Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0018801 (heart failure)
72,216 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Atrial natriuretic peptide (ANP) binds to natriuretic peptide receptor-A (NPR-A), a membrane guanylyl cyclase, and to natriuretic peptide receptor-C (NPR-C), which plays a role in peptide clearance. Rat ANP (rANP) mutants that bind rat NPR-A selectively over rat NPR-C were isolated from randomized libraries of rANP-display phage by differential panning. One variant was identified with reduced NPR-C binding; rANP (G16R, A17E, Q18A) [rANP(REA18)]. Synthetic rANP(REA18) was equipotent with rANP in stimulating cGMP production from cloned rat NPR-A (ED50 = 1.8 nM) and was reduced in NPR-C binding by approximately 200-fold. When infused into conscious rats at 0.325 microg/min for 30 min rANP elicited an identical decrease in blood pressure compared with 0.25 microg/min of rANP(REA18), however the natriuretic (P < 0.05) and diuretic (P = 0.07) responses to rANP(REA18) were greater. These data are consistent with a role for NPR-C as a local decoy receptor attenuating NPR-A effects in the kidney, where these receptors are coexpressed. Improved NPR-A specificity could provide more effective natriuretic peptides for treatment of acute renal failure or heart failure.
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PMID:Novel analog of atrial natriuretic peptide selective for receptor-A produces increased diuresis and natriuresis in rats. 877 Aug 69

Brain natriuretic peptide (BNP) plasma levels increase in patients with myocardial infarction and may reflect the degree of left ventricular dysfunction. The changes in plasma level of BNP during exercise in the recovery phase and the clinical significance were investigated in 60 patients (55 men and 5 women; mean age 62.3 +/- 9.8 years) with initial acute infarction. Cardiopulmonary exercise testing was performed with a treadmill using the ramp protocol in 60 patients in the first month and 46 in the third month after the onset of the disease. Blood samples for measuring BNP and atrial natriuretic peptide (ANP) were obtained in the resting control state and immediately after peak exercise. Plasma BNP in the first month had a significant negative correlation with anaerobic threshold (AT) and peak oxygen uptake (peak VO2), and the serial change in plasma BNP from the first to third month had a significant negative correlation with the serial change of AT (peak: r = -0.35, p < 0.05) and peak VO2 (rest: r = -0.35, p < 0.05; peak: r = -0.45, p < 0.01). The serial change of plasma ANP had no relationships with the serial change of AT or peak VO2. Because the serial change ratio of plasma BNP reflects the serial change of exercise tolerance in the recovery phase of myocardial infarction, we conclude that the serial measurement of plasma BNP level is a useful non-invasive parameter for predicting latent heart failure in patients with myocardial infarction.
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PMID:[Changes in plasma level of brain natriuretic peptide during exercise in recovery phase of myocardial infarction and the clinical significance]. 886 84

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.
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PMID:Neutral endopeptidase inhibition: augmented atrial and brain natriuretic peptide, haemodynamic and natriuretic responses in ovine heart failure. 886 10

Synthetic human brain natriuretic peptide (sBNP) is a polypeptide with the same amino acid sequence as the naturally occurring hormone. Preclinical studies have demonstrated that BNP has potent hemodynamic, diuretic, and natriuretic effects that might be beneficial in treating patients with heart failure. This study was a randomized, double-blind, placebo-controlled, ascending-dose trial of sBNP administered as a single intravenous bolus in 27 heart failure patients. Six groups of patients received sequentially increasing doses of sBNP (0.3, 1, 3, 10, 15, and 20 micrograms/kg, respectively) as a single intravenous injection, and hemodynamics were assessed by pulmonary artery monitoring catheter. The 10 and 15 micrograms/kg doses of sBNP resulted in significant reductions in pulmonary capillary wedge pressure (-73%, p < 0.001), mean pulmonary artery pressure (-41%, p < 0.001), mean arterial blood pressure (-28%, p = 0.001), and systemic vascular resistance (-53%, p = 0.004). Significant increases occurred in cardiac index (68%, p < 0.001) and stroke volume index (72%, p < 0.001). The magnitude and duration of hemodynamic changes were dose dependent. There were no adverse effects. sBNP injected as a single intravenous bolus in heart failure patients improves hemodynamics in a dose-related fashion. Further clinical investigations to determine the use of sBNP in decompensated heart failure are clearly warranted.
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PMID:Hemodynamic effects of a single intravenous injection of synthetic human brain natriuretic peptide in patients with heart failure secondary to ischemic or idiopathic dilated cardiomyopathy. 888 62

