Salt-dependent renal effects of an angiotensin II antagonist in healthy subjects

This study was designed to evaluate in healthy volunteers the renal hemodynamic and tubular effects of the orally active angiotensin II receptor antagonist losartan (DuP 753 or MK 954). Losartan or a placebo was administered to 23 subjects maintained on a high-sodium (200 mmol/d) or a low-sodium (50 mmol/d) diet in a randomized, double-blind, crossover study. The two 6-day diet periods were separated by a 5-day washout period. On day 6, the subjects were water loaded, and blood pressure, renal hemodynamics, and urinary electrolyte excretion were measured for 6 hours after a single 100-mg oral dose of losartan (n = 16) or placebo (n = 7). Losartan induced no significant changes in blood pressure, glomerular filtration rate, or renal blood flow in these water-loaded subjects, whatever the sodium diet. In subjects on a low-salt diet, losartan markedly increased urinary sodium excretion from 115 +/- 9 to 207 +/- 21 mumol/min (P < .05). The fractional excretion of endogenous lithium was unchanged, suggesting no effect of losartan on the early proximal tubule in our experimental conditions. Losartan also increased urine flow rate (from 10.5 +/- 0.4 to 13.1 +/- 0.6 mL/min, P < .05); urinary potassium excretion (from 117 +/- 6.9 to 155 +/- 11 mumol/min); and the excretion of chloride, magnesium, calcium, and phosphate. In subjects on a high-salt diet, similar effects of losartan were observed, but the changes induced by the angiotensin II antagonist did not reach statistical significance. In addition, losartan demonstrated significant uricosuric properties with both sodium diets.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pharmacological profile of valsartan, a non-peptide angiotensin II type 1 receptor antagonist. 5th communication: hemodynamic effects of valsartan in dog heart failure models

Hemodynamic effects of valsartan ((S)-N-valeryl-N-?[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]meth yl?valine, CAS 137862-53-4, CGP 48933), a non-peptide angiotensin II type 1 receptor antagonist were examined in dogs with heart failure induced acutely by coronary artery ligation and chronically by rapid-ventricular pacing. Coronary artery ligation induced decrease in cardiac output and increase in left ventricular end-diastolic pressure. Valsartan at 10 mg/kg i.v. reduced blood pressure, heart rate, left ventricular pressure, left ventricular end-diastolic pressure and total systemic resistance. Similar changes were observed with enalaprilat at 0.1 mg/kg i.v. Rapid left ventricular pacing for 2 weeks reduced cardiac contractility. Valsartan, administered at a dose of 100 mg/kg/d p.o. for 2 weeks, lowered left ventricular end-diastolic pressure. Valsartan reduced preload and afterload in these two dog heart failure models.     

Influence of the angiotensin II antagonist valsartan on left ventricular hypertrophy in patients with essential hypertension

BACKGROUND: Left ventricular hypertrophy (LVH) represents an independent risk factor in patients with essential hypertension. Because reversal of LVH may be associated with an improvement of prognosis, the influence of new antihypertensive compounds, such as angiotensin II AT1 receptor antagonists, on LVH should be determined. METHODS AND RESULTS: In a randomized, double-blind trial, 69 predominantly previously untreated hypertensive patients with echocardiographically proven LVH, ie, left ventricular mass index (LVMI) >134 g/m2 in men and >110 g/m2 in women and/or end-diastolic septal thickness >12 mm, received either the angiotensin II antagonist valsartan or atenolol for 8 months. Echocardiographic data of 58 patients were available. After 8 months of valsartan treatment (n=29), LVMI decreased from 127+/-23 to 106+/-25 g/m2 (ratio [R]=0.83; 95% CI, 0.79 to 0.87; P<0.0001 versus baseline). Under atenolol (n=29), LVMI decreased to a smaller extent, from 127+/-25 to 117+/-27 g/m2 (R=0.92; 95% CI, 0.86 to 0.98; P=0.0082 versus baseline). The mean reduction of LVMI came to 21 g/m2 under valsartan and only to 10 g/m2 under atenolol (R=0.91; 90% CI, 0.85 to 0.97 versus atenolol). Baseline mean blood pressure values were determined to be 163+/-12/101+/-6 mm Hg before treatment with valsartan and 160+/-14/103+/-6 mm Hg before atenolol treatment. After 8 months of treatment, mean blood pressure decreased to 146+/-13/90+/-7 mm Hg with valsartan and to 147+/-18/90+/-7 mm Hg with atenolol. Nine patients in the valsartan group and 8 patients in the atenolol group required additional medication with hydrochlorothiazide. CONCLUSIONS: Antihypertensive treatment with the angiotensin II antagonist valsartan for 8 months produced a significant regression of LVH in predominantly previously untreated patients with essential hypertension. The drug may be safely administered in this subset of hypertensive patients; however, the long-term benefit in terms of risk reduction has still to be evaluated in further trials.     

