Effects of atrial natriuretic peptide infusion and its metabolism in patients with chronic renal failure.

Synthetic alpha-human atrial natriuretic peptide (hANP) was infused continuously at a rate of 80 ng/kg/min for 20 min into normal volunteers and patients with chronic renal failure (CRF) receiving hemodialysis. Blood pressure (BP) decreased significantly both in normals and in patients with CRF. The magnitude and the duration of the decrease, however, were greater in patients with CRF. The plasma aldosterone concentration (PAC) decreased significantly in normals and only minimally in patients with CRF. The half time (T1/2) of plasma hANP in patients with CRF (M +/- SE: 4.5 +/- 0.5 min) was longer than that in normals (1.8 +/- 0.2 min). Moreover, the metabolic clearance rate in patients with CRF (64 +/- 7 ml/kg/min) was less than in normals (150 +/- 20 ml/kg/min). Thus, the T1/2 in plasma of hANP in patients with CRF was noticeably longer than in a normal control group. These findings suggest that hANP suppresses PAC regardless of electrocyte imbalances and/or volume change induced by kidney dysfunction and that the kidney may be important in degrading hANP.     

Effect of water immersion on levels of atrial natriuretic peptide in patients with chronic renal failure

An effect of a 2-hour water immersion on the blood serum ANP was investigated in 20 haemodialysed patients with chronic renal failure and in 15 healthy individuals. Water immersion produced an increase in volume in both healthy individuals and the patients of similar degree. Baseline ANP concentration (290.0 +/- 21.9 pg/mL) was significantly higher in the dialysed patients than that in healthy individuals (66.0 +/- 5.5 pg/mL). Water immersion decreased mean arterial pressure (previously significantly higher in the patients) in both healthy individuals and examined patients, significantly increased secretory renal function (significantly higher in healthy individuals than in the examined patients), and increased ANP (previously significantly higher in healthy subjects). A significant correlation between ANP level in blood serum and changes in volume was seen only in healthy individuals. The obtained results suggest a contribution of other than changed volume factors of ANP release regulation and other than ANP factors to pathomechanism of post-immersion drop of the arteria blood pressure and increased secretory renal function in both healthy individuals and patients with renal failure.     

Local action of endogenous renal tubular atrial natriuretic peptide

Up‐regulation of atrial natriuretic peptide (ANP) mRNA in the kidneys in several disorders has been demonstrated; however, evidence that ANP synthesized by the kidney exerts a local function has never been produced. Therefore, we investigated whether endogenous ANP could modulate high glucose‐stimulated TGF‐β1, collagen type I and nuclear factor‐κB (NF‐κB) in NRK‐52E cells using transfection of ANP and ANP small interfering RNA (siANP). NRK‐52E cells were grown with or without transfection with ANP plasmid; cells were also transfected with ANP siRNA or control siRNA. These cells were then stimulated with a high glucose concentration to modulate ANP, TGF‐β1, collagen type I, NF‐κB and IκB‐α, and the results showed that ANP, TGF‐β1, collagen type I and NF‐κB significantly increased in untransfected cells, and the transfection of ANP significantly attenuated high glucose‐activated TGF‐β1, collagen I and NF‐κB expression. ANP siRNA knocked‐down ANP but significantly increased TGF‐β1 and collagen I under normal glucose conditions; ANP siRNA decreased IκB‐α but strongly enhanced high glucose‐activated TGF‐β1, collagen type I and NF‐κB. In contrast, medium from ANP‐transfected cells attenuated high glucose‐activated TGF‐β1 and collagen type I expression in NRK‐52E cells transfected with siANP. In conclusion, our results demonstrated that siANP increased activation of TGF‐β1, collagen type I and NF‐κB in NRK‐52E cells under high glucose conditions, and medium from ANP‐transfected cells attenuated high glucose‐activated TGF‐β1 and collagen type I. This is the first study to demonstrate the auto/paracrine action of endogenous ANP in renal tubular cells on the attenuation of hyperglycemia‐activated TGF‐β1 and NF‐κB expression. J. Cell. Physiol. 219: 776–786, 2009. © 2009 Wiley‐Liss, Inc.     

