Presence of the atrial natriuretic factor (ANF) in human ascitic fluid

Presence of atrial natriuretic factor (ANF)-like material was demonstrated by radioimmunoassay in ascitic fluid of 14 patients with cirrhosis of the liver. Immunoreactive ANF concentrations (M +/- SEM) were 2.4 +/- 0.5 fmol/ml in ascites, significantly lower (p less than 0.001) than the corresponding plasma concentrations of 15.5 +/- 2.6 fmol/ml. High performance gel permeation chromatography and reverse phase high performance chromatography of the ascitic ANF immunoreactivity showed correspondence to the alpha human ANF (99-126). ANF levels in ascites were significantly (p less than 0.01) correlated to levels in plasma (r = 0.66).     

Increased renin release by exogenous prostaglandin E1 in liver cirrhosis with and without ascites

To evaluate the sensitivity of the renin-angiotensin-aldosterone system in patients with liver cirrhosis, prostaglandin E1 was intravenously administered at the rate of 50 micrograms/hour for two hours to the 11 control subjects and 11 patients with liver cirrhosis (6 compensated and 5 decompensated). Basal plasma renin activity (PRA) in decompensated patients was significantly higher than those in control and compensated cirrhotics (P less than 0.01). Basal plasma aldosterone was also higher in decompensated than in control and compensated patients, but without significance. PGE1 had no virtual effect on PRA in control, but stimulated PRA in liver cirrhotics, in which statistical significance was only observed in decompensated (basal vs. one hour after PGE1: 2.4 +/- 0.9 ng/ml/min (mean +/- SE) vs. 6.9 +/- 2.1: P less than 0.025). The rate of renin release was significantly higher in compensated than in decompensated (327 +/- 50% vs. 143 +/- 26: P less than 0.05). Though PGE1 also increased plasma aldosterone in liver cirrhotics, statistical change was not seen. Fractional excretion of urinary sodium after PGE1 increased significantly in control (P less than 0.025), but not in liver cirrhotics. These results indicate that the renin-angiotensin-aldosterone system is easily activated by PGE1 in patients with liver cirrhosis and further suggest that the sensitivity of this system in compensated is more augmented than in decompensated patients.     

Haemodynamic effects of angiotensin II in conscious, non-ascitic cirrhotic rats

The effect of angiotensin II (AII) on systemic and regional haemodynamics was studied in 18 control and 18 cirrhotic, non-ascitic conscious rats (CCl4/phenobarbital model). Cirrhotic rats were found to retain sodium and to have normal plasma renin and plasma aldosterone concentrations when compared with control animals. Cirrhotic rats showed an enhanced cardiac output (34.4 +/- 0.5 vs. 27.5 +/- 2.0 ml/min in controls) and decreased peripheral resistances (2.96 +/- 0.25 vs. 3.95 +/- 0.31 mm Hg/min/100 g/ml in controls) under basal conditions. When AII was administered cardiac output decreased by 10.7 +/- 1.2% in cirrhotic rats, whereas it increased in control animals (11.2 +/- 2%, p less than 0.005). The AII-induced increase in arterial pressure was lower in cirrhotic than in control rats. The renal blood supply was particularly impaired by AII in cirrhotics, with a maintained flow to other organs (muscle, testes). It is concluded that the response to AII is disturbed in rats with hepatic cirrhosis even in a stage without ascites and with plasma renin and aldosterone concentrations similar to those of control animals.     

