Vasopressin and angiotensin II in the conscious dog: synergistic effects on renal excretory parameters?

1. The renal effects of angiotensin II were investigated (a) with and without acute blockade of the effects of aldosterone and (b) with and without concomitant infusion of vasopressin. Angiotensin II (2 ng min-1 kg-1) and/or vasopressin (5 pg min-1 kg-1) was infused intravenously into conscious water-diuretic dogs and the effects were quantified by measurements of renal excretion of water, Na+ and K+, as well as determination of plasma renin activity and plasma levels of atrial natriuretic peptide and catecholamines. 2. Angiotensin II alone increased blood pressure by 7% (P < 0.05), decreased effective renal blood flow markedly and reduced urine flow and osmolar and free water clearances. Na+ and K+ excretion did not change significantly. Aldosterone blockade with canrenoate increased Na+ excretion by a factor of 10; subsequent infusion of angiotensin II decreased Na+ excretion by about 50%, the other renal effects being qualitatively similar to those seen without blockade. As expected, vasopressin also decreased diuresis and free water clearance substantially; however, the effect of combined infusion of angiotensin II and vasopressin was not compatible with the notion of additive effects of the two peptides. 3. Angiotensin II alone or in combination with vasopressin did not change the plasma concentrations of atrial natriuretic peptide, adrenaline, noradrenaline, or dopamine. Vasopressin alone exerted its antidiuretic effect without affecting plasma renin activity, plasma aldosterone concentration or renal excretion of Na+ and K+.(ABSTRACT TRUNCATED AT 250 WORDS)

Atrial natriuretic peptide concentrations in umbilical cord plasma from pre-eclamptic women.

Atrial natriuretic peptide (ANP) was measured in arterial and venous umbilical cord plasma at the time of delivery by cesarean section in pre-eclamptic (n = 7) and normal women (n = 6). In addition venous samples were obtained from pre-eclamptic (n = 7) and normal pregnant women (n = 7) near term. ANP plasma levels were higher in pregnant women with pre-eclampsia than in normal pregnant women (27.9 +/- 4.4 [mean +/- SEM] and 14.1 +/- 2.5 pmol l-1, respectively, P less than 0.05). Immediately after delivery plasma ANP in pre-eclamptic mothers was 66.7 +/- 12.8 pmol l-1 compared to 13.9 +/- 2.2 pmol l-1 in normal mothers (P less than 0.01). However, in the pre-eclamptic group the levels of ANP in arterial and venous umbilical cord plasma (19.5 +/- 4.2 and 16.7 +/- 4.3 pmol l-1, respectively) were significantly (P less than 0.01) lower than ANP levels in arterial and venous cord plasma (39.6 +/- 1.0 and 31.1 +/- 4.2 pmol l-1, respectively) from normal mothers. It is concluded that the increased ANP plasma level in pre-eclamptic women originates from a maternal source. In addition, since the ANP level is lower in cord plasma than in maternal plasma in pre-eclampsia, feto-placental volume homeostasis may also be changed in pre-eclampsia.

Plasma concentration of atrial natriuretic peptide in normal pregnant women and in pregnant women with preeclampsia.

Plasma concentration of atrial natriuretic peptide (ANP) was determined in pregnant women with preeclampsia, in normal pregnant and in nonpregnant women by a specific radioimmunoassay. Results did not show important differences between nonpregnant controls and normal pregnant women, but a significant rise was seen in women with preeclampsia compared to nonpregnant controls. Marked interindividual variation was found in all three groups. The mechanism of ANP release may differ between those women with normal pregnancy and those with preeclampsia. It is unclear whether the increased level of ANP in preeclampsia is an effect or a cause of the disease.

Changes in plasmaconcentration of ANP and aldosterone in normal pregnancy and pregnancy complicated by pre-eclampsia.

Changes in plasmaconcentration of ANP in normal pregnancy and pregnancy complicated by pre-eclampsia were examined and compared to non-pregnant controls. The maternal plasma concentration increased gradually during normal pregnancy but values did not deviate significantly from non-pregnant women. A further increase was demonstrated post partum. In pre-eclampsia maternal plasma ANP levels increased significantly compared with normal gravida at the same gestational age and non-pregnant controls. After delivery ANP decreased significantly. Non correlation between ANP and aldosterone were found in either normal pregnancy nor pregnancy complicated by pre-eclampsia. It is not yet clear how important ANP is for the regulation of blood pressure and sodium and water balance during normal pregnancy and pregnancy complicated by pre-eclampsia.