Human pharmacokinetic/pharmacodynamic profile of irbesartan: a new potent angiotensin II receptor antagonist

BACKGROUND: Inhibition of the renin-angiotensin system has been the focus of considerable research as the enzymatic pathway resulting in the production of angiotensin II is implicated in the development of hypertension and cardiovascular disease. ANGIOTENSIN CONVERTING ENZYME INHIBITORS: Blocking the renin-angiotensin system with angiotensin converting enzyme (ACE) inhibitors is an effective blood pressure control measure, but is less than ideal due to incomplete blockade and the effects of concomitant blockade of kinase II. ANGIOTENSIN II RECEPTOR ANTAGONISTS: Angiotensin II receptor antagonists block the renin-angiotensin system at the receptor level, and thus impede the system regardless of the pathway responsible for the formation of ACE. Irbesartan is a new, unique angiotensin II receptor antagonist with favorable pharmacokinetic/pharmacodynamic properties that are close to ideal for an antihypertensive agent. Irbesartan is a specific AT1 receptor antagonist with rapid oral bioavailability (peak plasma concentrations occurring at 1.5-2 h after administration) and a long half-life (11-15 h) that provides 24-h blood pressure control with a single daily dose. The maximal blood pressure fall occurs between 3 and 6 h after the dose. Unlike other angiotensin II receptor antagonists, irbesartan is relatively unaffected by food or drugs. CONCLUSIONS: The pharmacokinetic/pharmacodynamic properties of irbesartan have been demonstrated to provide superior blood pressure control and tolerability in all classes of hypertension and patient populations.     

Inhibition of sympathetic outflow by the angiotensin II receptor antagonist, eprosartan, but not by losartan, valsartan or irbesartan: relationship to differences in prejunctional angiotensin II receptor blockade

It is well established that angiotensin II can enhance sympathetic nervous system function by activating prejunctional angiotensin II type I (AT1) receptors located on sympathetic nerve terminals. Stimulation of these receptors enhances stimulus-evoked norepinephrine release, leading to increased activation of vascular alpha 1-adrenoceptors and consequently to enhanced vasoconstriction. In the present study, the effects of several chemically distinct nonpeptide angiotensin II receptor antagonists were evaluated on pressor responses evoked by activation of sympathetic outflow through spinal cord stimulation in the pithed rat. Stimulation of thoracolumbar sympathetic outflow in pithed rats produced frequency-dependent pressor responses. Infusion of sub-pressor doses of angiotensin II (40 ng/kg/min) shifted leftward the frequency-response curves for increases in blood pressure, indicating augmented sympathetic outflow. Furthermore, pressor responses resulting in spinal cord stimulation were inhibited by the peptide angiotensin II receptor antagonist, Sar1, Ile8 [angiotensin II] (10 micrograms/kg/min). These results confirm the existence of prejunctional angiotensin II receptors at the vascular neuroeffector junction that facilitate release of norepinephrine. The nonpeptide angiotensin II receptor antagonist, eprosartan (0.3 mg/kg i.v.), inhibited the pressor response induced by spinal cord stimulation in a manner similar to that observed with the peptide antagonist, Sar1, Ile8[angiotensin II]. In contrast, equivalent doses (0.3 mg/kg i.v.) of other nonpeptide angiotensin II receptor antagonists, such as losartan, valsartan, and irbesartan, had no effect on spinal cord stimulation of sympathetic outflow in the pithed rat. Although the mechanism by which eprosartan, but not the other nonpeptide angiotensin II receptor antagonists, inhibits sympathetic outflow in the pithed rat is unknown, one possibility is that eprosartan is a more effective antagonist of prejunctional angiotensin II receptors that augment neurotransmitter release. Because eprosartan is more effective in inhibiting sympathetic nervous system activity compared to other chemically distinct nonpeptide angiotensin II receptor antagonists, eprosartan may be more effective in lowering systolic blood pressure and in treating isolated systolic hypertension.     