The effect of atrial natriuretic peptide on acid-base balance in rats with chronic renal failure

We explored the effects of 12-hour infusion of atrial natriuretic peptide (alpha-rANP:rat, 1-28) on arterial acid-base balance, using 5/6 nephrectomized rats with chronic renal failure. Before the infusion, nephrectomized rats had a higher mean arterial blood pressure, greater urine volume, and lower creatinine clearance than the normal controls, but they did not show a significant difference in arterial hydrogen ion concentration (pH), plasma bicarbonate concentration (HCO3-), partial pressure of carbon dioxide (PCO2), plasma base excess (BE), or plasma ANP concentration. alpha-rANP infusion produced a continuous blood pressure reduction in both nephrectomized and control rats. Urine volume and urinary sodium and potassium excretion tended to increase at 2-hour infusion, but not at 12-hour infusion. In the controls alpha-rANP significantly increased pH from 7.47 to 7.50, and decreased PCO2 by 14%. In contrast, in nephrectomized rats alpha-rANP significantly decreased pH from 7.48 to 7.44, HCO3- by 13%, and BE from -0.07 to -3.22 meq/l. Rats with chronic renal failure had greater reduction in HCO3- than the controls (p less than 0.05). There was no difference in plasma ANP level between the two groups. Thus, it is indicated that the long-term infusion of alpha-rANP reduces pH in rats with chronic renal failure, thereby adversely affecting the acid-base balance.     

Atrial natriuretic peptide concentration and natriuretic hormone activity in plasma of patients with chronic renal failure

To elucidate further the possible role of atrial natriuretic peptide (ANP) and hypothetical natriuretic hormone (NH) in volume and BP regulation in chronic renal failure (CRF) we measured plasma ANP, digitalis-like substances (DLS) and Na+-K+-ATPase activity (using 86Rb influx into RBC) in 9 patients with CRF before and after hemodialysis. Volume expansion between consecutive dialyses led in all patients to the elevation of plasma ANP (83.4 +/- 14.2 pmol/l) reaching in some overhydrated subjects and/or patients with concomitant cardiac insufficiency concentration greater than 150 pmol/l. Reduced 86Rb influx into RBC before hemodialysis (37.7 +/- 4.9% of controls) was accompanied by higher DLS concentrations (201 +/- 32 pmol/l). Ultrafiltration during hemodialysis with ECFV reduction lowered both ANP and DLS concentrations to 28.1 +/- 9.4 pmol/l and to 151 +/- 23 pmol/l, respectively, and abolished partly the inhibition of Na+-K+-ATPase activity (64.9 +/- 7.6% of controls). These changes corresponded to the degree of ECFV alteration. Our results suggest that both natriuretic principles are activated during ECFV expansion in CRF, probably as a corrective mechanism, with a tendency to normalize when ECFV is reduced during hemodialysis.     

Rosiglitazone treatment restores renal responsiveness to atrial natriuretic peptide in rats with congestive heart failure

The thiazolidinedione (TZD) class of Peroxisome proliferator‐activated receptor gamma agonists has restricted clinical use for diabetes mellitus due to fluid retention and potential cardiovascular risks. These side effects are attributed in part to direct salt‐retaining effect of TZDs at the renal collecting duct. A recent study from our group revealed that prolonged rosiglitazone (RGZ) treatment caused no Na+/H₂O retention or up‐regulation of Na⁺ transport‐linked channels/transporters in experimental congestive heart failure (CHF) induced by surgical aorto‐caval fistula (ACF). The present study examines the effects of RGZ on renal and cardiac responses to atrial natriuretic peptide (ANP), Acetylcholine (Ach) and S‐Nitroso‐N‐acetylpenicillamine (SNAP‐NO donor). Furthermore, we assessed the impact of RGZ on gene expression related to the ANP signalling pathway in animals with ACF. Rats subjected to ACF (or sham) were treated with either RGZ (30 mg/kg/day) or vehicle for 4 weeks. Cardiac chambers pressures and volumes were assessed invasively via Miller catheter. Kidney excretory and renal hemodynamic in response to ANP, Ach and SNAP were examined. Renal clearance along with cyclic guanosine monophosphate (cGMP), gene expression of renal CHF‐related genes and ANP signalling in the kidney were determined. RGZ‐treated CHF rats exhibited significant improvement in the natriuretic responses to ANP infusion. This ‘sensitization’ to ANP was not associated with increases in neither urinary cGMP nor in vitro cGMP production. However, RGZ caused down‐regulation of several genes in the renal cortex (Ace, Nos3 and Npr1) and up‐regulation of ACE2, Agtrla, Mme and Cftr along down‐regulation of Avpr2, Npr1,2, Nos3 and Pde3 in the medulla. In conclusion, CHF+RGZ rats exhibited significant enhancement in the natriuretic responses to ANP infusion, which are known to be blunted in CHF. This ‘sensitization’ to ANP is independent of cGMP signalling, yet may involve post‐cGMP signalling target genes such as ACE2, CFTR and V2 receptor. The possibility that TZD treatment in uncomplicated CHF may be less detrimental than thought before deserves additional investigations.     