Growth hormone and carbohydrate intolerance in cirrhosis

Patients with cirrhosis of the liver often have insulin resistance and elevated circulating growth hormone levels. This study was undertaken (a) to evaluate glucose intolerance, insulin resistance and abnormal growth hormone secretion and (b) to determine if GH suppression improves insulin resistance. Glucose tolerance tests (GTT), intravenous insulin tolerance tests (IVITT), arginine stimulation tests (AST) and glucose clamp studies before and during GH suppression with somatostatin were performed in a group of patients with alcohol-induced liver cirrhosis. During GTT cirrhotic subjects had a 2-hour plasma glucose of 200 +/- 9.8 ng/dl (N = 14) compared to 128 +/- 8.0 ng/dl in normal controls (N = 15), P less than 0.001. Basal GH was elevated in cirrhotic patients and in response to arginine stimulation reached a peak of 17.0 +/- 5.4 ng/ml (N = 7), compared to a peak of 11.3 +/- 1.8 ng/ml in 5 normal controls (P = NS). During IVITT patients with cirrhosis had a glucose nadir of 60.0 +/- 4.0 mg/dl (N = 9), compared to 29.0 +/- 7.0 mg/dl in controls (N = 5), P less than 0.001. Peak GH levels during IVITT were not significantly different in cirrhotics and controls. Glucose utilization rates in 4 patients with cirrhosis of the liver before somatostatin mediated GH suppression was 3.1 +/- 0.5 mg/kg/min and 6.5 +/- 1.5 mg/kg/min during somatostatin infusion, P less than 0.025. We conclude that patients with alcohol induced cirrhosis have sustained GH elevations resulting in insulin resistance which improves after GH suppression.     

Opioid peptides attenuate blood pressure increase in acute respiratory failure

Plasma opioid peptides, norepinephrine, atrial natriuretic factor (ANF) and blood pressure (BP) were assessed in 24 chronic obstructive pulmonary disease patients with acute respiratory failure. Hypoxemic-hypercapnic patients had high BP, beta-endorphin, Met-enkephalin and dynorphin B, whereas hypoxemic-normocapnic and hypoxemic-hypocapnic patients showed normal BP, high beta-endorphin, and normal Met-enkephalin and dynorphin B. Norepinephrine and ANF were high in all patients, particularly in hypoxemic-hypercapnic patients. Infusion with the opioid antagonist naloxone hydrochloride significantly increased systolic blood pressure (SBP) in hypoxemic-hypercapnic (182.0 +/- 3.2 versus 205.1 +/- 3.0 mmHg; P < 0.01), hypoxemic-normocapnic (149.3 +/- 1.8 versus 169.1 +/- 2.2 mmHg; P < 0.01) and hypoxemic-hypocapnic (147.3 +/- 1.3 versus 166.8 +/- 2.2 mmHg; P < 0.01) patients, norepinephrine in hypoxemic-hypercapnic patients (3583.2 +/- 371.8 versus 5371.3 +/- 260.0 fmol/ml; P < 0.01), and reduced ANF in hypoxemic-normocapnic (18.3 +/- 0.8 versus 11.9 +/- 1.0 fmol/ml; P < 0.05) and hypoxemic-hypocapnic (18.1 +/- 1.2 versus 12.1 +/- 2.1 fmol/ml; P < 0.05) patients. These results indicate that the endogenous opioid system attenuates SBP responses in acute respiratory failure by affecting norepinephrine or ANF release.     

Water immersion increases the concentration of the immunoreactive N-terminal fragment of proatrial natriuretic factor in human plasma

Atrial natriuretic factor (ANF) N-terminal (ANF 1-98) and C-terminal (ANF 99-126) fragments were determined by radioimmunoassay in human plasma. Mean basal plasma ANF N-terminal concentrations in 9 healthy subjects were 461 +/- 58 fmol/ml, significantly (p less than 0.0001) higher than ANF C-terminal concentrations (4.8 +/- 0.5 fmol/ml). Central volume stimulation by one hour head-out water immersion (WI) induced a significant (p less than 0.01) increase of the C-terminal peptide levels to 11.6 +/- 2.3 fmol/ml, paralleled by a significant (p less than 0.001) increase of the N-terminal fragment levels to 749 +/- 96 fmol/ml. Increases of plasma concentrations of both fragments upon WI correlated significantly (r = 0.71; p less than 0.05). These data suggest cosecretion of the N-terminal fragment with the C-terminal fragment of pro ANF 1-126 following a physiological stimulus of ANF release in man.     

