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.

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.

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.

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.

scholarly journals Adrenomedullin modulates the neurohumoral response to acute volume loading in normal conscious sheep

2002 ◽  
Vol 173 (1) ◽  
pp. 123-129 ◽  
Author(s):  
CJ Charles ◽  
MG Nicholls ◽  
MT Rademaker ◽  
AM Richards
Keyword(s):  
Natriuretic Peptide ◽  
Peripheral Resistance ◽  
Physiological Role ◽  
Plasma Renin ◽  
Cyclic Guanosine Monophosphate ◽  
Guanosine Monophosphate ◽  
Right Atrial ◽  
Volume Loading ◽  
Post Infusion ◽  
Conscious Sheep

The physiological role of adrenomedullin (ADM) in volume and pressure homeostasis remains unclear. Accordingly, we assessed possible modulatory actions of ADM infusions on the neurohumoral response to acute volume loading with dextran in normal conscious sheep. Dextran (15 ml/kg), given with concurrent ADM (5.5 pmol/kg per min--raising plasma ADM from below detection to approximately 10 pmol/l) or vehicle control infusions, induced matched significant (P<0.001 by ANOVA) falls in hematocrit (27-30%) during both ADM and control and similar increases in right atrial pressure (approximately 10 mmHg). Compared with control, both systemic (P=0.033) and pulmonary (P=0.005) arterial pressure and peripheral resistance (P=0.004) were reduced during ADM but were raised post-infusion. The dextran-induced increase in cardiac output was augmented by ADM (P=0.048). Dextran-induced increases in plasma atrial natriuretic peptide (ANP; P=0.008), brain natriuretic peptide (BNP; P=NS) and cyclic guanosine monophosphate (cGMP; P=0.003) were augmented post-ADM infusions. The dextran-induced fall in plasma renin activity (PRA) was attenuated by ADM (P=0.039) whereas plasma aldosterone levels were unaltered. ADM augmented the increase in urinary volume during the second 2-h clearance period post-dextran. Our data indicate that ADM modifies the hemodynamic and hormonal response to an acute volume challenge, enhances natriuretic peptide secretion and reduces systemic vascular resistance. These results provide further evidence that ADM plays a physiological role in volume and pressure homeostasis.

scholarly journals Natriuretic peptides in cardiovascular diseases

2008 ◽  
Vol 13 (2) ◽  
Author(s):  
Mariusz Piechota ◽  
Maciej Banach ◽  
Anna Jacoń ◽  
Jacek Rysz
Keyword(s):  
Heart Failure ◽  
Coronary Artery Disease ◽  
Coronary Artery ◽  
Cardiovascular Diseases ◽  
Natriuretic Peptide ◽  
Natriuretic Peptides ◽  
Ventricular Dysfunction ◽  
Left Ventricular ◽  
Peptide Family ◽  
Artery Disease

AbstractThe natriuretic peptide family comprises atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), C-type natriuretic peptide (CNP), dendroaspis natriuretic peptide (DNP), and urodilatin. The activities of natriuretic peptides and endothelins are strictly associated with each other. ANP and BNP inhibit endothelin-1 (ET-1) production. ET-1 stimulates natriuretic peptide synthesis. All natriuretic peptides are synthesized from polypeptide precursors. Changes in natriuretic peptides and endothelin release were observed in many cardiovascular diseases: e.g. chronic heart failure, left ventricular dysfunction and coronary artery disease.

Abstract 814: Atorvastatin Attenuates Oxidative Stress And Improves Neuronal Nitric Oxide Synthase In The Brain Stem Of Heart Failure Mice

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Joseph Francis ◽  
Li Yu ◽  
Anuradha Guggilam ◽  
Srinivas Sriramula ◽  
Irving H Zucker
Keyword(s):  
Oxidative Stress ◽  
Nitric Oxide ◽  
Myocardial Infarction ◽  
Heart Failure ◽  
Brain Stem ◽  
Mrna Expression ◽  
Natriuretic Peptide ◽  
Left Ventricular ◽  
Neuronal Nos ◽  
The Brain

3-Hydroxyl-3-methylglutaryl coenzyme A reductase inhibitors (statins) have been shown to reduce the incidence of myocardial infarction independent of their lipid-lowering effects. Nitric oxide (NO) in the central nervous system contributes to cardiovascular regulatory mechanisms. Imbalance between nitric oxide (NO) and superoxide anion (O 2 . − ) in the brain may contribute to enhanced sympathetic drive in heart failure (HF). This study was done to determine whether treatment with atorvastatin (ATS) ameliorates the imbalance between NO and O 2 . − production in the brain stem and contributes to improvement of left ventricular (LV) function. Methods and Results: Myocardial infarction (MI) was induced by ligation of the left coronary artery or sham surgery. Subsequently, mice were treated with ATS (10 μg/kg) (MI + ATS), or vehicle (MI + V). After 5 weeks, echocardiography revealed left ventricular dilatation in MI mice. Realtime RT-PCR indicated an increase in the mRNA expression of the LV hypertrophy markers, atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP). Neuronal NOS (nNOS) and endothelial NOS (eNOS) mRNA expression were significantly reduced, while that of NAD(P)H oxidase subunit (gp91phox) expression was elevated in the brain stem of MI mice. Compared with sham-operated mice, ATS-treated mice showed reduced cardiac dilatation, decreased ANP and BNP in the LV. ATS also reduced gp91phox expression and increased nNOS mRNA expression in the brain stem, while no changes in eNOS and iNOS were observed. Conclusion: These findings suggest that ATS reduces oxidative stress and increases neuronal NOS in the brain stem, and improves left ventricular function in heart failure.

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