A possible role of atrial natriuretic peptide in ethanol-induced acute diuresis.

The acute effects of ethanol on plasma atrial natriuretic peptide levels were investigated in 4 clinically healthy males, aged 24-26 years, consumed either 750 ml of water as a control study, or the same beverage with 1 ml/kg alcohol added, which increased the plasma alcohol concentration to 99.12 +/- 15.10 mg/dl at 60 min. Plasma atrial natriuretic peptide levels were significantly higher in the alcohol study compared to the control study at each time point (10, 20, 30, 60, 120 min after drinking onset), and with a peak at 10 min. Atrial natriuretic peptide levels showed a positive significant correlation with plasma antidiuretic hormone in the control group, while no relationship was found between the two peptides in the alcohol study. Moreover, a significant correlation exists between plasma atrial natriuretic peptide levels and systolic arterial blood pressure, and heart rate, and between the variations in atrial natriuretic peptide values and the variations in plasma sodium, serum ethanol, and plasma osmolality in the alcohol study. Acute ethanol intake causes an increase in urinary volume, and a decrease in urinary potassium excretion and urinary osmolality, and no change in urinary sodium excretion. These data suggest that acute ethanol administration causes a rapid increase in plasma levels of atrial natriuretic peptide, which could be an important factor of ethanol-induced diuresis. The main mechanisms for increased atrial natriuretic peptide release from atria after acute ethanol ingestion seem to be atrial stretch, due to the increase in arterial blood pressure, in heart rate, in sympathetic tone, and in plasma osmolality, and to a direct secretory effect by antidiuretic hormone.     

Evaluation of atrial natriuretic peptide and brain natriuretic peptide in atrial granules of rats with experimental congestive heart failure.

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/microm2 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/microm2 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/microm2 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.     

Cardiac secretion of atrial natriuretic factor with exercise in chronic congestive heart failure patients.

We have previously reported a fivefold increase of plasma atrial natriuretic factor (ANF) in patients with congestive heart failure (CHF) compared with normal subjects. However, given the marked increase of ANF under basal conditions, the extent to which ANF secretion can further increase under physiological stress is not been clarified in CHF. We therefore evaluated ANF secretion during ergometric exercise in 11 patients with CHF, with peripheral venous ANF samples obtained at rest and peak exercise. In seven patients, simultaneous peripheral venous and right ventricular ANF samples were obtained to estimate myocardial ANF secretion. Hemodynamic characteristics of exercise included a significant increase of heart rate, mean arterial pressure, and cardiac output (all P < 0.01); reduction of systemic vascular resistance (P < 0.001); and increase of right atrial and pulmonary wedge pressures (P < 0.001). ANF was abnormally elevated at baseline (108 +/- 58 fmol/ml) yet increased further to 183 +/- 86 fmol/ml with exercise (P < 0.003). A step-up of right ventricular ANF, particularly during exercise, was consistent with active myocardial secretion, despite elevated baseline ANF levels.     