Hormonal interactions and renal function during mechanical ventilation and ANF infusion in humans

To investigate the influence of atrial natriuretic factor (ANF) on renal function during mechanical ventilation (MV), we examined the renal and hormonal responses to synthetic human ANF infusion in eight patients during MV with zero (ZEEP) or 10 cmH2O positive end-expiratory pressure (PEEP). Compared with ZEEP, MV with PEEP was associated with a reduction in diuresis (V) from 208 +/- 51 to 68 +/- 11 ml/h (P less than 0.02), in natriuresis (UNa) from 12.4 +/- 3.3 to 6.2 +/- 2.1 mmol/h (P less than 0.02), and in fractional excretion of sodium (FENa) from 1.07 +/- 0.02), 0.21 to 0.67 +/- 0.17% (P less than 0.02) and with an increase in plasma renin activity (PRA) from 4.83 +/- 1.53 to 7.85 +/- 3.02 ng.ml-1.h-1 (P less than 0.05). Plasma ANF levels markedly decreased during PEEP in four patients but showed only minor changes in the other four patients, and mean plasma ANF levels did not change (163 +/- 33 pg/ml during ZEEP and 126 +/- 30 pg/ml during PEEP). Glomerular filtration rate and renal plasma flow were unchanged. Infusion of ANF (5 ng.kg-1.min-1) during PEEP markedly increased V and UNa by 110 +/- 61 and 107 +/- 26%, respectively, whereas PRA decreased from 7.85 +/- 3.02 to 4.40 +/- 1.5 ng.ml-1.min-1 (P less than 0.05). In response to a 10 ng.kg-1.min-1 ANF infusion, V increased to 338 +/- 79 ml/h during ZEEP but only to 134 +/- 45 ml/h during PEEP (P less than 0.02), whereas UNa increased, respectively, to 23.8 +/- 5.3 and 11.3 +/- 3.3 mmol/h (P less than 0.02).(ABSTRACT TRUNCATED AT 250 WORDS)     

Cardiac secretion of atrial natriuretic factor with exercise in chronic congestive heart failure patients.

We have previously reported a fivefold increase of plasma atrial natriuretic factor (ANF) in patients with congestive heart failure (CHF) compared with normal subjects. However, given the marked increase of ANF under basal conditions, the extent to which ANF secretion can further increase under physiological stress is not been clarified in CHF. We therefore evaluated ANF secretion during ergometric exercise in 11 patients with CHF, with peripheral venous ANF samples obtained at rest and peak exercise. In seven patients, simultaneous peripheral venous and right ventricular ANF samples were obtained to estimate myocardial ANF secretion. Hemodynamic characteristics of exercise included a significant increase of heart rate, mean arterial pressure, and cardiac output (all P < 0.01); reduction of systemic vascular resistance (P < 0.001); and increase of right atrial and pulmonary wedge pressures (P < 0.001). ANF was abnormally elevated at baseline (108 +/- 58 fmol/ml) yet increased further to 183 +/- 86 fmol/ml with exercise (P < 0.003). A step-up of right ventricular ANF, particularly during exercise, was consistent with active myocardial secretion, despite elevated baseline ANF levels.     

Effects of synthetic atrial natriuretic factor (ANF) on renin-aldosterone axis in the conscious newborn calf

The effects of synthetic atrial natriuretic factor (ANF) on the renin-aldosterone axis were studied in fifteen 4-7 day-old male milk-fed calves divided into 3 groups of 5 animals each. Synthetic ANF intravenous (i.v.) administration (1.6 micrograms/kg body wt over 30 min) induced a transient significant fall in plasma renin activity (from 2.5 +/- 0.3 to 1.7 +/- 0.3 ng angiotensin l/ml/h; P less than 0.05) but failed to reduce basal plasma aldosterone levels in the first group of animals. Administration (i.v.) of angiotensin II (AII) (0.8 micrograms/kg body wt for 75 min) was accompanied by a progressive fall in plasma renin activity (from 2.2 +/- 0.3 to 0.8 +/- 0.1 ng angiotensin l/ml/h; P less than 0.01) and by an increase in plasma aldosterone levels (from 55 +/- 3 to 86 +/- 5 pg/ml; P less than 0.01) both in the second and the third groups; addition of ANF to AII infusion (AII: 0.5 mu/kg body wt for 45 min; AII: 0.3 micrograms/kg body wt and ANF 1.6 micrograms/kg body wt during 30 min) in the third group did not modify plasma renin activity or AII-stimulated plasma aldosterone levels when compared to the AII-treated group. These findings show that in the newborn calf ANF is able to reduce plasma renin activity but fails to affect basal and AII-stimulated plasma aldosterone levels, suggesting that the zona glomerulosa of the newborn adrenal cortex is insensitive to a diuretic, natriuretic and hypotensive dose of the atrial peptide.     

