Comparative Bioactivity of Atrial and Brain Natriuretic Peptides in An Ovine Model of Heart Failure

1997 ◽  
Vol 92 (2) ◽  
pp. 159-165 ◽  
Author(s):  
Miriam Tessa Rademaker ◽  
Christopher John Charles ◽  
Eric Arnold Espiner ◽  
Christopher Miles Frampton ◽  
Michael Gary Nicholls ◽  
...  
Keyword(s):  
Heart Failure ◽  
Natriuretic Peptide ◽  
Urine Volume ◽  
Peripheral Resistance ◽  
Pressure Control ◽  
Guanosine Monophosphate ◽  
Metabolic Clearance ◽  
Ovine Model ◽  
Metabolic Clearance Rate ◽  
Brain Natriuretic Peptides

1. Whereas many studies have detailed the effects of exogenous atrial natriuretic peptide (ANP) infusions in heart failure, and a limited number have examined the effects of brain natriuretic peptide (BNP), none have directly compared the bioactivity of similar doses of ANP and BNP under standard conditions of impaired cardiac function. We compared the hormonal, haemodynamic and renal effects of 3 h infusions of ANP, BNP and a vehicle control in eight sheep with pacing-induced heart failure (225 beats/min for 8–12 days). 2. Infusion of ANP and BNP increased plasma ANP (P < 0.001) (276 ± 27 versus control 142 ± 26 pmol/l) and BNP (P < 0.001) (257 ± 34 versus control 45 ± 5 pmol/l) respectively, in association with increased cyclic 3′,5′-guanosine monophosphate [control, 40 ± 6; ANP, 53 ± 6 (P < 0.05); BNP, 57 ± 7 nmol/l (P < 0.001)]. Metabolic clearance rate and half-life were similar for both peptides. Infusion of ANP and BNP similarly reduced mean arterial pressure [control, 73.0 ± 1.6; ANP, 67.6 ± 1.2 (P < 0.01); BNP, 65.7 ± 1.7 mmHg (P < 0.001)], left atrial pressure (both P < 0.05) (control, 22.0 ± 0.7; ANP, 19.9 ± 1.0; BNP, 19.8 ± 0.9 mmHg) and peripheral resistance [control, 50.3 ± 4.1 mmHg l−1 min−1; ANP, 46.0 ± 2.8 (P < 0.05); BNP, 43.8 ± 4.5 (P < 0.01)], and increased urine volume (2-3-fold, both P < 0.05), sodium excretion (> 10-fold, both P < 0.01) and haematocrit levels relative to control (both P < 0.05). Infused BNP tended to raise plasma ANP levels (by 28 pmol/l), while ANP increased plasma BNP (by 18 pmol/l). Plasma aldosterone was reduced by approximately 40% by both peptides (both P < 0.05). 3. In conclusion, ANP and BNP are both powerfully natriuretic, similarly suppress aldosterone and appear equipotent in reducing preload and after-load in this model of pacing-induced heart failure.

Natriuretic peptide analogues with distinct vasodilatory or renal activity: integrated effects in health and experimental heart failure

2020 ◽  
Author(s):  
Miriam T Rademaker ◽  
Nicola J A Scott ◽  
Cho Yeow Koh ◽  
R Manjunatha Kini ◽  
A Mark Richards
Keyword(s):  
Heart Failure ◽  
Blood Pressure ◽  
Natriuretic Peptide ◽  
Acute Decompensated Heart Failure ◽  
Unmet Need ◽  
Urine Volume ◽  
Plasma Renin ◽  
Decompensated Heart Failure ◽  
Guanosine Monophosphate ◽  
High Dose

Abstract Aims Management of acute decompensated heart failure (ADHF) requires disparate treatments depending on the state of systemic/peripheral perfusion and the presence/absence of expanded body–fluid volumes. There is an unmet need for therapeutics that differentially treat each aspect. Atrial natriuretic peptide (ANP) plays an important role in blood pressure and volume regulation. We investigate for the first time the integrated haemodynamic, endocrine and renal effects of human ANP analogues, modified for exclusive vasodilatory (ANP-DRD) or diuretic (ANP-DGD) activities, in normal health and experimental ADHF. Methods and results We compared the effects of incremental infusions of ANP analogues ANP-DRD and ANP-DGD with native ANP, in normal (n = 8) and ADHF (n = 8) sheep. ANP-DRD administration increased plasma cyclic guanosine monophosphate (cGMP) in association with dose-dependent reductions in arterial pressure in normal and heart failure (HF) sheep similarly to ANP responses. In contrast to ANP, which in HF produced a diuresis/natriuresis, this analogue was without significant renal effect. Conversely, ANP-DGD induced marked stepwise increases in urinary cGMP, urine volume, and sodium excretion in HF comparable to ANP, but without accompanying vasodilatory effects. All peptides increased packed cell volume relative to control in both states, and in HF, decreased left atrial pressure. In response to ANP-DRD-induced blood pressure reductions, plasma renin activity rose compared to control only during the high dose in normals, and not at all in HF—suggesting relative renin inhibition, with no increase in aldosterone in either state, whereas renin and aldosterone were both significantly reduced by ANP-DGD in HF. Conclusion These ANP analogues exhibit distinct vasodilatory (ANP-DRD) and diuretic/natriuretic (ANP-DGD) activities, and therefore have the potential to provide precision therapy for ADHF patients with differing pathophysiological derangement of pressure–volume homeostasis.