Atrial natriuretic peptide during head-up tilt induced hypovolaemic shock in man.

To evaluate the importance of right atrial filling pressure versus central blood volume for the plasma concentration of atrial natriuretic peptide in man, head-up tilt to 50 degrees maintained until the appearance of presyncopal symptoms was carried out in six healthy males. Head-up tilt increased thoracic electrical impedance from 35.4 +/- 0.9 (mean and SE) to 39.2 +/- 0.9 ohm, mean arterial pressure from 64.5 +/- 3.6 to 76.6 +/- 3.0 mmHg and heart rate from 51 +/- 3 to 85 +/- 4 beats min-1 (P less than 0.01). After 35 +/- 7 min presyncopal symptoms appeared, together with a decrease in mean arterial pressure to 51 +/- 4 mmHg and in heart rate to 59 +/- 7 beats min-1 (P less than 0.01). Central venous pressure (2.1 +/- 1.0 mmHg) did not change significantly, but atrial natriuretic peptide decreased from 9.4 +/- 1.6 to 4.2 +/- 1.3 pmol l-1 (P less than 0.01) and was inversely related to thoracic impedance (r = -0.65, n = 44, P less than 0.001). The results indicate that changes in the central blood volume rather than in central venous pressure determine the secretion of atrial natriuretic peptide in man.

Hepatic-intestinal disposal of endogenous human alpha atrial natriuretic factor99-126 in patients with cirrhosis.

Hepatic-intestinal disposal of endogenous human alpha atrial natriuretic factor99-126 (ANF) was assessed in 13 patients with cirrhosis (six Child-Turcotte class A, five class B, and two class C) and eight control subjects. The Fick principle was applied during hepatic vein catheterization. Arterial ANF concentration in patients with cirrhosis [11.1 +/- 1.6 (SEM) pmol/L] was not significantly different from that of the control subjects (14.9 +/- 4.2 pmol/L, NS). Arteriohepatic venous extraction ratio of ANF (0.43 +/- 0.05 in cirrhosis vs 0.37 +/- 0.09 in controls, NS), hepatic-intestinal clearance (274 +/- 46 vs 237 +/- 46 ml/min, NS) and removal rate (2.9 +/- 0.88 vs 3.1 +/- 0.77 pmol/min, NS) were closely similar in patients and controls. The present results give no indication that significantly reduced hepatic-intestinal disposal of ANF has a role in causing altered circulating plasma levels of this peptide in cirrhosis. This is in keeping with the presence of vascular clearance receptors and peptidases for ANF degradation independent of hepatocellular function.

Increase in plasma sodium enhances natriuresis in response to a sodium load unable to change plasma atrial peptide concentration.

The influence of plasma sodium concentration in the control of sodium excretion was investigated in conscious, water-diuretic dogs. NaCl was infused for 60 min as a hypertonic or isotonic solution at a rate of 60 mumol NaCl min-1 kg-1 body wt. Plasma sodium concentration rose only during hypertonic infusion (P less than 0.05). Sodium excretion increased markedly with both infusions (hypertonic, from 2.4 +/- 0.6 to 105 +/- 27 mumol min-1; isotonic, from 3.9 +/- 1.3 to 58 +/- 17 mumol min-1). Fractional sodium excretion increased more during hypertonic than during isotonic infusion. Hypertonic infusion decreased diuresis from 3.1 +/- 0.5 to 1.3 +/- 0.6 ml min-1, while isotonic infusion elicited an increase from 3.9 +/- 0.5 to 7.2 +/- 0.7 ml min-1. Plasma renin activity and plasma aldosterone decreased markedly in both series (P less than 0.05), the relative changes in the two series being very similar. Central venous pressure increased (2.8 +/- 0.7 to 4.5 +/- 1.0 mmHg) during isotonic infusion but not significantly during hypertonic infusion. Arterial pressure, heart rate and plasma levels of atrial natriuretic peptide and catecholamines did not change measurably in either series. It is concluded that simultaneous increases in extracellular volume and sodium concentration cause a larger natriuretic response than a change in volume alone, and that a 40-fold increase in sodium excretion may occur without measurable changes in plasma atrial natriuretic peptide concentration.