Effects of the angiotensin II antagonist valsartan on blood pressure, proteinuria, and renal hemodynamics in patients with chronic renal failure and hypertension

The roles of differentiation, mitotic activity and intrinsic promoter strength in the maintenance of heterochromatic silencing were investigated during development using an inducible lacZ gene as an in vivo probe. Heterochromatic silencing is initiated at the onset of gastrulation, approximately 1 hour after heterochromatin is first visible cytologically. A high degree of silencing is maintained in the mitotically active imaginal cells from mid-embryogenesis until early third instar larval stage, and extensive relaxation of silencing is tightly associated with the onset of differentiation. Relaxation of silencing can be triggered in vitro by ecdysone. In contrast, timing and extent of silencing at both the initiation and relaxation stages are insensitive to changes in cell cycle activity, and intrinsic promoter strength also does not influence the extent of silencing by heterochromatin. These data suggest that the silencing activity of heterochromatin is developmentally programmed.     

Lack of effect of food on the steady state pharmacokinetics of BMS-181101, an antidepressant, in healthy subjects

An annual atmospheric pollen survey was performed for 14 consecutive years in the autumn at Sakado city, Saitama prefecture. The survey was performed on the transition of pollen dispersion of major allergen plants: ragweed (Ambrosia spp.), Humulus japonicus, Artemisia spp. and Gramineae. 1. Annual total pollen count of ragweed showed marked increases beginning from 1991. Total pollen count in 1991 was 8.8 times and that in 1996 was 18.6 times that in 1983. This increase is probably caused by marked proliferation of giant ragweed which is left without mowing as it is on a dry riverbed, and consequently produces much more pollen than short ragweed. 2. Annual increases in total pollen counts of other major plants which disperse their pollen in the same season as ragweed were 0.95 times in 1991 and 0.5 times in 1996 that in 1983 for Humulus japonicus, 0.68 times in 1991 and 1.5 times in 1996 that in 1983 for Artemisia spp. and 1.3 times in 1991 and 1.4 times in 1996 that in 1983 for Gramineae. None of these species showed a marked increase of pollen dispersion although they showed some annual variation. The above findings suggest that changes in the proliferous state of various allergenic plants due to environmental change should be considered with respect to characteristics of pollen allergy.     

Valsartan, a new angiotensin II antagonist: antihypertensive effects over 24 hours

This study was done to assess the antihypertensive efficacy of once-daily valsartan 20 mg, 80 mg, 160 mg, and 320 mg over 24 hours using ambulatory blood pressure monitoring (ABPM). A total of 217 adult outpatients with uncomplicated essential hypertension (office mean sitting diastolic blood pressure [DBP] of > or = 95 to < or = 115 mm Hg) participated in this multicenter, double-masked, placebo-controlled study. Patients were randomized to receive valsartan 20 mg, 80 mg, 160 mg, 320 mg, or placebo for 8 weeks. Twenty-four-hour ABPM was done at baseline and after 8 weeks of treatment. All valsartan doses produced significant decreases in average ambulatory systolic blood pressure (SBP) and DBP over 24 hours compared with placebo. A trend to greater reductions compared with placebo was observed for doses of valsartan 80 mg and greater (80 mg, -6.61 mm Hg DBP, -11.04 mm Hg SBP; 160 mg, -5.51 mm Hg DBP, -10.61 mm Hg SBP; 320 mg, -8.44 mm Hg DBP, -14.34 mm Hg SBP) compared with valsartan 20 mg (-3.52 mm Hg DBP, -5.92 mm Hg SBP). Valsartan produced consistent reductions compared with placebo during both day (> 6 AM to < or = 10 PM) and night (> 10 PM to < or = 6 AM). However, in all groups, the circadian pattern of blood pressure over 24 hours was preserved and was similar to that observed at baseline (but shifted into the normotensive range in a parallel fashion). The data show that single daily doses of valsartan 80 mg and greater provide effective control of both DBP and SBP over a 24-hour period without loss of diurnal variation.     

