased plasma norepinephrine levels and induced natriuresis. Conclusions: In cirrhotic rats, losartan at a very low dose increases splanchnic vascular resistance, decreases portal pressure and improves kidney function, possibly by an increased vascular responsiveness to α1‐adrenoceptor agonists.     

New angiotensin II type 1 receptor blocker olmesartan improves portal hypertension in patients with cirrhosis

Aim: To evaluate the effect of the new oral angiotensin II type 1 receptor blocker olmesartan on portal hemodynamics in patients with cirrhosis. Methods: From January 2005 to March 2006, 18 cirrhosis patients treated with endoscopic band ligation for primary esophageal variceal bleeding were included in the present study. Hepatic venous pressure gradient (HVPG) of the patients was >/=12 mmHg at baseline measurement. The patients were given 10 mg olmesartan orally once daily for 2 weeks. Eighteen cirrhosis patients with esophageal variceal bleeding who did not receive any antihypertensive agents were included in the study as control. On day 14, HVPG, blood pressure, heart rate, and parameters of hepatic and renal function were examined after the treatment. Responders were defined as those with HVPG reduction of >20% versus baseline. Results: Olmesartan significantly reduced HVPG by -16.8 +/- 22.0% (P = 0.031) and mean arterial pressure by -13.1 +/- 10.8% (P = 0.0041). Six of 18 (33.3%) patients in the olmesartan group showed >20% reduction of HVPG from baseline values. None of the patients treated with olmesartan had any complications. Conclusion: Olmesartan reduces portal pressure and may be safe and highly effective in the treatment of portal hypertension.     

Portal and Systemic Hemodynamics and Humoral Factors in Cirrhosis with and without Ascites

The pathogenesis of salt and water retention in cirrhosis remains unclear. Systemic and portal hemodynamic parameters, including cardiac output, portal pressure gradient and systemic vascular resistance, were measured in six patients with untreated ascites and in six patients with hepatic cirrhosis with no history of ascites. Renal blood flow, urinary volume, and humoral factors, including plasma renin, aldosterone, angiotensin II, and urine kallikrein, were measured. Significant differences were seen between the two groups in urine volume, urine sodium and fractional sodium excretion, plasma angiotensin II, and the ratio between plasma renin activity and urinary kallikrein excretion (PRA:UKallV). A strong correlation existed between urinary sodium excretion and the PRA:UKallV ratio. No significant differences were detected between the groups in portal, renal, and systemic hemodynamics. The present results suggest that humoral changes occur early in ascites. Altered relationships between intrarenal hormone systems, such as the renin-angiotensin and kallikrein-kinin systems, may be important in salt and water retention.     

Splanchnic and hepatic renin metabolism in alcoholic cirrhosis. Lack of evidence of a splanchnic source of production or of significantly impaired hepatic clearance

Cirrhosis is frequently associated with increased arterial plasma renin activity. This could be the result of increased renin production or diminished renin clearance. We measured plasma renin activity in simultaneous portal, hepatic vein, and femoral artery blood samples in 7 patients with clinically stable alcoholic cirrhosis to determine whether hepatic extraction of renin is reduced and whether, as has been suggested, there is a splanchnic source of plasma renin activity in this condition. Plasma renin activity (mean +/- S.E. in ng/ml/min) was similar in portal, arterial, and hepatic venous samples (portal: 8.0 +/- 3.7; arterial: 7.6 +/- 3.1; hepatic vein: 6.4 +/- 2.3). Hepatic extraction of plasma renin activity, calculated as [arterial-hepatic vein)/arterial) X 100, was 14 +/- 6%, not significantly different from reported normal values (26 +/- 3%, n = 46). The intrinsic hepatic clearance of plasma renin activity (235 +/- 89 ml/min) and the hepatic renin extraction rate (1.801 +/- 1.032 micrograms/min) were also similar to estimated normal values. The intrinsic clearance and extraction rates of renin correlated with arterial plasma renin activity (r = 0.93, P less than 0.01 and r = 0.79, P less than 0.05). These data indicate that in clinically stable patients with alcoholic cirrhosis: (1) hepatic renin clearance is not significantly impaired; and (2) there is not a splanchnic source of plasma renin activity. Therefore, increased peripheral plasma renin activity in this condition is due solely to increased renal renin production.     