NH2-terminal fragment of rat pro-atrial natriuretic factor in the circulation: identification, radioimmunoassay and half-life

A radioimmunoassay was developed to measure the NH2-terminal counterpart of rat pro-atrial natriuretic factor (pro-ANF) in plasma. Synthetic rat ANF (Asp 11-Ala 37) coupled to bovine serum albumin was used to immunize New Zealand rabbits. The antiserum demonstrated good immunoreactivity towards rat ANF (Asn 1-Arg 98), (Asn 1-Tyr 126), (Asp 11-Ala 37) and even human ANF (Asn 1-Ser 30). The standard curve had an ED80 of 9.5 +/- 2.5 and ED50 of 44.0 +/- 10.5 fmol/tube. Immunoreactive ANF NH2-terminal peptide was measured directly in rat plasma without prior extraction. In fact, extraction of ANF NH2-terminal from plasma by C18 silica gel chromatography revealed inconsistent recovery and a lack of parallelism. Morphine (0.75 mg/100 g), chosen to elicit increased ANF (Ser 99-Tyr 126) secretion, elevated its plasma concentration from 54.1 +/- 3.2 to 190.8 +/- 55.8 fmol/ml after 20 min. At the same time, the immunoreactive NH2-terminal fragment rose from 378 +/- 16 to 1181 +/- 201 fmol/ml. The identity of this immunoreactive material was verified following affinity chromatography and reverse-phase high-performance liquid chromatography (HPLC) of plasma from morphine-treated rats. Molecular sieving and amino acid sequencing demonstrated that it appears to be consistent with or identical to rat ANF (Asn 1-Arg 98). The disappearance rate of ANF (Asn 1-Arg 98) was studied by injecting radioactive material into anesthetized rats. The exponential decay was analyzed by a two-compartment model in which the fast and slow components had a half-life of 2.5 +/- 0.3 and 54.8 +/- 3.9 min, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)     

Synergism of atrial pressure and adrenergic stimulation for ANF release in the rat.

The effect of adrenergic stimulation on atrial natriuretic factor (ANF) release was studied in conscious rats. 60 min i.v. infusion of 15 micrograms/kg/min phenylephrine produced an elevation in mean arterial pressure of about 50 mmHg that was associated with an immediate, transitory increase in both central venous (CVP) and left ventricular end-diastolic (LVEDP) pressures. Heart rate was not changed. The elevation in CVP, but not LVEDP, persisted until 5 min, together with a 50-fold increase in plasma C-terminal ANF concentrations (from 19 +/- 5 to 1010 +/- 339 fmol/ml); at 30 min, in the absence of any increases in CVP or LVEDP, plasma ANF was still elevated by 5-fold (114 +/- 35 fmol/ml). It is suggested that adrenergic stimulation 'per se' can induce ANF release, independently of atrial pressure. Furthermore, combined adrenergic stimulation and increased atrial wall tension could result in a potentiation of the ANF secretory response 'in vivo', in the case where both stimuli are present concomitantly.     

A sensitive radioimmunoassay of alpha human atrial natriuretic polypeptide using monoclonal antibody recognizing human form ring structure