Antidiuretic effect of subnormal levels of arginine vasopressin in normal humans.

The renal responses to 120-min infusions of arginine vasopressin (AVP) were investigated in healthy volunteers undergoing water diuresis induced by an oral water load of 20 ml/kg body wt. AVP at 1 pg.min-1.kg-1 (approximately 10(-15) mol.min-1.kg-1) decreased urine flow (12.2 +/- 1.7 to 7.4 +/- 1.5 ml/min) and free water clearance (9.7 +/- 1.5 to 4.8 +/- 1.4 ml/min) and increased urine osmolality (Uosmol; 71 +/- 6 to 115 +/- 15 mosmol/kgH2O); 5 pg.min-1.kg-1 elicited pronounced antidiuresis (14.4 +/- 0.9 to 0.9 +/- 0.3 ml/min) with maximal Uosmol of 621 +/- 95 mosmol/kg. In response to 25 pg.min-1.kg-1, maximal Uosmol was 869 +/- 38 mosmol/kg. Responses developed gradually and stabilized within the 2nd h of infusion. AVP at 1 and 5 pg.min-1.kg-1 was without effect for at least 20 min. Only 25 pg.min-1.kg-1 caused a significant rise in plasma AVP (1.2 +/- 0.2-2.0 +/- 0.1 pg/ml), and with this dose sodium excretion decreased. The rates of K+ excretion, as well as plasma aldosterone and atrial natriuretic peptide concentrations, were unaffected by AVP. It is concluded that the human kidney is sensitive to changes in the rate of secretion of AVP of less than 1 pg.min-1.kg-1 and that the maximal change occurs after 1-2 h of constant infusion. It is estimated that the rate of infusion of AVP required to produce isosmolar urine during overhydration is approximately 3 pg.min-1.kg-1.

Branched chain enriched amino acid versus glucose treatment of hepatic encephalopathy. A double-blind study of 65 patients with cirrhosis.

We studied the effects of infusion of a branched chain enriched amino acid mixture versus glucose on acute hepatic encephalopathy in patients with cirrhosis. Sixty-five patients were randomly treated with 1 g/kg per day of an amino acid mixture with 40% branched chain contents (32 patients), or isocaloric glucose (33 patients) for a maximum of 16 days. The regimens further included glucose infusion to a total of 26.5 kcal/kg per day and lactulose. The patients took part in the study for 5-6 days. In each group 17 patients woke up. In the amino acid group eleven died and four developed renal failure. In the glucose group ten died, three developed renal and two respiratory failure, and one remained encephalopathic. The coma score worsened in three of the patients who died in the amino acid group, but in all patients who died in the glucose group. The negative nitrogen balance on entry reversed in the amino acid group, but not in the glucose group. Thus, the branched chain enriched amino acid supplement did not change the prognosis for wake-up, but had other effects on the cerebral state and on nitrogen homeostasis.

Changes in serum electrolyte and atrial natriuretic peptide concentrations, acid-base and haemodynamic status after rapid infusion of isotonic saline and Ringer lactate solution in healthy volunteers.

Opinions differ on the use of isotonic sodium chloride and Ringer lactate solution for extracellular volume depletion. We have compared changes in serum electrolyte concentrations and acid-base and haemodynamic status after rapid infusion of 2 litre of either isotonic sodium chloride or Ringer lactate solution in healthy volunteers. Changes within groups were small and statistically insignificant. Central venous pressure changes were associated with secretion of atrial natriuretic peptide, but this response was delayed.

Normal renal tubular response to changes of sodium intake in hypertensive man.