Low dose of nitroglycerin failed to improve splanchnic hemodynamics in patients with cirrhosis: evidence for an impaired cardiopulmonary baroreflex function

High doses of nitroglycerin may decrease portal pressure in patients with cirrhosis with untoward effects such as arterial hypotension and a decrease in systemic O2 uptake. In the present study, low doses of nitroglycerin (7 to 15 micrograms per min, i.v.) were administered in 11 patients with cirrhosis in order to unload cardiopulmonary baroreceptor--one of the possible mechanisms by which nitroglycerin may improve splanchnic hemodynamics--and moreover to avoid deleterious systemic effects. Nitroglycerin significantly decreased right atrial pressure (-35%) and pulmonary wedged pressure (-27%) with significant increase in plasma norepinephrine concentration (+23%), which indicated that cardiopulmonary baroreceptor unloading was achieved. Changes in systemic hemodynamics were slight, although significant, with a decrease in arterial pressure (-8%) and an increase in heart rate (+8%); this indicates a minimal effect on high-pressure baroreflexes. In contrast, no significant change was observed in hepatic venous pressure gradient, hepatic blood flow and azygos blood flow. However, the fraction of cardiac output reaching the azygos system significantly increased by 18%. Plasma renin activity did not change significantly. Moreover, O2 transport and uptake were significantly decreased. These findings show that low doses of nitroglycerin failed to improve splanchnic hemodynamics in patients with cirrhosis. These results suggest an impaired cardiopulmonary baroreflex function which is probably located on the efferent arch.     

Dual renin-angiotensin system blockade restores blood pressure-renin dependency in individuals with low renin concentrations

BACKGROUND: The prevailing sodium intake and renin-angiotensin system status influence the blood pressure response to an angiotensin II type 1 (AT1) receptor antagonist or an angiotensin I converting enzyme inhibitor, which is known to be reinforced by a low sodium intake or administration of a diuretic. OBJECTIVE: To investigate the possibility that combining both drugs might be more effective in conditions of high sodium intake than blocking the renin-angiotensin system in a single step. METHODS: In a placebo-controlled, four-period crossover study in 12 normotensive volunteers who received a high sodium chloride intake (more than 250 mmol/day for 6 days), the haemodynamic and renin effects of a single oral dose of irbesartan 150 mg combined with fosinopril 20 mg were compared with those of a usual daily dose of fosinopril (20 mg) and a high dose of irbesartan (300 mg). RESULTS: The changes in blood pressure induced by fosinopril and irbesartan alone were not different from those of placebo, whereas the combination significantly decreased blood pressure. Simultaneously, it increased plasma active renin and prorenin concentrations to a greater extent than did each single-site blocker. CONCLUSION: In low-renin conditions, combined renin-angiotensin system blockade enables the demonstration of a persistent renin-dependency of the blood pressure. Through its more efficient blockade of the renin-angiotensin system, demonstrated by the increase in renin and prorenin, combined renin-angiotensin system blockade is more effective than doubling the usual dose of an AT1 receptor antagonist. This may offer an alternative strategy for treating patients with a range of renin concentrations, and may potentially increase the cardio- and nephrotective benefits through a more complete blockade of the renin-angiotensin system.     

Randomized comparison of long-term losartan versus propranolol in lowering portal pressure in cirrhosis

BACKGROUND & AIMS: It has been suggested that losartan, an angiotensin II (A-II) type 1 receptor blocker, may have a pronounced portal pressure reducing effect, far greater than that of propranolol. This randomized controlled trial compared the hemodynamic and renal effects of continued 6-week administration of losartan (n = 25) vs. propranolol (n = 15) in portal hypertensive patients with cirrhosis treated endoscopically after a variceal bleeding episode. METHODS: Hepatic venous pressure gradient (HVPG), systemic hemodynamics, renal function, and vasoactive factors were measured before and at 6 weeks of treatment. RESULTS: Losartan did not reduce HVPG (-2% +/- 12%, NS) but significantly decreased mean arterial pressure (MAP, -8% +/- 10%, P = 0.001). On the contrary, propranolol significantly reduced HVPG (-10% +/- 11%, P = 0.003) and cardiac output (-16% +/- 12%, P = 0.001) but did not modify MAP (2.5% +/- 10%, NS). Losartan increased A-II levels, reduced aldosterone, and decreased glomerular filtration rate (GFR) in Child B patients. Propranolol did not modify renal function. Adverse events related to therapy were mild and similar in both groups. CONCLUSIONS: Unlike propranolol, long-term losartan administration does not significantly reduce HVPG in patients with cirrhosis treated after a variceal bleeding episode, and it caused hypotension and reduced GFR in patients with moderate liver failure. Therefore, losartan is not an alternative to propranolol in preventing variceal rebleeding.     