Numerous hormonal and neuroendocrine changes have been described in patients with chronic cardiac failure. These affect the balance of vasodilator and vasoconstrictor factors in favour of the latter, to the detriment of the circulation. Whether this is a reaction to central cardiac (haemodynamic) abnormalities, or is an integral part of the syndrome of heart failure, remains to be determined. Catecholamine levels are increased, especially in severe heart failure, and contribute to the vasoconstriction and probably also to lethal ventricular arrhythmias. The renin-angiotensin-aldosterone system (RAAS) is also activated, causing fluid retention and further vasoconstriction. In the earlier stages, some of this increase may be iatrogenic due to the use of loop diuretics or inhibitors of angiotensin converting enzyme, but there is evidence for independent RAAS activation in more severe grades of heart failure. The role of vasoconstrictor peptides such as neuropeptide Y and endothelin is briefly considered. Counterbalancing these are vasodilator peptides, in particular atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP). The possibility of therapeutic interventions to increase circulating natriuretic hormone levels is discussed.
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PMID:Neuroendocrine changes in chronic cardiac failure. 889 39

To examine tissue and plasma atrial (ANP) and brain natriuretic peptide (BNP) responses to left ventricular hypertrophy (LVH) 7 sheep underwent suprarenal aortic banding (20 mmHg initial pressure differential). Median survival time was 15 days. Proximal mean aortic pressure (MAP) increased from 65.1 +/- 5.0 mmHg (baseline) to 111.6 +/- 7.5 mmHg (day 7, p < 0.0001). Distal systolic aortic pressure fell from 85.5 +/- 8.7 mmHg (baseline) to 55.6 +/- 6.4 mmHg (day 7, p = 0.0002). Maximal plasma ANP (26.9 +/- 3.6 vs 10.1 +/- 1.2 pmol/L, p = 0.005) and BNP (15.3 +/- 3.6 vs. 3.5 +/- 1.0 pmol/L, p = 0.006) were recorded at 15 +/- 4.0 days. Coarctation induced rapid increases in PRA and plasma aldosterone and a fall in urinary sodium. Post-mortem examination of hearts confirmed LVH. Compared with controls, tissue ANP concentration was reduced in left atrium (p = 0.04) and LV (p = 0.04). BNP concentration was reduced in left atrium (p = 0.02) but tended to be higher in LV. In conclusion, suprarenal aortic coarctation leads to progressive hypertension resulting in LVH, progressive increases in plasma ANP and BNP and, in most cases, death from heart failure.
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PMID:Natriuretic peptides in sheep with pressure overload left ventricular hypertrophy. 892 45

Atrial natriuretic peptide (ANP) and Brain natriuretic peptide (BNP) are cardiac hormones with similar actions and potency in humans yet with distinctly different effects on plasma cyclic guanosine monophosphate (cGMP). Because most biological actions of natriuretic peptides are thought to be mediated by the guanylate cyclase (G-C) receptors via cGMP, we have compared the biological and G-C-stimulating effects of equimolar infusions of ANP and BNP (2 pmol/kg.min), or vehicle control, on renal, hormonal and hemodynamic function in 8 normal subjects. In addition, the modulating effects of ANP and BNP on the biological actions of infused angiotension II (AngII) were studied. During ANP infusions, plasma ANP concentration increased from 8.8 +/- 0.7 pmol/L to 34 +/- 3 pmol/L at 120 min. Similar increments in plasma BNP occurred during BNP infusions (7.3 +/- 0.6 pmol/L preinfusion, 37 +/- 1 pmol/L at 120 min). Increase in plasma cGMP during ANP infusions was 4-fold that observed during BNP infusions yet natriuresis, contraction in plasma volume, and inhibition of plasma aldosterone were comparable. By contrast, ANP (but not BNP) significantly inhibited the plasma aldosterone response to AngII (P < 0.001). The pressor response to AngII was unaltered by ANP or BNP. Thus, at plasma ANP/BNP levels observed in mild heart failure, ANP is more potent than BNP in inhibiting the aldosterone response to AngII. Comparable natriuresis and inhibition of basal aldosterone is seen, despite much less stimulation of plasma cGMP by BNP, suggesting a different mechanism of hormone action-possibly via non-G-C receptor pathways.
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PMID:Differing biological effects of equimolar atrial and brain natriuretic peptide infusions in normal man. 892 31