In a comparative study the influence of changes in dietary sodium intake on blood pressure, renal function, extracellular fluid volume, the renin-angiotensin-aldosterone system and plasma concentrations of arginine vasopressin, atrial natriuretic factor and cyclic guanosine monophosphate (GMP) was investigated in 12 patients with essential hypertension and in 10 normotensive controls. The subjects were studied after 4 days on a low (50 mmol/day), medium (180 mmol/day) or high (380 mmol/day) sodium intake. Renal sodium handling was assessed by simultaneous measurements of 51Cr-ethylenediaminetetraacetic acid (EDTA), lithium and sodium clearances. Identical values for the extracellular fluid volume, glomerular filtration rate and proximal and distal tubular resorption rates of sodium and water were found in the hypertensive patients and the controls at all three levels of sodium intake. In both groups, raising the sodium intake from low to high significantly increased 51Cr-EDTA and lithium clearance (an indirect measure of end-proximal fluid delivery), with intermediate values for the medium-sodium diet. The estimated values of fractional proximal and distal sodium resorption decreased when sodium intake was raised; the absolute proximal sodium resorption rate did not change, whereas the absolute distal sodium resorption rate as well as the extracellular fluid volume and sodium clearance increased. Blood pressure and the heart rate were unaffected by sodium intake. In both hypertensives and controls, plasma concentrations of active renin, angiotensin II and aldosterone decreased with increasing sodium intake, arginine vasopressin did not change, and atrial natriuretic factor and cyclic GMP increased.(ABSTRACT TRUNCATED AT 250 WORDS)

On the pathogenesis of arterial blood pressure elevation early in the course of diabetic nephropathy.

We measured plasma- and extracellular fluid volume (125I-albumin, 51Cr-EDTA), plasma concentrations of renin, angiotensin I and II, aldosterone and atrial natriuretic peptide by radio-immunoassays in insulin-dependent diabetic (IDDM) patients with (n=28) and without (n=11) nephropathy and in 14 normal control subjects matched for sex and age. Glomerular filtration rate (GFR) (ml/min/1.73 m2, single intravenous bolus 51Cr-EDTA technique) was within normal range in all nephropathic patients; 107 (range 78-134). Mean arterial blood pressure (mmHg) was elevated 102 +/- 13 (+/- S.D.) compared to the diabetic and normal control group, 92 +/- 8 and 87 +/- 5, respectively (p less than 0.01). Plasma volume was identical in all three groups while extracellular volume (1/1.73 m2) was expanded in nephropathic patients, 14.5 +/- 1.5 vs 13.1 +/- 0.9 and 12.4 +/- 1.3 in the diabetic and non-diabetic control groups, respectively (p less than 0.05). A significant correlation between extracellular fluid volume and mean arterial blood pressure was found (n=53, r=0.49, p less than 0.001). Active renin was significantly increased in patients with diabetic nephropathy compared with the normal control subjects, while all the remaining hormones were about the same in the three groups. Our study suggests that fluid retention plays a dominant role in the initiation and maintenance of arterial blood pressure elevation early in the course of diabetic nephropathy.

Changed cyclic guanosine monophosphate atrial natriuretic factor relationship in hypertensive man.

Plasma concentrations of atrial natriuretic factor (ANF) and cyclic guanosine monophosphate (cGMP) were measured in 10 patients with essential hypertension and 10 normotensive controls on the fifth day of a low (50 mmol/day), a medium (180 mmol/day) and a high (380 mmol/day) dietary sodium intake. Plasma ANF and cGMP concentrations were less on the low than on the high sodium intake. Values for ANF on the medium sodium intake were intermediate. In normotensive subjects cGMP concentrations did not differ significantly on the low and the medium sodium intake. As compared with the controls plasma concentrations of cGMP were significantly increased in hypertensive patients on all three levels of sodium intake, while ANF concentrations were identical in the two groups. Since cGMP is a second messenger to ANF the data suggest an increased cellular response to ANF in patients with essential hypertension.

Atrial natriuretic peptide in atrial fibrillation before and after electrical cardioversion therapy.

In eight patients with atrial fibrillation of less than 3 months duration and without congestive heart failure the plasma concentration of atrial natriuretic peptide was determined one day before, the day after and again 30 days after electrical cardioversion therapy. The pretreatment plasma concentration of the peptide was 99 pg mg-1 (23-480, median and range). The day after cardioversion to sinus rhythm the peptide concentration had normalized to 36 pg ml-1 (18-151). The plasma concentration of atrial natriuretic peptide remained stable in all but one patient for a period of 30 days (46 pg ml-1, 16-695) (P = 0.03). In conclusion, the plasma concentration of atrial natriuretic peptide in patients with atrial fibrillation was significantly reduced after electrical cardioversion to sinus rhythm and remained stable for a period of 30 days.