Effectiveness and safety of the angiotensin II antagonist irbesartan in children with chronic kidney diseases

BACKGROUND: Studies in adults with chronic kidney diseases demonstrate that the orally available angiotensin II antagonist irbesartan reduces arterial pressure and pathological proteinuria, mostly with an excellent tolerability profile. Little information is available on irbesartan in childhood. METHODS: A total of 44 pediatric outpatients with chronic kidney disease (27 male and 17, aged 3.7 to 18 years, median 10 years) were given irbesartan once a day during 18 weeks for arterial hypertension (N = 23), proteinuria (N = 8), or both (N = 13). RESULTS: In patients with hypertension, the use of irbesartan 4.1 (3.1-5.3) mg/kg body weight daily (median and interquartile range) was associated with a decrease (P <.005) in arterial pressure by 17 (13-22)/10 (7-12) mm Hg. In patients with overt proteinuria the urinary protein excretion decreased (P <.01) during treatment with irbesartan (2.9 [2.0-4.8] mg/kg body weight) by 52 (0-75) mg/[m(2) x h]), whereas plasma albumin increased (P <.05) by 4 (1-5) g/L. The frequency of abdominal pain, constipation, cough, diarrhea, dizziness, edema, fatigue, headache, insomnia, myalgia, orthostasis, and rash was similar before and with irbesartan. Plasma sodium slightly decreased, whereas plasma potassium increased, with irbesartan (P <.01). CONCLUSIONS: In pediatric patients with chronic kidney diseases, irbesartan given once a day for 18 weeks significantly reduces arterial pressure and proteinuria, with an excellent tolerability and side effect profile.     

Effects of isosorbide dinitrate on portal hypertension in alcoholic cirrhosis

It has recently been reported that vasodilators lower portal pressure in patients with cirrhosis. This effect, however, is not definitively proven. The effect of isosorbide dinitrate (5 mg sublingually) on splanchnic and systemic hemodynamics was investigated in 13 patients with alcoholic cirrhosis and portal hypertension. The administration of isosorbide dinitrate reduced hepatic venous pressure gradient by 34% (P less than 0.001), mean arterial pressure by 30% (P less than 0.001), cardiac index by 17% (P less than 0.001) and systemic vascular resistance by 11% (P = 0.05). Hepatic blood flow was not affected by the treatment. Significant correlations were found between the decrease in hepatic venous pressure gradient and that of cardiac index (P less than 0.05) and mean arterial pressure (P less than 0.05). These data indicate that isosorbide dinitrate lowers portal pressure in patients with cirrhosis. Decrease in cardiac output, rise in splanchnic arterial vascular resistance and decrease in porto-hepatic resistance seem to participate in determining the effect.     

Hemodynamic effects of a clonidine-induced decrease in sympathetic tone in patients with cirrhosis

A decrease in plasma noradrenaline--a reflection of sympathetic nervous system activity--by clonidine, a centrally acting alpha 2-agonist, could reduce the hyperdynamic circulation observed in cirrhosis and may thereby decrease portal hypertension. Plasma noradrenaline concentration and plasma renin activity as well as systemic and splanchnic hemodynamics were measured in 12 patients with cirrhosis and ascites before and after administration of either 150 micrograms of clonidine or placebo. Plasma noradrenaline concentration significantly decreased in all patients after clonidine administration, whereas plasma renin activity did not change significantly. There were statistically significant reductions of cardiac output (-17.4%), mean arterial pressure (-12.2%), hepatic venous pressure gradient (-19.7%) and azygos blood flow (-26.6%) after administration of clonidine. No significant correlation was found between the reduction of plasma noradrenaline concentration and changes in systemic or splanchnic hemodynamics. Hepatic blood flow was not changed by clonidine. Placebo administration had no effect on any laboratory or hemodynamic measurement. We conclude that the reduction in sympathetic nervous system activity by clonidine and the subsequent decrease in the hyperdynamic circulation suggests that sympathetic overactivity contributes to the circulatory derangements in patients with cirrhosis.     