A monoclonal antibody (C351) against alpha human atrial natriuretic polypeptide (alpha hANP) recognizing human form ring structure was established and applied to a radioimmunoassay of plasma alpha hANP. The minimum detectable amount in terms of 10% radioligand displacement relative to zero dose were 0.28 fmol/tube, corresponding to 0.7 fmol/ml in plasma after extraction using Sep-Pak C18 cartridges. When the mean plasma levels at recumbent position in fasted morning were compared in 10 young (less than 30 years) and 10 elderly (greater than or equal to 50 years) healthy subjects taking normal sodium diet, it was slightly higher in the latter (3.2 +/- 0.4 vs 4.7 +/- 0.5 fmol/ml, mean +/- SE, p less than 0.05). After i.v. infusion of hypertonic saline (2.5% NaCl) at a rate of 0.24 ml/kg/min for 20 min in 6 normal subjects (26 to 35 years), it was increased from 4.1 +/- 0.4 to 5.9 +/- 0.7 fmol/ml (p less than 0.01). In 6 patients with essential hypertension (34 to 57 years), it was elevated with high salt intake, i.e. 3.3 +/- 0.3, 3.9 +/- 1.03 and 7.6 +/- 1.5 fmol/ml under 34, 170 and 340 mEq NaCl/day for 7 days, respectively. From these results, the radioimmunoassay of plasma IR-alpha hANP using MAb C351 seems to be quite suitable to detect rather small changes at low plasma concentrations and to investigate a physiological importance of alpha hANP in man.     

The effect of angiotensin II and ADH on the secretion of atrial natriuretic factor

Studies in intact animals have suggested that angiotensin II (AII) and antidiuretic hormone (ADH) increase the plasma concentration of atrial natriuretic factor (ANF). The purpose of these studies was to examine the effects of AII and ADH on ANF secretion in a rat heart-lung preparation under conditions where aortic pressure could be regulated and other indirect effects of these hormones eliminated. ANF secretion was estimated as the total amount of ANF present in a perfusion reservoir at the end of each 30-min period. A pump was used to deliver a fluorocarbon perfusate to the right atrium at rates of either 2 or 5 ml/min. In a time control series where venous return was maintained at 2 ml/min for three 30-min periods ANF secretion was 672 +/- 114, 794 +/- 91, and 793 +/- 125 pg/min (n = 6, P greater than 0.05). When venous return was increased from 2 to 5 ml/min ANF secretion increased from 669 +/- 81 to 1089 +/- 127 pg/min (P less than 0.01). The addition of AII to the perfusate in concentrations of 50, 100, or 200 pg/ml (n = 6 in each group) had no significant effect on basal ANF secretion or the ANF response to increasing venous return. Similarly, the addition of ADH to the perfusate in concentrations of 5, 25, or 100 pg/ml had no significant effect on ANF release from the heart. These results suggest that the ability of AII and ADH to increase plasma ANF concentration in vivo may be due to the effects of these hormones on right or left atrial pressure.     

The production of 1,2-propanediol in ethanol treated rats

Chronic administration of ethanol in the most commonly used experimental diet (Lieber, C. S., and DeCarli, L. M. (1976) Fed. Proceed. 35, 1232-1236) resulted in the production of 1,2-propanediol within one week of initiation of alcohol feeding. After two weeks 1,2-propanediol levels were 8.8 +/- 1.6 nmol/ml in alcohol treated animals. No 1,2-propanediol was apparent in pair fed control animals at any time during this study. Consistent with the proposed mechanism of production of 1,2-propanediol in acetone treated rats (Casazza, J. P., Felver, M. E., and Veech, R. L. (1984) J. Biol. Chem. 259, 231-236), both liver acetone and acetol monooxygenase activities and blood beta-hydroxybutyrate were elevated in ethanol treated animals. Acetone and acetol monooxygenase activities were 0.118 +/- 0.016 and 0.110 +/- 0.016 umol/min/g liver after two weeks of ethanol treatment. Acetone and acetol monooxygenase activities in pair fed controls were 0.016 +/- 0.002 and 0.015 +/- 0.002 umol/min/g liver. beta-Hydroxybutyrate levels were highest after one week of treatment; 1.64 +/- 0.12 umol/ml in ethanol treated rats and 0.16 +/- 0.02 umol/ml in pair fed controls. Throughout this study serum acetol and 2,3-butanediol were less than the detection limits of these assays (less than 5 nmol/ml).     

