M. G. Buckley

Raised concentrations of plasma atrial natriuretic peptides in cardiac transplant recipients.

Plasma atrial natriuretic peptide concentrations were measured by radioimmunoassay six to 77 weeks after operation in eight cardiac transplant recipients with no appreciable evidence of cardiac failure or rejection and in eight control subjects matched for age, sex, race, and blood pressure. Plasma atrial natriuretic peptide concentrations were significantly higher in the cardiac transplant recipients (mean 19.4 (SE 3.9) ng/l) than in the controls (7.3 (1.2) ng/l p less than 0.01). The mechanisms underlying these raised values were not clear. These findings suggest that the transplanted atria may secrete atrial peptides and also that innervation is not obligatory for secretion of atrial natriuretic peptides to occur. Before this can be confirmed, however, it remains to be established what the relative contribution of donor and recipient atrial tissue is to the secretion of these peptides.

Dietary sodium and inhibition of neutral endopeptidase 24.11 in essential hypertension.

Basal atrial natriuretic peptide levels and the response to exogenous atrial natriuretic peptide are influenced by dietary sodium intake. In view of interest in the therapeutic potential of elevating plasma atrial natriuretic peptide by inhibition of neutral endopeptidase 24.11, we studied the renal and hormonal effects of 200 mg of the oral endopeptidase 24.11 inhibitor candoxatril in eight patients with untreated essential hypertension on high sodium (350 mmol/day) and low sodium (10 mmol/day) diets. With endopeptidase 24.11 inhibition, plasma atrial natriuretic peptide increased more than twofold on low and high sodium diets (p<0.05). Plasma N-terminal pro-atrial natriuretic peptide increased on the high sodium intake but was unaffected by candoxatril. Urinary sodium excretion increased threefold on the low sodium and sixfold on the high sodium diet (p<0.05). The absolute increase in urinary sodium excretion during the 24 hours after treatment compared with placebo was 18±8 mmol on the low sodium and 98±34 mmol on the high sodium diet (p<0.05). Plasma renin activity was suppressed by treatment on the low but not on the high sodium diet (p<0.05). Blood pressure did not change in the 6 hours after a single dose of candoxatril. These findings show that sodium intake is a major determinant of the response to endopeptidase 24.11 inhibition. The lack of effect on N-terminal pro-atrial natriuretic peptide suggests that candoxatril does not influence cardiac secretion of atrial natriuretic peptide or catabolism of N-terminal pro-atrial natriuretic peptide, and the latter does not appear to play a role in the response to candoxatril.

Concentrations of N-terminal ProANP in human plasma: evidence for ProANP (1-98) as the circulating form.

Plasma levels of immunoreactive N-terminal ProANP have been measured in plasma from 19 healthy individuals, 15 patients with essential hypertension, 8 cardiac transplant recipients and 8 patients with chronic renal failure using two separate radioimmunoassays (RIAs), one directed against ProANP (1-30) and the other against ProANP (79-98). The mean concentrations of ProANP (1-30) and ProANP (79-98) were elevated in these groups of patients. There were positive correlations between levels of ProANP (1-30) and ProANP (79-98), with a correlation coefficient of 0.97 (P less than 0.001, n = 50). In healthy individuals a 2-1 (isotonic) saline infusion significantly increased both ANP (99-126) (P less than 0.05, n = 8) and N-terminal ProANP (P less than 0.005, n = 8) within 15 min of the end of the infusion. Plasma N-terminal ProANP levels were still significantly elevated after 75 min (P less than 0.05, n = 8) and 225 min (P less than 0.05, n = 8), by contrast ANP (99-126) had returned to basal values. Gel filtration of plasma extracted on Sep-Pak C-18 from normal individuals and patients gave a single immunoreactive peak for N-terminal ProANP as measured by both N-terminal ProANP assays, indicating an absence of small N-terminal fragments and the presence of a single high molecular weight form. These studies demonstrate that the major circulating N-terminal ANP in man is probably ProANP (1-98) and that it is cosecreted with ANP (99-126).

Brain and atrial natriuretic peptides : a dual peptide system of potential importance in sodium balance and blood pressure regulation in patients with essential hypertension

Objective To examine the changes in plasma brain natriuretic peptide (BNP), atrial natriuretic peptide (ANP) and blood pressure in patients with essential hypertension on a low, normal and high sodium intake. Design and methods Twelve patients with mild-to-moderate essential hypertension were studied. Plasma, urinary and blood pressure measurements were made with the patients on their usual sodium intake, then on the fifth day of a low (10 mmol/day) and on the fifth day of a high (350 mmol/day) sodium intake, the sequence being allocated randomly. Results Plasma levels of BNP and ANP increased significantly on the high sodium intake compared with when the patients were on their normal diet. The mean blood pressure on the high sodium intake was not significantly different from that with the patients on their normal diet. In contrast, plasma BNP and ANP decreased on the low sodium intake, but were not significantly different compared with when the patients were on their normal diet. However, there was a significant reduction in the mean blood pressure on the low sodium intake compared with when the patients were on their normal diet. Compared with the normal diet, BNP and ANP plasma levels showed similar percentage decreases on the low sodium intake and similar percentage increases on the high sodium intake. Conclusions These findings suggest that BNP and ANP are released in response to a common stimulus during changes in dietary sodium intake. The changes in plasma BNP and ANP observed with sodium restriction and sodium loading indicate the potential importance of BNP and ANP as a dual peptide system contributing to the maintenance of sodium balance and blood pressure regulation in patients with essential hypertension, during changes in dietary sodium intake.