Effect of indomethacin on the renal response to angiotensin II receptor blockade in healthy subjects

BACKGROUND: Non-steroidal anti-inflammatory drugs are known to promote sodium retention and to blunt the blood pressure lowering effects of several classes of antihypertensive agents including beta-blockers, diuretics and angiotensin converting enzyme (ACE) inhibitors. The purpose of the present study was to investigate the acute and sustained effects of indomethacin on the renal response to the angiotensin II receptor antagonist valsartan and to the ACE inhibitor enalapril. METHODS: Twenty normotensive subjects maintained on fixed sodium intake (100 mmol sodium/day) were randomized to receive for one week: valsartan 80 mg o.d., enalapril 20 mg o.d., valsartan 80 mg o.d. + indomethacin 50 mg bid and enalapril 20 mg o.d. + indomethacin 50 mg bid. This single-blind study was designed as a parallel (valsartan vs. enalapril) and cross-over trial (valsartan or enalapril vs. valsartan + indomethacin or enalapril + indomethacin). Renal hemodynamics and urinary electrolyte excretion were measured for six hours after the first and seventh administration of each treatment regimen. RESULTS: The results show that valsartan and enalapril have comparable renal effects characterized by no change in glomerular filtration rate and significant increases in renal plasma flow and sodium excretion. The valsartan- and enalapril-induced renal vasodilation is not significantly blunted by indomethacin. However, indomethacin similarly abolishes the natriuresis induced by the angiotensin II antagonist and the ACE inhibitor. CONCLUSIONS: This observation suggests that although angiotensin receptor antagonists do not affect prostaglandin metabolism, the administration of a non-steroidal anti-inflammatory drug blunts the natriuretic response to angiotensin receptor blockade.     

Antinociceptive effects of angiotensin-converting enzyme inhibitors and an angiotensin II receptor antagonist in mice

Potential involvement of brain endogenous angiotensin II in the nociception was investigated in mice by using ACE inhibitors and an angiotensin II antagonist. The mice were allocated to the groups which were orally treated with spirapril (5 mg/kg), trandolapril (5 mg/kg), enalapril (30 mg/kg), losartan (10 mg/kg), or vehicle for 1 day (single dose groups) and 7 days (repeated doses groups). Significantly longer jump latencies were obtained for the groups repeatedly treated with spirapril, trandolapril and losartan, while the group with enalapril gained no effect. In contrast, the single dosing of all agents failed to show antinociceptive effect. The brain ACE activity was determined ex vivo immediately after the hot-plate test, and showed to be suppressed for the groups repeatedly treated with spirapril or trandolapril. In the group repeatedly treated with losartan, ex vivo autoradiography depicted the marked decrease in angiotensin II-binding capacity to the sites containing exclusively AT1 receptors within the blood-brain barrier. The antinociceptive effects of repeated doses of spirapril and losartan were reversed by naloxone. These results suggest that brain endogenous angiotensin II is likely to be involved in central nociceptive mechanisms by its antagonistic interaction with endogenous opioid system.     

Circulating plasma prekallikrein and tissue kallikrein in normotensive and hypertensive humans: effects of angiotensin II infusion

Kinins lower blood pressure but the stimuli leading to kinin generation and their origin are less well known. We administered angiotensin II in graded infusion doses to patients with primary hypertension and normotensive controls to study the effects of on circulating kallikreins. Angiotensin II infusion did not significantly alter plasma prekallikrein or tissue kallikrein levels and the plasma levels and their changes did not correlate with blood pressure levels or changes. In the normotensive group prekallikrein levels and renin activity correlated negatively with urinary sodium and chloride excretion during basal conditions and partially during the infusion. U-tissue kallikrein concentration increased in the normotensive group. Thus, acute elevation of blood pressure induced by angiotensin II does not activate the circulating kallikrein-kinin systems. Data rather indicate that the circulating kallikrein-kinin systems may be related to alterations in volume and sodium balance and that these mechanisms may be altered in primary hypertension.     