Interactions of atrial and brain natriuretic peptides at pathophysiological levels in normal men

1995 ◽  
Vol 269 (6) ◽  
pp. R1397-R1403 ◽  
Author(s):  
P. J. Hunt ◽  
E. A. Espiner ◽  
A. M. Richards ◽  
T. G. Yandle ◽  
C. Frampton ◽  
...  
Keyword(s):  
Natriuretic Peptide ◽  
Sodium Excretion ◽  
Urine Volume ◽  
Random Order ◽  
Normal Male ◽  
Metabolic Clearance ◽  
Physiological Effects ◽  
Brain Natriuretic Peptides ◽  
Normal Humans ◽  
Normal Men

Atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) are both circulating plasma hormones that are secreted by the heart and have similar physiological effects. We have shown previously that abrupt increases in plasma BNP in normal humans impair the clearance of ANP from plasma and result in additive physiological effects. Because large increases in plasma ANP are reported to have no effect on plasma BNP levels in patients with heart failure, we have studied ANP-BNP interactions in eight normal male subjects receiving background infusions of BNP (2 pmol.kg-1.min-1 for 5 h). Each subject also received a coinfusion of ANP ("active" day, 2 pmol.kg-1.min-1 for 2 h) or vehicle ("placebo" day) using a balanced random order, single-blind design. Metabolic clearance rate of ANP (mean 4.1 +/- 0.6 l/min) and disappearance rate from the plasma (t1/2 3.4 +/- 0.3 min) were similar to values measured previously in the absence of exogenous BNP. In contrast, steady-state plasma BNP levels were reversibly increased (mean BNP increment 10 pmol/l) during the administration of ANP (P = 0.038). Associated with these changes were significant (additive) physiological effects. Thus the addition of ANP increased plasma and urine guanosine 3',5'-cyclic monophosphate (P < 0.001 for both) and lowered systolic blood pressure (P = 0.049). When ANP was coinfused, significant differences were also observed in urine volume (P = 0.001) and sodium excretion (P = 0.043) between the infusion period (when urine volume and sodium excretion were enhanced) and postinfusion period (when values decreased). Taken together, our findings of similar interactions between ANP-BNP and BNP-ANP infusions occurring at pathophysiological concentrations of these two peptides, suggest that the interactions result from dissociation of prebound hormone, presumably from biological or clearance receptors.

Clearance receptors and endopeptidase: equal role in natriuretic peptide metabolism in heart failure

1997 ◽  
Vol 273 (5) ◽  
pp. H2372-H2379 ◽  
Author(s):  
Miriam Tessa Rademaker ◽  
Christopher John Charles ◽  
Teddy Kosoglou ◽  
Andrew A. Protter ◽  
Eric Arnold Espiner ◽  
...  
Keyword(s):  
Heart Failure ◽  
Natriuretic Peptide ◽  
Urine Volume ◽  
Peripheral Resistance ◽  
Plasma Aldosterone ◽  
Peptide Receptor ◽  
Therapeutic Value ◽  
Combined Administration ◽  
Peptide Metabolism ◽  
Dose Dependent

The effects of separate and combined endopeptidase inhibition (by SCH-32615) and natriuretic peptide receptor C blockade [by C-ANP-(4—23)] on the clearance and bioactivity of atrial (ANP) and brain (BNP) natriuretic peptides was investigated in eight sheep with heart failure. SCH-32615 and C-ANP-(4—23) administered separately induced significant and proportionate dose-dependent rises in plasma ANP, BNP, and guanosine 3′,5′-cyclic monophosphate (cGMP) levels. Associated with these changes were reductions in arterial pressure, left atrial pressure, and peripheral resistance and increases in cardiac output, urine volume, sodium excretion, and creatinine clearance. SCH-32615 induced greater diuresis and natriuresis than C-ANP-(4—23). Combined administration of SCH-32615 and C-ANP-(4—23) induced greater than additive rises in plasma ANP, BNP, and cGMP concentrations, with enhanced hemodynamic effects, diuresis, and natriuresis and reduced plasma aldosterone levels. In conclusion, we find that the enzymatic and receptor clearance pathways contribute equally to the metabolism of endogenous ANP and BNP in sheep with heart failure. Combined inhibition of both degradative pathways was associated with enhanced hormonal, hemodynamic, and renal effects and may have greater potential therapeutic value than either agent separately.