Specific binding of atrial natriuretic factor to renal glomeruli during day or night antiorthostatic suspension in the rat

We observed a significant increase in plasma atrial natriuretic factor (ANF) in antiorthostatic hypokinetic suspension (AOH) rats after 2 h of suspension when the experiment was made during day. Plasma ANF was investigated in relation to renal glomerular ANF receptors during AOH at night. The aim of this study was 1) to compare the day and night ANF responses to AOH 2) to determine whether the renal glomerular ANF receptors are involved. The rats were divided into 2 groups: i) 24 population cage (PC), and ii) 24 were attached by the tail (Morey's model) and remained in the horizontal position (attached horizontal-AH). Six AH were suspended (30 degrees) for 2 hours (AOH) and sacrificed with the controls: PC and AH (12.00h). The same experiment was made during the night (24.00h). A significant increase in plasma ANF was found in both AOH and AH after 2 h of suspension during day and night (19 +/- 2.3 pg/ml vs 9 +/- 0.95 and 18 +/- 3 pg/ml vs 10.2 +/- 1.8 respectively). PC rats had a significantly higher ANF level (38 +/- 5 pg/ml) than AH or AOH. The glomerular ANF receptor population was slightly lower in AOH than in AH (429 +/- 12 fmol/mg protein vs 507 +/- 5) during day. During night, a significantly lower number of ANF receptors was observed in AOH animals as compared to AH (168 +/- 2 fmol/mg protein vs 455 +/- 3). A decrease in glomerular receptors was also noted in PC during night. Day-time head-down tilt, bed rest or head-out water induced a natriuretic and diuretic response, whereas the normal recumbency at night does not lead to such effects. We conclude that the natriuretic and diuretic response not observed during night was associated with elevated plasma ANF levels and decreased ANF receptor density.     

Serum neopterin levels in liver cirrhosis

Neopterin is a pyrazino-pyrimidine compound which is biosynthesized by macrophages. Increased concentrations of neopterin have been reported in conditions causing a stimulation of cellular immunity, such as viral and other infections, graft versus host disease, autoimmune disease and different malignancies. Recently, urinary neopterin levels have been found increased in patients with acute viral hepatitis and NANB chronic hepatitis. In the present study, neopterin serum levels have been measured in 23 cirrhotic patients (6 HBV related, and 17 cryptogenetic cirrhosis, 7 of them occurring in alcoholic subjects) and in 24 normal subjects. Mean values of serum neopterin were significantly increased in cirrhotics (3.92 +/- 3.28 ng/ml versus 1.24 +/- 0.51 ng/ml in controls, p less than 0.01). Serum neopterin values were not found to be significantly different in cirrhotics assessed in three different clinical classes according to Child's classification and in cirrhotics with and without serological findings of active disease. In fact, in cirrhotic patients, serum neopterin levels did not correlate with the values of serum AST, ALT, ALP, GGT and gamma-globulin. These data show that increased levels of serum neopterin occur in cirrhotic patients, but there is no relation between serum neopterin values and the activity or the clinical severity of the disease. The results are consistent with the hypothesis that activated macrophages are involved in all stages of liver cirrhosis irrespective of its aetiology.     

Endothelin-3 like immunoreactivity in plasma of patients with cirrhosis of the liver.

A highly specific and sensitive radioimmunoassay (RIA) has been established for determination of endothelin-3 like immunoreactivity in human plasma to investigate its possible role in hemodynamic alterations due to liver disease. Crossreactivity with other endothelin isoforms was always below 4 %, the lower detection limit following extraction on Sep-Pak C18 cartridges was 0.5 pg/ml. The concentration of endothelin-3 (mean +/- SEM) was 4.16 +/- 0.56 pg/ml (n = 13) in plasma of patients with cirrhosis of the liver, three fold higher than in age matched controls (1.35 +/- 0.27 pg/ml, n = 12, p less than 0.01). Plasma immunoreactivity was confirmed to be endothelin-3 related by reverse-phase HPLC. These data could suggest a role of plasma endothelin-3 in circulatory changes, as they occur in cirrhosis of the liver.     