Biochemical effects of losartan, a nonpeptide angiotensin II receptor antagonist, on the renin-angiotensin-aldosterone system in hypertensive patients

We investigated the effects of angiotensin II (Ang II) type 1 receptor blockade with losartan on the renin-angiotensin-aldosterone system in hypertensive patients (supine diastolic blood pressure, 95 to 110 mm Hg). Qualifying patients (n = 51) were allocated to placebo, 25 or 100 mg losartan, or 20 mg enalapril. Blood pressure, plasma drug concentrations, and renin-angiotensin-aldosterone system mediators were measured on 4 inpatient days: end of placebo run-in, after first dose, and 2 and 6 weeks of treatment. Plasma drug concentrations were similar after the first and last doses of losartan. At 6 weeks, 100 mg losartan and 20 mg enalapril showed comparable antihypertensive activity. Four hours after dosing, compared with the run-in day, 100 mg losartan increased plasma renin activity 1.7-fold and Ang II 2.5-fold, whereas enalapril increased plasma renin activity 2.8-fold and decreased Ang II 77%. Both drugs decreased plasma aldosterone concentration. For losartan, plasma renin activity and Ang II increases were greater at 2 than at 6 weeks. Effects of losartan were dose related. After the last dose of losartan, plasma renin activity and Ang II changes were similar to placebo changes by 36 hours. These results indicate that long-term blockade of the feedback Ang II receptor in hypertensive patients produces modest increases of plasma renin activity and Ang II that do not appear to affect the antihypertensive response to the antagonist.     

Systemic and renal effects of an ET(A) receptor subtype-specific antagonist in healthy subjects

1. Endothelins (ETs) might play a pathophysiological role in a variety of vascular diseases. The aim of the present study was to characterize the effects of BQ-123, a specific ET(A) receptor antagonist on systemic and renal haemodynamics in healthy subjects. This was done at baseline and during infusion of exogenous ET-1. 2. The study was performed in a balanced, randomized, placebo-controlled, double blind 4 way cross-over design in 10 healthy male subjects. Subjects received co-infusions of ET-1 (2.5 ng kg(-1) min(-1) for 120 min) or placebo and BQ-123 (15 microg min(-1) for 60 min and subsequently 60 microg min(-1) for 60 min) or placebo. Renal plasma flow (RPF) and glomerular filtration rate (GFR) were assessed by the para-aminohippurate (PAH) and the inulin plasma clearance method, respectively. 3. BQ-123 alone had no renal or systemic haemodynamic effect. ET-1 significantly reduced RPF (-24%, P<0.001) and GFR (-12%, P=0.034). These effects were abolished by co-infusion of either dose of BQ-123 (RPF: P=0.0012; GFR: P=0.020). 4. BQ-123 reversed the renal haemodynamic effects induced by exogenous ET-1 in vivo. This indicates that vasoconstriction in the kidney provoked by ET-1 is predominantly mediated by the ET(A) receptor subtype.     

Pharmacokinetics of clentiazem after intravenous and oral administration in healthy subjects

This study characterized the pharmacokinetics of clentiazem (CLZ) after a single intravenous bolus (IV) and oral (PO) dose in humans. Twenty-four healthy male subjects (28.5 +/- 5.2 years; 77 +/- 8.2 kg) received IV (20 mg) and PO (80 mg) doses of CLZ as part of a four-way, randomized, complete crossover study. Serial blood samples were drawn up to 48 hours after administration of the drug. Plasma samples were analyzed for CLZ and three metabolites by a high-pressure liquid chromatography method. The values (mean [CV, %]) for systemic clearance, volume of distribution at steady-state, and half-life of CLZ were 63.6 L/hour (23.5), 756.1 L (19.1), and 10.6 hours (33.1), respectively, after IV administration. The peak plasma CLZ concentration (Cmax) and time to Cmax were 37.0 ng/mL (38.7) and 3.7 hours (22.9), respectively, with a lag time after PO administration. The absolute bioavailability of PO CLZ was 45% (30.7). The ratio of area under the curve of N-desmethyl CLZ to that of CLZ increased from 0.15 (57.0) after IV to 0.60 (21.4) after PO administration, suggesting a significant first-pass effect. The mean residence time and mean absorption time of CLZ were 12.3 hours (24.3) and 3.1 hours (88.1), respectively. The plasma concentration-time data of CLZ can be described by either a one- or two-compartment pharmacokinetic model.     

