Clearance of brain natriuretic peptide in patients with chronic heart failure: indirect evidence for a neutral endopeptidase mechanism but against an atrial natriuretic peptide clearance receptor mechanism

1992 ◽  
Vol 82 (6) ◽  
pp. 619-623 ◽  
Author(s):  
Chim C. Lang ◽  
Joseph G. Motwani ◽  
Wendy J. R. Coutie ◽  
Allan D. Struthers
Keyword(s):  
Heart Failure ◽  
Chronic Heart Failure ◽  
Atrial Natriuretic Peptide ◽  
Human Brain ◽  
Brain Natriuretic Peptide ◽  
Natriuretic Peptide ◽  
Neutral Endopeptidase ◽  
Striking Similarity ◽  
Plasma Atrial Natriuretic Peptide ◽  
Atrial Natriuretic

1. Brain natriuretic peptide is a new natriuretic hormone with striking similarity to atrial natriuretic peptide, but there are no previous data concerning its clearance in man. Two pathways of clearance for atrial natriuretic peptide are recognized: degradation by neutral endopeptidase and binding to atrial natriuretic peptide clearance receptors. We have examined the effect of candoxatril, an inhibitor of neutral endopeptidase (dose range 10–200 mg), and the effect of an infusion of a pharmacological dose [45 μg (90 μg in two patients)] of synthetic human atrial natriuretic peptide on plasma human brain natriuretic peptide-like immunoreactivity levels in seven patients with mild to moderate chronic heart failure. 2. Plasma human brain natriuretic peptide-like immunoreactivity levels were elevated in all patients (mean ± sem 22.0 ± 6.2 pmol/l) compared with healthy control subjects (1.3 ± 0.2 pmol/l, n = 11). 3. In all patients, candoxatril increased both plasma atrial natriuretic peptide (P < 0.05) and plasma human brain natriuretic peptide-like immunoreactivity (P < 0.05) levels. 4. By contrast, an exogenous infusion of atrial natriuretic peptide had no effect on plasma human brain natriuretic peptide-like immunoreactivity levels despite increasing the plasma atrial natriuretic peptide concentration to 424 ± 74 pmol/l, which is a level of atrial natriuretic peptide which would have ‘swamped’ all atrial natriuretic peptide clearance receptors. 5. We have therefore shown that plasma human brain natriuretic peptide-like immunoreactivity levels in chronic heart failure are increased by a neutral endopeptidase inhibitor, but are unchanged by an exogenous infusion of atrial natriuretic peptide. Our results suggest that in patients with chronic heart failure, degradation by neutral endopeptidase is an important pathway for clearance of brain natriuretic peptide. By an indirect approach, we did not find any evidence of a role for atrial natriuretic peptide clearance receptors in the metabolism of brain natriuretic peptide in these patients. Although this is in agreement with work in vitro, there could be alternative explanations for the lack of a change in circulating human brain natriuretic peptide-like immunoreactivity during exogenous administration of atrial natriuretic peptide.

Neutral Endopeptidase Inhibition: Augmented Atrial and Brain Natriuretic Peptide, Haemodynamic and Natriuretic Responses in Ovine Heart Failure

1996 ◽  
Vol 91 (3) ◽  
pp. 283-291 ◽  
Author(s):  
Miriam Tessa Rademaker ◽  
Christopher John Charles ◽  
Eric Arnold Espiner ◽  
Michael Gary Nicholls ◽  
Arthur Mark Richards ◽  
...  
Keyword(s):  
Heart Failure ◽  
Atrial Natriuretic Peptide ◽  
Brain Natriuretic Peptide ◽  
Natriuretic Peptide ◽  
Fold Increase ◽  
Neutral Endopeptidase ◽  
Haemodynamic Effects ◽  
Similar Extent ◽  
Endopeptidase 24.11 ◽  
Atrial Natriuretic

1. Atrial and brain natriuretic peptide are both circulating hormones subject to degradation by neutral endopeptidase 24.11. Whereas endogenous levels of atrial natriuretic peptide are increased by neutral endopeptidase inhibition in most pathophysiological states, the effect on brain natriuretic peptide and the influence of cardiac status is less clear. To further evaluate the role of neutral endopeptidase 24.11, we directly compared the responses of atrial and brain natriuretic peptide, together with the effects on other vasoactive hormones, haemodynamics and renal indices, to a neutral endopeptidase inhibitor, SCH32615, and a vehicle control in eight conscious sheep before and during pacing-induced heart failure. 2. In normal animals, SCH32615 significantly increased concentrations of plasma atrial natriuretic peptide (22±5 pmol/l compared with 14±2 pmol/l in control, 1.6-fold increase) and brain natriuretic peptide (6.5±1.2 pmol/l compared with 4.1±0.7 pmol/l in control, 1.6-fold increase), whereas in heart failure, plasma levels of atrial natriuretic peptide (306±38 pmol/l compared with 187±25 pmol/l in control, 1.6-fold increase) and brain natriuretic peptide (93±11 pmol/l compared with 55 ± 9 pmol/l in control, 1.7-fold increase) were elevated to a significantly greater absolute, but proportionately similar, extent. In both normal and heart-failed animals, SCH32615 induced reductions in mean arterial pressure and left atrial pressure and increases in haematocrit, plasma cGMP and endogenous creatinine clearance. However, only in heart failure did neutral endopeptidase inhibition induce a significant and marked natriuresis (> 10-fold increase) and diuresis (4-fold increase), together with suppression of renin activity and haemodynamic effects including decreased peripheral resistance and raised cardiac output. 3. In conclusion, neutral endopeptidase inhibition increases plasma concentrations of atrial and brain natriuretic peptide to a proportionately similar extent in both normal and heart-failed sheep. The striking natriuresis and diuresis and additional haemodynamic effects demonstrated in sheep with heart failure, where natriuretic peptide levels are elevated compared with normal sheep, supports the concept that neutral endopeptidase inhibition augments endogenous atrial and brain natriuretic peptide.