Atrial natriuretic peptide-renin-aldosterone system in cirrhosis of the liver: circadian study

Plasma levels of immunoreactive atrial natriuretic peptide (ANP), plasma renin activity (PRA), and plasma aldosterone (PA) were measured for an entire day at 6:00 am, 8:00 am, 12:00 pm, 6:00 pm, 8:00 pm, and 12:00 am in 6 healthy subjects, in 10 patients with compensated cirrhosis of the liver, and in 10 cirrhotics with ascites. The subjects, after synchronized standard life conditions lasting for 6 days were held in a clinostatic position during the study. The data were analyzed by the "cosinor" method. The results show significant circadian rhythms for the three biological variables in healthy subjects. In the compensated cirrhotic group, a circadian rhythm was detected only for PA. No rhythm was demonstrated in the ascitic patients. These data suggest that in cirrhosis of the liver, great variations in secretion rhythmicity for PRA and ANP are present, while maintaining the intrinsic PA rhythmicity, which is lost in patients with ascites. This progressive derangement in PA circadian rhythm in the ANP-PRA-PA system can be considered as an index of evolution in the natural history of cirrhosis of the liver.     

Renin-angiotensin system and plasma aldosterone in Cushing's syndrome

The renin-angiotensin system was studied in eight patients with Cushing's syndrome (four with adrenal adenoma and four with adrenal hyperplasia) and in five normal controls. Basal plasma renin activity (PRA) and aldosterone concentration (PAC) were similar in supine position among Cushing's syndrome due to adrenal adenoma (PRA; 1.0 +/- 0.3 ng/ml/h, PAC; 7.4 +/- 1.0 ng/dl, mean +/- SE), those due to adrenal hyperplasia (1.0 +/- 0.2, 6.9 +/- 0.8) and the controls (0.8 +/- 0.1, 6.4 +/- 0.4). The PRA after furosemide (1 mg/kg i.v.) and 120 min. upright posture stimulation was similar among Cushing's syndrome due to adrenal adenoma (2.2 +/- 0.7 ng/ml/h), those due to adrenal hyperplasia (2.6 +/- 1.7) and the controls (2.5 +/- 1.2). However, the PAC response after the stimulation in Cushing's syndrome due to adrenal hyperplasia (7.1 +/- 1.2 ng/dl) was significantly lower than that in the controls (17.5 +/- 2.1) (p less than 0.01), although there was no significant difference between the PAC response in Cushing's syndrome due to adrenal adenoma (12.6 +/- 1.0) and the controls. These results indicate that PAC response to furosemide and upright pasture stimulation might be suppressed in Cushing's syndrome due to adrenal hyperplasia.     

Role of endothelin receptor subtypes in volume-stimulated ANF secretion

The role of endothelin (ET) receptors was tested in volume-stimulated atrial natriuretic factor (ANF) secretion in conscious rats. Mean ANF responses to slow infusions (3 x 3.3 ml/8 min) were dose dependently reduced (P < 0.05) by bosentan (nonselective ET-receptor antagonist) from 64.1 +/- 18.1 (SE) pg/ml (control) to 52.6 +/- 16.1 (0.033 mg bosentan/rat), 16.1 +/- 7.6 (0. 33 mg/rat), and 11.6 +/- 6.5 pg/ml (3.3 mg/rat). The ET-A-receptor antagonist BQ-123 (1 mg/rat) had no effect relative to DMSO controls, whereas the putative ET-B antagonist IRL-1038 (0.1 mg/rat) abolished the response. In a second protocol, BQ-123 (>/=0.5 mg/rat) nonsignificantly reduced the peak ANF response (106.1 +/- 23.0 pg/ml) to 74.0 +/- 20.5 pg/ml for slow infusions (3.5 ml/8.5 min) but reduced the peak response (425.3 +/- 58.1 pg/ml) for fast infusions (6.6 ml/1 min) by 49.9% (P < 0.001) and for 340 pmoles ET-1 (328.8 +/- 69.5 pg/ml) by 83.5% (P < 0.0001). BQ-123 abolished the ET-1-induced increase in arterial pressure (21.8 +/- 5.2 mmHg at 1 min). Changes in central venous pressure were similar for DMSO and BQ-123 (slow: 0.91 and 1.14 mmHg; fast: 4.50 and 4.13 mmHg). The results suggest 1) ET-B receptors mainly mediate the ANF secretion to slow volume expansions of <1.6%/min; and 2) ET-A receptors mainly mediate the ANF response to acute volume overloads.