Age differences in renal response to atrial natriuretic peptide in rabbits

Plasma levels of atrial natriuretic peptide (ANP) and the effect of exogenous ANP on renal function have been studied in newborn and adult rabbits. In order to investigate an age difference in responsiveness to ANP, we studied the renal effects of alpha-human ANP (1-28) administered at the same dose per kg body weight in adult and neonatal rabbits. Plasma basal ANP levels were similar in 18 newborn (4- to 11-day-old) compared to 7 adult rabbits (150 +/- 16 and 151 +/- 28 pg/ml, resp.). Eleven newborn and 11 adult rabbits were anesthetized and mechanically ventilated. After a control period, each animal received an hANP loading dose (3 micrograms/kg i.v.), followed by an infusion of 0.3 micrograms/kg/min. Blood gases remained stable throughout the experiment in both groups. Mean blood pressure decreased in newborn (28.5 +/- 0.8 to 26.2 +/- 1.0 mmHg) and adult (92 +/- 3 to 84 +/- 3 mmHg) animals. Percent hANP-induced changes in renal functions in newborn and adult rabbits were, respectively: urine flow rate: -21 +/- 4% and +57 +/- 8%; urinary sodium excretion: +4 +/- 7% and +81 +/- 11%; glomerular filtration rate (GFR): -19 +/- 4% and -4 +/- 6%; renal blood flow (RBF): -22 +/- 4% and -11 +/- 5%. As expected, diuresis and natriuresis increased in adult rabbits. Failure of hANP to increase natriuresis and diuresis in newborn rabbits could be related to the marked decrease in GFR, receptor immaturity and/or interactions with other hormonal systems.     

Attenuated diuretic and natriuretic effects of atrial natriuretic peptide in rats with heart failure

Plasma levels of atrial natriuretic peptide (ANP) and renal responses to ANP were examined in rats with chronic cardiac failure produced by coronary artery ligation and in sham-operated controls. Plasma ANP levels were elevated in the rats with severe cardiac failure as compared with the controls (P less than 0.001). ANP injections at the doses of 1, 5, 25 and 50 micrograms/kg increased water and sodium excretion significantly at all but the lowest dose in the controls; only the two largest doses caused clear diuresis and natriuresis in the heart failure group. The diuretic and natriuretic effects of ANP were significantly weaker at the doses of 5 and 25 micrograms/kg in the rats with heart failure as compared with the controls. We conclude, that natriuretic and diuretic effects of ANP are attenuated in this chronic heart failure mode.     

Plasma atrial natriuretic peptide in patients with Graves' disease

In order to clarify the effect of thyroid hormone on the plasma atrial natriuretic peptide (ANP) concentration, 14 patients with Graves' disease and 6 normal control subjects were studied. They were all under constant sodium intake because dietary sodium is known to affect the amount of plasma ANP. Sodium intake remained constant at 171 mEq daily for five consecutive days at which time the ANP concentration was measured. Graves' disease patients were tested both before and after surgery. The preoperative, hyperthyroid ANP level concentration in Graves' disease patients was 6.7 +/- 2.3 fmol/ml compared to a significantly lower level of 4.2 +/- 1.4 fmol/in normal control subjects. Seven days after surgery when Graves' disease patients became euthyroid their ANP markedly decreased to 4.2 +/- 2.9 fmol/ml. In the present study we were able to confirm that under a constant sodium diet, high plasma ANP in patients with Graves' disease was reduced after surgery when they became euthyroid. Results also suggest that high circulating ANP might play an important role in sodium and water metabolism and hemodynamic changes in hyperthyroidism.     

Plasma atrial natriuretic peptide in conscious rats with reduced renal mass

The effect of salt intake and reduction of renal mass (RRM) on plasma immunoreactive atrial natriuretic peptide (iANP) levels in conscious rats was studied. Rats were divided into RRM and sham-operated groups, and then further subdivided into groups infused with 1 or 6 mEq of sodium per day. Plasma urea nitrogen increased in the groups with RRM. Plasma sodium, sodium balance, and heart rate did not differ between the sham and RRM groups. Rats with RRM maintained on 1 mEq of sodium per day did not have an elevation of water intake, arterial pressure, or plasma iANP. Rats with RRM maintained on 6 mEq of sodium per day had significantly (P less than 0.05) elevated water intake, arterial pressure, and plasma iANP. Arterial pressure and plasma iANP were correlated (r = 0.800) for rats with RRM on either 1 or 6 mEq of sodium per day. Increased plasma iANP in the RRM group on 6 mEq per day was not caused by either RRM or high sodium alone; it was an effect of RRM plus high salt intake. The increase in plasma iANP in the RRM group may be caused by the increase in arterial pressure, possibly due to an increase in extracellular fluid volume. ANP may not be responsible for the sustained increase in fractional sodium excretion observed in RRM.     