scholarly journals Evaluation of Atrial Natriuretic Peptide and Brain Natriuretic Peptide in Atrial Granules of Rats with Experimental Congestive Heart Failure

2001 ◽  
Vol 49 (10) ◽  
pp. 1293-1300 ◽  
Author(s):  
Gad M. Bialik ◽  
Zaid A. Abassi ◽  
Ilan Hammel ◽  
Joseph Winaver ◽  
Dina Lewinson
Keyword(s):  
Heart Failure ◽  
Congestive Heart Failure ◽  
Atrial Natriuretic Peptide ◽  
Brain Natriuretic Peptide ◽  
Natriuretic Peptide ◽  
Aortocaval Fistula ◽  
Granule Formation ◽  
Gold Particles ◽  
The Mean ◽  
Atrial Natriuretic

The natriuretic peptides are believed to play an important role in the pathophysiology of congestive heart failure (CHF). We utilized a quantitative cytomorphometric method, using double immunocytochemical labeling, to assess the characteristics of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) in atrial granules in an experimental model of rats with CHF induced by aortocaval fistula. Rats with CHF were further divided into decompensated (sodium-retaining) and compensated (sodium-excreting) subgroups and compared with a sham-operated control group. A total of 947 granules in myocytes in the right atrium were analyzed, using electron microscopy and a computerized analysis system. Decompensated CHF was associated with alterations in the modal nature of granule content packing, as depicted by moving bin analysis, and in the granule density of both peptides. In control rats, the mean density of gold particles attached to both peptides was 347.0 ± 103.6 and 306.3 ± 89.9 gold particles/μm2 for ANP and BNP, respectively. Similar mean density was revealed in the compensated rats (390.6 ± 81.0 and 351.3 ± 62.1 gold particles/μm2 for ANP and BNP, respectively). However, in rats with decompensated CHF, a significant decrease in the mean density of gold particles was observed (141.6 ± 67.3 and 158.0 ± 71.2 gold particles/μm2 for ANP and BNP, respectively; p < 0.05 compared with compensated rats, for both ANP and BNP). The ANP:BNP ratio did not differ between groups. These findings indicate that the development of decompensated CHF in rats with aortocaval fistula is associated with a marked decrease in the density of both peptides in atrial granules, as well as in alterations in the quantal nature of granule formation. The data further suggest that both peptides, ANP and BNP, may be regulated in the atrium by a common secretory mechanism in CHF.

Effects of Physiological Increments in Human α-Atrial Natriuretic Peptide and Human Brain Natriuretic Peptide in Normal Male Subjects

1994 ◽  
Vol 86 (6) ◽  
pp. 723-730 ◽  
Author(s):  
B. M. Y. Cheung ◽  
J. E. C. Dickerson ◽  
M. J. Ashby ◽  
M. J. Brown ◽  
J. Brown
Keyword(s):  
Atrial Natriuretic Peptide ◽  
Human Brain ◽  
Brain Natriuretic Peptide ◽  
Natriuretic Peptide ◽  
Physiological Role ◽  
Sodium Balance ◽  
Urinary Flow ◽  
Male Subjects ◽  
The Brain ◽  
Atrial Natriuretic

1. Brain natriuretic peptide, closely related to atrial natriuretic peptide in structure, may be an important circulating hormone. Its physiological role is unclear. First, we studied the effects of incremental infusions of brain natriuretic peptide in six healthy men on plasma brain natriuretic peptide levels and the pharmacokinetics of brain natriuretic peptide. Synthetic human brain natriuretic peptide-32 was infused intravenously, at an initial rate of 0.4 pmol min−1 kg−1, doubling every 15 min until the dose rate reached 6.4 pmol min−1 kg−1, at which rate the infusion was maintained for 30 min. 2. The brain natriuretic peptide infusion raised the brain natriuretic peptide-like immunoreactivity from 1.4 ± 0.5 pmol/l to 21.4 ± 7.6 pmol/l. Brain natriuretic peptide-like immunoreactivity after the end of infusion was consistent with a bi-exponential decay, with half-lives of 2.1 min and 37 min. 3. Next, we studied the effects of low-dose infusion of brain natriuretic peptide to mimic physiological increments in the circulating levels in comparison with atrial natriuretic peptide. Six dehydrated male subjects received intravenous infusions of atrial natriuretic peptide and brain natriuretic peptide, separately and in combination, in a randomized double-blind, placebo-controlled, four-part cross-over design. Atrial natriuretic peptide and brain natriuretic peptide were given at the rate of 0.75 and 0.4 pmol min−1 kg−1, respectively, for 3 h. The control infusion consisted of the vehicle. 4. Analysis of variance showed that atrial natriuretic peptide and atrial natriuretic peptide plus brain natriuretic peptide, but not brain natriuretic peptide alone, increased urinary flow and decreased urinary osmolality significantly. However, urinary sodium excretion was significantly increased by atrial natriuretic peptide, brain natriuretic peptide and atrial natriuretic peptide plus brain natriuretic peptide. 5. None of the four infusates significantly altered the blood pressure, heart rate or glomerular filtration rate. 6. This study showed, for the first time, that physiological increments in brain natriuretic peptide, like those in atrial natriuretic peptide, are natriuretic. Although atrial natriuretic peptide and brain natriuretic peptide do not appear to interact synergistically, they are likely to act in concert in the physiological regulation of sodium balance.

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