Changes in active and inactive renin and in angiotensin II across the kidney in essential hypertension and renal artery stenosis

Investigations were performed in 26 patients with essential hypertension and 24 with unilateral renal artery stenosis. In each patient blood was drawn simultaneously and in triplicate, from both renal veins and aorta, for measurement of plasma concentrations of active and inactive renin and of angiotensin II. In 19 patients estimates of individual renal plasma flow were obtained in order to calculate secretion rates for active and inactive renin, and to assess the contribution of renin secretion rate and of renal plasma flow to the renal vein renin ratio. In patients with essential hypertension there was evidence that the kidney secreted active renin (18% mean increase in renal vein concentration above that of arterial plasma; P less than 0.001), but no evidence of secretion of inactive renin (4% mean increase; NS). There was a tendency for the kidney to extract angiotensin II (8% mean decrease in renal vein concentration below that of arterial plasma; P = 0.07). The affected kidney in patients with renal artery stenosis showed marked secretion of active renin (364% mean increase; P less than 0.001) and also secreted inactive renin (80% mean increase; P less than 0.05) with net generation of angiotensin II across the renal circulation (100% mean increase; P less than 0.05). The contralateral kidney exhibited suppressed secretion of active renin (3% mean increase; NS) with no evidence of secretion of inactive renin (2% mean increase; NS), and marked extraction of angiotensin II (50% mean decrease; P less than 0.001). The correlation between combined secretion rate of active renin by both kidneys and the arterial concentration of active renin in patients with essential and renovascular hypertension taken together was strongly positive (r = 0.82; P less than 0.01). The same correlation for inactive renin was weak (r = 0.32; NS). The correlation between the combined secretion rates of active renin by both kidneys and the circulating plasma concentration of angiotensin II (r = +0.60; P less than 0.05) was both significant and positive. By contrast, the total 'secretion' rate of angiotensin II by both kidneys was inversely related to arterial plasma angiotensin II (r = -0.92; P less than 0.001). This latter relationship suggests an important role for the kidney in clearing angiotensin II from the circulation, this being more marked the higher the arterial angiotensin II concentration.(ABSTRACT TRUNCATED AT 400 WORDS)     

Angiotensin converting enzyme gene polymorphism predicts blood pressure response to angiotensin II receptor type 1 antagonist treatment in hypertensive patients

OBJECTIVES: To determine whether polymorphisms in the renin-angiotensin system can predict blood pressure-lowering response to antihypertensive treatment; more specifically, in response to treatment with irbesartan or atenolol. DESIGN AND METHODS: Eighty-six patients with hypertension were randomized to double-blind treatment with either the angiotensin II type 1 receptor antagonist irbesartan or the beta1 adrenergic receptor blocker atenolol and followed for 3 months. We analysed angiotensinogen T174M and M235T, angiotensin converting enzyme (ACE) I/D and angiotensin II type 1 receptor A1166C polymorphisms and related them to blood pressure reduction. RESULTS: The mean reductions in blood pressure were similar for both treatments. In the irbesartan group, individuals homozygous for the ACE gene I allele showed a greater reduction in diastolic blood pressure, exceeding those with the D allele (-18 +/- 11 SD versus -7 +/- 10 mmHg, P = 0.0096). This was not the case during treatment with atenolol, and the interaction term between type of treatment and ACE II genotype was significant (P = 0.0176). The angiotensinogen and angiotensin II type 1 receptor polymorhisms were not related to the response to treatment. CONCLUSIONS: ACE genotyping predicted the blood pressure-lowering response to antihypertensive treatment with irbesartan but not atenolol. Thus, specific genotypes might predict the response to specific antihypertensive treatment.     

Simultaneous radioimmunoassay of six angiotensin peptides in arterial and venous plasma of man

Using antibodies raised against angiotensin I and II, and high-performance liquid chromatography (HPLC) of plasma extracts, we have quantified six angiotensin peptides in venous (cubital vein) and arterial (brachial) plasma of normal male subjects. The concentrations of venous plasma (fmol/ml, mean +/- s.d., n = 29) for these six peptides were: pentapeptide-(4-8): 1.5 +/- 1.1; hexapeptide-(3-8): 1.0 +/- 0.8; heptapeptide-(2-8): 2.4 +/- 2.6; octapeptide-(1-8): 10.7 +/- 6.6; nonapeptide-(2-10): 3.7 +/- 2.1; and decapeptide-(1-10): 18.7 +/- 10.7. No significant differences in the levels of each peptide were found for arterial and venous plasma; thus the rate of production of these peptides in the forearm is equivalent to their rate of clearance by the forearm. Both angiotensin I and II were significantly correlated with plasma renin, and there was a highly significant correlation between angiotensin I and II. With respect to the mechanism of local production of angiotensin, the close correlations between renin and angiotensin I and II in venous blood provide evidence that, for the forearm, plasma renin is a major determinant of local production of angiotensin. The ratio of angiotensin I:II, 1.83: 1, was similar for arterial and venous plasma, and indicates that despite the ubiquitous distribution of the angiotensin converting enzyme, the conversion of angiotensin I to angiotensin II is a significant rate-limiting step in angiotensin II formation.     