Central venous pressure--a physiological stimulus for secretion of atrial natriuretic peptide in humans?

A sensitive radio-immunoassay (RIA) for the measurement of human alpha-atrial natriuretic peptide (ANP) in extracted plasma was developed and used in a study of the possible effect of posture on the concentration of ANP in plasma. The least detectable quantity was less than 2 pg per tube equivalent to 5 pg ml-1 plasma. In the middle sensitivity range (approximately 50 pg per tube), the within-assay and between-assay coefficients of variation were 4.0 and 2.8%, respectively. The recovery of ANP added to plasma prior to extraction was 95-101%. High pressure liquid chromatography (HPLC) of plasma extracts revealed that endogenous ANP was eluted in the same fractions as synthetic ANP. In order to investigate the effect of posture on the concentration of ANP in plasma six healthy volunteers were exposed to five positions in the following sequence: supine, standing, sitting, supine and 10 degrees head-down tilt on a tilt-table. The concentration of ANP was lower in the standing and sitting position than in the supine and head-down tilted position. In another study six healthy volunteers were subjected to passive tilting on a tilt-table in order to evaluate the effect of tilting on blood pressure (BP), heart rate, central venous pressure (CVP) and the concentration of ANP in plasma. It was found that a fall in CVP was accompanied by a significant decrease in the concentration of ANP and that a rise in CVP was accompanied by a rapid increase in the concentration of ANP in plasma. The results are in agreement with the hypothesis that CVP is a physiological stimulus for the secretion of ANP.

Organ extraction of atrial natriuretic peptide (ANP) in man. Significance of sampling site.

Arterial plasma immunoreactivity of endogenous human alpha-atrial natriuretic peptide (ANP) underwent mean 54%, 28% and 40% extraction during one passage through the circulation in the kidney (n = 12), liver-intestine (n = 14) and lower limb (n = 8), respectively, in supine fasting subjects with no detectable disease or subjects with cardiovascular or hepatic disorders of minor degree undergoing a haemodynamic investigation. No extraction was identified across the lungs as evaluated by the same concentration of ANP in pulmonary and femoral arteries (n = 7). The concentration of ANP in a superficial arm vein relative to the femoral artery varied considerably and extractions from 0% up to 58% were identified (mean 18%). The results suggest a high degree of, but only to some extent selective, extraction of ANP, which may account for its proposed short plasma half-life. Due to the different concentrations of ANP in various vascular beds, sampling site should be thoroughly specified.

Circulating atrial natriuretic peptide (ANP) and central blood volume (CBV) in cirrhosis.

Endogenous alpha-atrial natriuretic peptide (ANP) in plasma is elevated in various hypervolaemic conditions. Possible relationships between circulating immunoreactive ANP and cardiovascular and splanchnic haemodynamics were therefore studied in patients with cirrhosis (n = 16) and controls (n = 12). Arterial plasma concentration of ANP in supine patients was (mean +/- SEM) 33 +/- 4 vs 41 +/- 10 pg/ml (9.9 +/- 1.2 vs 12.3 +/- 3.0 fmol/l) in controls (n.s.), and there was a weak direct correlation with right atrial pressure (r = 0.36, P = 0.05). There was no relationship with the presence of ascites or diuretic treatment. Central blood volume (CBV, i.e. the blood volume in the heart cavities, lungs, and aorta), determined from the mean transit time of 125I-labelled of 125I-labelled albumin and cardiac output, was significantly reduced in cirrhotics compared to controls (1.45 +/- 0.12 vs. 1.83 +/- 0.10 l, P less than 0.02) and inversely correlated with portal pressure (r = 0.42, P less than 0.05), whereas total plasma volume was somewhat increased (3.51 +/- 0.2 vs. 3.19 +/- 0.2, 0.05 less than P less than 0.1). A high arterio-venous extraction of ANP was found in the splanchnic system (extraction ratio 0.44 vs 0.28), kidney (0.45 vs 0.54), lower limb (0.53 vs 0.40), and forearm (0.27 vs 0.18) in patients and controls, respectively (n.s.). Our results suggest that the lack of elevation of circulating ANP in cirrhosis, even in the presence of actual fluid retention, may be explained by central hypovolaemia in these patients. Turnover and degradation of ANP is rapid and normal, as evaluated from the tissue extraction ratios.