Intrarenal vascular effects of angiotensin I and angiotensin II

The effects of angiotensin I (250 pmol) and angiotensin II (7.5 pmol) on total renal blood flow and its cortical distribution were examined in 25 dogs anesthetized with pentobarbital. These peptides were administered as bolus injections directly into the left renal artery. Right and left renal blood flows were measured with noncannulating electromagnetic flow probes. The distribution of renal cortical blood flow was measured with 15-micrometers radioactive microspheres. Because angiotensin I is converted to angiotensin II extrarenally as well as intrarenally, the distribution of renal blood flow in response to the bolus injection of angiotensin agonists was measured before these peptides could have recirculated through the kidney. This maneuver precluded the possibility that blood flow changes were due to the extrarenal formation of vasoactive metabolites of angiotensin I or angiotensin II. Control total renal blood flow averaged 3.0 +/- 0.1 ml.min-1.g kidney wt-1 and was decreased 25% by both angiotensin I and angiotensin II. Outer renal cortical flow (zone I) was 5.1 +/- 0.3 ml.min-1.g-1 and was decreased to 3.9 +/- 0.3 ml.min-1.g-1 by both angiotensin I and angiotensin II. On the average, angiotensin I decreased inner cortical renal blood flow from a control of 1.8 +/- 0.2 to 1.2 +/- 0.2 ml.min-1.g-1; angiotensin II decreased inner cortical renal blood flow from a control of 1.9 +/- 0.2 to 1.4 +/- 0.2 ml.min-1.g-1. Analysis on a per-experiment basis revealed that angiotensin I, compared with angiotensin II, produced a proportionally greater decrease in inner cortical renal blood flow relative to its effects on outer cortical blood flow.     

Renal vascular responses to angiotensin II in conscious spontaneously hypertensive and normotensive rats

It has been postulated that exaggerated renal sensitivity to angiotensin II may be involved in the development and maintenance of hypertension in the spontaneously hypertensive rat (SHR). The purpose of this study was to compare the renal vascular responses to short-term angiotensin II infusions (50 ng/kg/min, i.v.) in conscious SHRs and Wistar-Kyoto (WKY) rats. Renal cortical blood flow was measured in conscious rats by using quantitative renal perfusion imaging by magnetic resonance, and blood pressure was measured by an indwelling carotid catheter attached to a digital blood pressure analyzer. Renal vascular responses to angiotensin II were similar in control SHRs and WKY rats. Pretreatment with captopril to block endogenous production of angiotensin II significantly augmented the renal vascular response to exogenous angiotensin II in the SHRs but not in the WKY rats. The renal vascular responses to angiotensin II were significantly greater in captopril-pretreated SHRs than in WKY rats (cortical blood flow decreased by 1.66 +/- 0.13 ml/min/g cortex in WKY rats compared with 2.15 +/- 0.14 ml/min/g cortex in SHR; cortical vascular resistance increased by 10.5 +/- 1.4 mm Hg/ml/min/g cortex in WKY rats compared with 15.6 +/- 1.7 mm Hg/ml/min/g cortex in SHRs). Responses to angiotensin II were completely blocked in both strains by pretreatment with the angiotensin II AT1-receptor antagonist losartan. Results from this study in conscious rats confirm previous findings in anesthetized rats that (a) the short-term pressor and renal vascular responses to angiotensin II are mediated by the AT1 receptor in both SHRs and WKY rats, and (b) the renal vascular responses to angiotensin II are enhanced in SHRs compared with WKY rats when endogenous production of angiotensin II is inhibited by captopril pretreatment.     