Contrasting endocrine responses to acute oral compared with intravenous sodium loading in normal humans

There is evidence in animals and in humans for accelerated natriuresis after oral compared with intravenous sodium loading. To assess the role of atrial natriuretic peptide (ANP) as a contributory mechanism, we compared the hormonal responses to an intravenous sodium load and to the same sodium load taken orally in three separate groups of healthy subjects in balance on low, normal, or high sodium intake. On each diet, there was a trend for an early delay in sodium excretion, followed by increased natriuresis after the oral compared with intravenous sodium load. On all levels of dietary sodium intake, there was a significant (∼2-fold) increase in plasma ANP levels after intravenous saline infusion. There was a significant suppression of the renin system both after oral and intravenous sodium loading. However, there was no acute increase in plasma ANP levels after the oral sodium load, except on the very low sodium intake. This striking and unexpected observation suggests that changes in plasma ANP levels appear to play little role in the early response to an acute oral sodium load in subjects with sodium intake in the range of 150-350 mmol/day. Endocrine mechanisms for the accelerated increase in sodium excretion after oral compared with intravenous sodium loading remain to be elucidated.

Investigation of the plasma concentrations and circulating forms of BNP and ANP in orthotopic cardiac transplant recipients.

Investigation of the plasma concentrations and circulating forms of BNP and ANP in orthotopic cardiac transplant recipients

Long-Term Reduction in Sodium Balance: Possible Additional Mechanism Whereby Nifedipine Lowers Blood Pressure

OBJECTIVE To assess the changes in sodium excretion and sodium balance after withdrawal of long term nifedipine. DESIGN Single blind, placebo controlled study in patients receiving fixed sodium and potassium intakes. SETTING Blood pressure unit of a teaching hospital in south London. PATIENTS Eight patients with mild to moderate uncomplicated essential hypertension who had been taking nifedipine 20 mg twice daily for at least six weeks. INTERVENTIONS Withdrawal of nifedipine and replacement with matching placebo for one week. MAIN OUTCOME MEASURES Urinary sodium excretion and cumulative sodium balance, body weight, plasma atrial natriuretic peptide concentrations, plasma renin activity and aldosterone concentrations, and blood pressure. RESULTS During nifedipine withdrawal there was a significant reduction in urinary sodium excretion (day 1: -62.7 mmol/24 h; 95% confidence interval -90.3 to -35.0) and each patient retained a mean of 146 (SEM 26) mmol sodium over the week of replacement with placebo. Body weight and plasma atrial natriuretic peptide concentrations increased during the placebo period and seemed to be associated with the amount of sodium retained. Systolic blood pressure rose from 157 (9) to 165 (9) mmHg (95% confidence interval of difference -7.1 to 22.1) when nifedipine was replaced with matching placebo, and the rise seemed to be related to the amount of sodium that was retained. CONCLUSIONS Nifedipine causes a long term reduction in sodium balance in patients with essential hypertension. This long term effect may contribute to the mechanism whereby nifedipine lowers blood pressure.

Renal tubular sodium handling and plasma atrial natriuretic peptide, renin activity and aldosterone in untreated men under normal living conditions

Abstract. The associations between renal tubular sodium handling and plasma levels of atrial natriuretic peptide, renin activity and aldosterone were studied in 295 untreated men under normal living conditions. The renal clearance of ingested lithium was used as a marker of proximal tubular sodium handling.

Atrial natriuretic peptide in human plasma — comparison of radioreceptor versus radioimmunoassay

A sensitive and specific procedure for the measurement of atrial natriuretic peptide (ANP) in human plasma by radioreceptor assay, using bovine adrenal membranes treated with Triton-X-100, is described. Plasma levels (mean +/- SEM) of ANP in healthy subjects on a normal sodium intake were 8.4 +/- 1.4 pg/ml and could be modified by changes in sodium intake with increases in sodium intake being associated with higher levels. Mean plasma ANP was approximately 2-fold higher in patients with essential hypertension and 4-fold higher in patients with cardiac or renal disease. The values obtained were comparable in magnitude to those obtained by radioimmunoassay and there was a strong correlation (r = 0.94; p less than 0.001) between the values obtained by radioimmuno- and radioreceptor-assay. These results suggest that circulating ANP corresponds to the biologically active peptide and point to an important role of the atrial peptides in the control of sodium balance.

Hormonal and renal responses to neutral endopeptidase inhibition in normal humans on a low and on a high sodium intake.

Abstract. Hormonal and renal effects of candoxatril, a neutral endopeptidase 24.11 inhibitor, were investigated in eight subjects equilibrated on a low sodium diet (10 mmol sodium per day) and a high sodium (350 mmol per day) diet. After candoxatril treatment, plasma ANP increased to a maximum at 2–4 h and declined to baseline within 24 h. The increases were relatively greater on the high sodium diet, which was also associated with increases in urinary sodium, with highest values at 4h. On the low sodium diet, the magnitude of the changes was significantly lower (24 h cumulative sodium excretion was 11.4± 5.5 mmol on the low sodium diet and 73.1± 25.6 mmol on the high sodium diet; P < 0.01). There were no significant effects on urinary potassium excretion, creatinine clearance or haematocrit. After candoxatril treatment there were reductions in PRA, especially on the low sodium diet. On either diet there were no effects on systemic blood pressure. These results demonstrate that dietary sodium intake is an important determinant of the renal and hormonal responses to neutral endopeptidase inhibition.