scholarly journals Haemodynamic, endocrine and renal actions of adrenomedullin 5 in an ovine model of heart failure

2012 ◽  
Vol 122 (9) ◽  
pp. 429-437 ◽  
Author(s):  
Miriam T. Rademaker ◽  
Christopher J. Charles ◽  
M. Gary Nicholls ◽  
A. Mark Richards
Keyword(s):  
Heart Failure ◽  
Natriuretic Peptide ◽  
Urine Volume ◽  
Peripheral Resistance ◽  
Plasma Renin ◽  
Left Ventricular ◽  
High Dose ◽  
Peptide Family ◽  
Post Infusion ◽  
Infusion Period

AM5 (adrenomedullin 5), a newly described member of the CGRP (calcitonin gene-related peptide) family, is reported to play a role in normal cardiovascular physiology. The effects of AM5 in HF (heart failure), however, have not been investigated. In the present study, we intravenously infused two incremental doses of AM5 (10 and 100 ng/min per kg of body weight each for 90 min) into eight sheep with pacing-induced HF. Compared with time-matched vehicle control infusions, AM5 produced progressive and dose-dependent increases in left ventricular dP/dt(max) [LD (low dose), +56 mmHg/s and HD (high dose), +152 mmHg/s] and cardiac output (+0.83 l/min and +1.81 l/min), together with decrements in calculated total peripheral resistance (−9.4 mmHg/min per litre and −14.7 mmHg/min per litre), mean arterial pressure (−2.8 mmHg and −8.4 mmHg) and LAP (left atrial pressure; −2.6 mmHg and −5.6 mmHg) (all P<0.001). HD AM5 significantly raised PRA (plasma renin activity) (3.5-fold increment, P<0.001), whereas plasma aldosterone levels were unchanged over the intra-infusion period and actually fell in the post-infusion period (70% decrement, P<0.01), resulting in a marked decrease in the aldosterone/PRA ratio (P<0.01). Despite falls in LAP, plasma atrial natriuretic peptide and B-type natriuretic peptide concentrations were maintained relative to controls. AM5 infusion also induced significant increases in urine volume (HD 2-fold increment, P<0.05) and urine sodium (2.7-fold increment, P<0.01), potassium (1.7-fold increment, P<0.05) and creatinine (1.4-fold increment, P<0.05) excretion and creatinine clearance (60% increment, P<0.05). In conclusion, AM5 has significant haemodynamic, endocrine and renal actions in experimental HF likely to be protective and compensatory in this setting. These results suggest that AM5 may have potential as a therapeutic agent in human HF.

Urine Electrolyte Response to 18-Hydroxy-11-Deoxycorticosterone in Normal Man

1977 ◽  
Vol 53 (5) ◽  
pp. 493-498 ◽  
Author(s):  
M. G. Nicholls ◽  
R. Fraser ◽  
G. Hay ◽  
P. Mason ◽  
B. Torsney
Keyword(s):  
Marked Effect ◽  
Plasma Concentrations ◽  
Urine Volume ◽  
Metabolic Clearance ◽  
Potassium Excretion ◽  
Metabolic Clearance Rate ◽  
Urine Ph ◽  
Urine Potassium ◽  
Normal Man ◽  
Plasma Half Life

1. To assess whether the adrenal corticosteroid 18-hydroxy-11-deoxycorticosterone [18-(OH)DOC] affects urine electrolyte excretion in normal man, seven male volunteers received 120 μg (353 nmol) intravenously in 1 h. This was compared with glucose (50 g/l; control) and aldosterone (80 μg, 222 nmol) infusions in the same subjects. 2. A definite though weak antinatriuretic response to 18-(OH)DOC was observed, whereas urine potassium excretion was not altered. Aldosterone increased urine potassium excretion and reduced sodium output. Urine pH was lowered by both corticosteroids, aldosterone in general having a more marked effect. Urine volume was not altered by 18-(OH)DOC. 3. Plasma concentrations of 18-(OH)DOC and aldosterone rose approximately tenfold during their respective infusions. Compared with that of aldosterone, the metabolic clearance rate of 18-(OH)DOC was slower and its plasma half-life was longer. 4. We have been able to demonstrate that 18-(OH)DOC has a definite, albeit weak antinatriuretic action in normal man, but whether or not this corticosteroid is capable of elevating the blood pressure in man remains to be shown.

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