Circulatory function and hepatorenal syndrome in cirrhosis

The pathogenic mechanism of hepatorenal syndrome is not well established. We investigated the circulatory function in cirrhosis before and after the development of hepatorenal syndrome. Systemic and hepatic hemodynamics and the activity of endogenous vasoactive systems were measured in 66 patients who had cirrhosis with tense ascites and normal serum creatinine levels; measurements were repeated at follow-up in 27 cases in whom hepatorenal syndrome had developed. At baseline, mean arterial pressure and cardiac output were significantly higher, and hepatic venous pressure gradient, plasma renin activity, and norepinephrine concentration were significantly lower in patients who did not develop hepatorenal syndrome compared with those presenting with this complication. Peripheral vascular resistance was decreased to the same extent in the two groups. Plasma renin activity and cardiac output were the only independent predictors of hepatorenal syndrome. Hepatorenal syndrome occurred in the setting of a significant reduction in mean arterial pressure (83 +/- 9 to 75 +/- 7 mmHg; P < .001), cardiac output (6.0 +/- 1.2 to 5.4 +/- 1.5 L/min; P < .01), and wedged pulmonary pressure (9.2 +/- 2.6 to 7.5 +/- 2.6 mmHg; P < .001) and an increase in plasma renin activity (9.9 +/- 5.2 to 17.5 +/- 11.4 ng/mL . hr; P < .001), norepinephrine concentration (571 +/- 241 to 965 +/- 502 pg/mL; P < .001), and hepatic venous pressure gradient. No changes were observed in peripheral vascular resistance. In conclusion, these data indicate that hepatorenal syndrome is the result of a decrease in cardiac output in the setting of a severe arterial vasodilation.     

Effect of 1-week losartan administration on bile duct-ligated cirrhotic rats with portal hypertension

BACKGROUND/AIMS: Nitric oxide and angiotensin play important roles in the pathogenesis of the hemodynamic derangement in cirrhosis and portal hypertension. The hemodynamic effects of losartan, an angiotensin II type 1 receptor antagonist, in cirrhotic patients with portal hypertension are conflicting. This study was undertaken to explore the possible mechanism of action of losartan on portal hypertension in cirrhotic rats produced by bile duct ligation (CBL). METHODS: Three weeks after surgery, CBL and sham-operated rats randomly received vehicle or losartan (3 mg/kg per 12 h by gavage) for 1 week. Hemodynamic values, hormone levels, and aortic eNOS protein expression were measured after drug administration. RESULTS: In CBL rats, 1-week losartan treatment decreased portal pressure and ameliorated hyperdynamic circulation associated with a blunted vascular response to N(omega)-nitro-L-arginine methyl ester infusion. The hematocrit increased and the plasma volume, aldosterone, plasma renin activity, norepinephrine, and nitrate and nitrite levels decreased. The eNOS protein expression was reduced in CBL rats receiving losartan compared with those receiving vehicle. CONCLUSIONS: One-week losartan treatment in CBL rats decreased portal pressure and ameliorated hyperdynamic circulation. In addition to the suppression of renin-angiotensin axis, the reduced aortic eNOS protein expression may play a partial role for the mechanism of action of losartan in CBL rats.     

Clinical usefulness of the angiotensin II receptor antagonist losartan in patients with portal hypertensive gastropathy

BACKGROUND/AIMS: An elevated portal vein pressure is an important factor in the onset of portal hypertensive gastropathy associated with liver cirrhosis, and propranolol or vasopressin (drugs with a portal hypotensive effect) are used to treat this problem. It has been reported that angiotensin II receptor antagonists, which were developed as antihypertensive agents, also have a portal hypotensive effect, but their usefulness for portal hypertensive gastropathy is unclear. In this study, the angiotensin II receptor antagonist losartan was administered to 16 portal hypertensive gastropathy patients, and its clinical usefulness was examined. METHODOLOGY: Losartan was administered once a day after breakfast at a dose of 25mg or 50mg. The effect on portal hypertensive gastropathy was evaluated from the endoscopic findings at baseline and after 4 weeks of administration. And changes of portal hemodynamics were monitored by pulse Doppler ultrasonography at baseline and after 4 weeks of administration. RESULTS: Portal hypertensive gastropathy was found to have improved in nine out of 16 patients for an efficacy rate of 56%. The efficacy rate in the 50mg group (n=6) was 83%, and was higher than the rate of 40% in the 25mg group (n = 10). The mean portal vein blood flow velocity was found to increase significantly, while the congestion index decreased significantly, supporting evidence of a decrease in portal pressure. CONCLUSIONS: Losartan may become one of the effective treatments for portal hypertensive gastropathy in the future.