Differential regulation of brain angiotensin II in genetically hypertensive and normotensive rats after nephrectomy

HLA-DR haplotypes in patients with scleroderma and vasculitis were compared with those in healthy controls from the Scottish population to investigate whether any associations exist between MHC antigens and development of specific autoantibodies. In patients with systemic vasculitis the presence of any antibodies against neutrophil cytoplasmic antigens (ANCA) was associated with an increased frequency of DR8 [p < 0.004], and no patients expressed the DR5 antigen. However, no significant differences were observed when these patients were subdivided into those with anti-myeloperoxidase (MPO) antibodies or anti-proteinase-3 (PR3) antibodies. Scleroderma patients as a whole showed a lower frequency of DR7 than controls [5.1% cf 28% in control population, p < 0.002]. Following subdivision by autoantibody profile, patients with circulating anti-centromere antibody (ACA) showed an increased frequency of DR1 compared to the control population [p < 0.001]. No scleroderma patient without ACA expressed this haplotype. Associations between MHC and some autoantibodies suggest that antigen presentation could lead to their production.     

Identical effects of indomethacin on renal function in healthy uninephrectomized subjects and in healthy control subjects

1. Animal studies have shown that prostaglandins are important for renal function after unilateral nephrectomy. In order to investigate the importance of prostaglandins for renal function in the fully adapted remnant kidney in healthy uninephrectomized subjects, the acute effects of indomethacin on renal haemodynamics, lithium clearance, urinary excretion rates of prostaglandin E2, sodium and water, and plasma levels of angiotensin II, aldosterone, atrial natriuretic peptide and arginine vasopressin were measured in 14 healthy uninephrectomized subjects (median time after nephrectomy 1.7 years) and in 14 matched healthy control subjects. In addition, nine healthy control subjects were studied without indomethacin and served as a time-control group. 2. Before indomethacin ingestion there was a significantly higher single-kidney urinary excretion rate of prostaglandin E2 in the uninephrectomized group (uninephrectomized group, 349.2 fmol/min; control group, 76.6 fmol/min; time-control group, 96.3 fmol/min). 3. Indomethacin ingestion resulted in equal changes in all parameters in both groups. These were significant decreases in glomerular filtration rate (-11.3% versus -14.6%), renal plasma flow (-6.5% versus -13.0%), urinary flow rate (-49.8% versus -49.4%), fractional sodium excretion (-44.5% versus -47.4%), lithium clearance (33.2% versus -23.8%) and urinary excretion rate of prostaglandin E2 (-93.8% versus -86.7%) (uninephrectomized versus control subjects, values are medians). In the time-control group no changes were observed in these parameters. 4. It is concluded that healthy uninephrectomized subjects with a fully adapted remnant kidney have a normal renal response to acute indomethacin-induced inhibition of prostaglandin synthesis.     

Effect of losartan, an angiotensin II receptor antagonist, on portal pressure in cirrhosis

Administration of angiotensin II causes an increase in portal pressure, and plasma concentration of angiotensin II is elevated in patients with cirrhosis, suggesting that angiotensin II may be involved in the pathogenesis of portal hypertension in cirrhosis. We evaluated the effect of the orally active angiotensin II receptor antagonist, losartan, on portal pressure in patients with cirrhosis and portal hypertension. Thirty patients with severe (hepatic venous pressure gradient [HVPG] >/= 20 mm Hg) and 15 patients with moderate (HVPG < 20 mm Hg) portal hypertension at baseline measurement were treated with an oral dose of 25 mg losartan once daily for 1 week and compared with 15 (HVPG >/= 20 mm Hg) and 10 (HVPG < 20 mm Hg), respectively, cirrhotic controls. On the seventh day, HVPG was determined again, and blood pressure, heart rate, body weight, and parameters of liver and kidney function were recorded. Losartan induced a significant (P <.001) decrease of HVPG in the patients with severe (-46.8% +/- 15.5%) and moderate (-44.1% +/- 14.7%) portal hypertension, while no significant change was seen in the controls. Losartan caused a slight but significant (P <.01) fall in mean arterial blood pressure (-3.1 +/- 5.0 and -3.5 +/- 4.3 mm Hg, respectively). One patient treated with losartan had a short symptomatic hypotensive reaction after the first dose of losartan that did not recur despite continued treatment. No deterioration of liver or kidney function was observed. The present study indicates that angiotensin II blockade with orally administered losartan is safe and highly effective in the treatment of portal hypertension.