The influence of neutral endopeptidase (NEP) inhibition with (S)-thiorphan on the hormonal, renal, and blood-pressure-lowering effects of an infusion of atrial (ANP), brain (BNP), and C-type natriuretic peptide (CNP) was evaluated in hypertensive transgenic rats (TGR) harboring an additional mouse renin gene (TGR(m(Ren2)27)). These TGR possess an activated natriuretic peptide system as compared with Sprague-Dawley rats (SDR), used in this study as control. (S)-Thiorphan significantly decreased blood pressure in anesthetized TGR but not in anesthetized SDR during the 60-min infusion period. Exogenously administered ANP decreased blood pressure in SDR with no significant effects in TGR after 60 min. In contrast, BNP infusion significantly decreased blood pressure in TGR, while changes in SDR were not significant. The blood pressure was further decreased after combined infusion of ANP and BNP with (S)-thiorphan in TGR. No effect on blood pressure was registered during infusion of CNP in either experimental group. The plasma levels of ANP, BNP, and cGMP were higher in TGR than in SDR, whereas plasma renin activity was lower. Co-administration of ANP, BNP, or CNP with the NEP inhibitor (S)-thiorphan potentiated the plasma ANP, BNP, and cGMP. Infusion of ANP alone did not affect BNP plasma levels of TGR and vice versa. In contrast, CNP infusion increased ANP plasma levels in both TGR and SDR. Renal excretion of sodium and cGMP increased after infusion of (S)-thiorphan and ANP or BNP in both TGR and SDR. The combination of ANP and (S)-thiorphan had a slightly greater effect on urinary excretion of sodium and cGMP in TGR than either compound alone, but the effects were more pronounced in SDR than in TGR. Finally, infusion of CNP alone and in combination with (S)-thiorphan influenced the excretion of sodium and cyclic GMP only slightly. These results indicate that inhibition of neutral endopeptidase by (S)-thiorphan potentiates the hemodynamic and renal effects of natriuretic peptides ANP and BNP, and to some extent those of CNP, in hypertensive TGR and normotensive SDR. In contrast to ANP and BNP, infusion of CNP had no effect on the blood pressure in anesthetized TGR or SDR. Inhibition of NEP therefore seems to be a promising way to potentiate endogenous levels of natriuretic peptides, which may be of therapeutic benefit in cardiovascular diseases such as hypertension or heart failure.
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PMID:Neutral endopeptidase inhibition potentiates the effects of natriuretic peptides in renin transgenic rats. 898 53

We investigated the expression of the yeast Kex2 family endoproteases furin and PACE4, and brain natriuretic peptide (BNP) in the atrium and ventricle after infarction as well as the conversion of the BNP precursor gammaBNP to BNP-45. In a rat heart failure model, plasma BNP rose in two phases--first at day 3, and again at day 14. BNP mRNA, as measured by Northern blot analysis, increased strongly at day 3, then at days 14 and 28 less strongly in the atrium, and in the ventricle it increased weakly at day 3, then strongly at days 14 and 28. Furin mRNA showed the same pattern of expression as that of BNP message, whereas PACE4 message stayed unchanged after the infarction. Both furin and BNP were immunostained in the myocardium adjacent to the infarcted tissue. We suggest that after myocardial infarction, furin is co-expressed with BNP in both the atrium and ventricle, and that furin may be responsible for the conversion of gammaBNP to BNP-45.
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PMID:Co-elevation of brain natriuretic peptide and proprotein-processing endoprotease furin after myocardial infarction in rats. 900 93

To evaluate the functional relationship between cardiac natriuretic peptides and endothelin-1 within the human kidney, we studied the effects exerted by infusion of brain natriuretic peptide on urinary endothelin-1 excretion. We studied twice in a single-blind manner five normal volunteers who received a constant infusion of 5% dextrose (250 mL/h) or human brain natriuretic peptide-32 at a dose of 4 pmol/kg per minute. Blood samples were drawn at intervals for measurement of hematocrit and concentrations of creatinine, electrolytes, brain natriuretic peptide, and endothelin-1. Urine was collected an intervals for measurement of flow rate and concentrations of creatinine, sodium, cGMP, and endothelin-1. Blood pressure and heart rate were measured every 15 minutes. Placebo administration did not change blood pressure, heart rate, or any of the other parameters measured in plasma and urine. As expected, brain natriuretic peptide infusion caused significant increases in its own plasma levels (basal versus peak levels [mean +/- SD], 1.45 +/- 0.20 versus 50.5 +/- 6.0 pmol/L, P < .01), in urinary cGMP (0.75 +/- 0.16 versus 1.92 +/- 0.81 fmol/min, P < .05), and in urinary sodium excretion (140.0 +/- 38.7 versus 624.2 +/- 181.6 mumol/min, P < .01). In addition, it caused an increase in urinary endothelin-1 excretion (4.32 +/- 2.11 versus 19.67 +/- 9.52 fmol/min, P < .05), without modifying plasma endothelin-1, blood pressure, heart rate, creatinine clearance, and urinary flow rate. Our data indicate that brain natriuretic peptide, at plasma levels comparable to those observed in patients with heart failure, causes a significant increase in urinary but not plasma endothelin-1, thus demonstrating a functional link between cardiac natriuretic peptides and renal release of endothelin-1.
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PMID:Urinary endothelin-1 excretion is enhanced by low-dose infusion of brain natriuretic peptide in normal humans. 903 83


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