Body fluid volume status and the renal response to atrial natriuretic peptide in rats.

The effect of altering the volumes of different body fluid compartments on the renal response to atrial natriuretic peptide (ANP) was studied in anesthetized rats before and during administration of the peptide at 170 ng/min. Four different groups were used. In the first (De), reduction of total body water content was induced by 48 h water deprivation. In the second (De+NaCl), an acute intravenous infusion after the same 48 h dehydration was used to restore the extracellular, but not the intracellular, fluid compartment. In the third (Eu+NaCl), euvolemic rats were infused with isotonic saline at the same rate as in group De+NaCl to expand both intravascular and interstitial components of extracellular fluid. In the fourth group (Eu+BSA) an infusion of hyperoncotic (6%) bovine serum albumin in isotonic saline was used to expand the intravascular volume while contracting the interstitial volume. Excretion of water and salt was predictably reduced in the De group compared with the others. This reduction was associated with increased tubular reabsorption, both upstream from the medullary collecting duct and in the duct itself. Administration of ANP did not significantly affect diuresis and saluresis, or tubular transport. By contrast, there were marked and similar diuretic and natriuretic responses to ANP in groups De+NaCl and Eu+NaCl, associated with transport inhibition primarily in the medullary collecting duct. Surprisingly, the rats infused with hyperoncotic solution (Eu+NaCl) also failed to show marked excretory or duct transport responses to ANP. According to the study design, the two nonresponding groups had, respectively, a decreased or a normal intracellular compartment, and a decreased or increased plasma volume. The common feature of both nonresponding groups was a decreased interstitial fluid compartment, whereas the two responding groups had normal or increased interstitial volume. We suggest, therefore, that a replete interstitial fluid compartment is essential for the renal response to ANP.     

Plasma levels of adrenomedullin and atrial natriuretic peptide in patients with congestive heart failure of various etiologies

OBJECTIVE: The aim of this study was to evaluate the plasma levels of the adrenomedullin (ADM) and atrial natriuretic peptide (ANP) in adult and pediatric patients with congestive heart failure (CHF) of various etiologies and to investigate their relations with haemodynamic variables e.g. echocardiographic left ventricular ejection fraction (LVEF) and fractional shortening (FS). SUBJECTS AND METHODS: The study was made in 38 adult and 21 pediatric patients with CHF of various etiologies and compared with 15 adult and 10 pediatric normal healthy controls. Patients with CHF were classified according to the New York Heart Association (NYHA) functional classification into grades II to IV in adult patients and into grade IV in all pediatric patients. ADM and ANP plasma levels were determined prior to the treatment with enzyme immunoassay. RESULTS: A statistically significant difference in the plasma levels of ADM and ANP were found between pediatrics and adult patients and corresponding healthy controls. Their levels were progressively increased with severity of NYHA class in adult patients. We found a significant positive correlation between plasma levels of each of ADM and ANP and pulse rate, systolic and diastolic blood pressure; and a significant negative correlation between their plasma levels and echocardiographic LVEF and FS. A significant positive correlation between plasma levels of ADM and ANP in both pediatrics and adult patients were also found. CONCLUSION: Plasma levels of ADM and ANP increased in adult and pediatric patients with CHF irrespective of the cause. They were positively correlated with each other and negatively correlated with LVEF and FS. These findings might have important clinical implications in that a noninvasive blood test may be used to identify high-risk subjects for HF for more invasive procedures.     

Atrial natriuretic hormone secretion in patients with renal failure

To study the effects of volume overload and renal failure on plasma levels of immunoreactive atrial natriuretic hormone (IR-ANH), we measured levels of this hormone in normal subjects, in patients with advanced chronic renal failure (CRF) with and without clinically evident volume overload, and in patients with end-stage renal disease (ESRD) treated with chronic hemodialysis. The levels were 13 +/- 2 pmol/l in normal volunteers, 77 +/- 24 pmol/l in patients with CRF without volume overload, and 219 +/- 50 pmol/l in patients with CRF and clinically evident volume overload (analysis of variance, p less than 0.001, alpha = 0.05 compared to normals). In patients with ESRD, the levels of IR-ANH were 145 +/- 46 pmol/l before dialysis and decreased to 87 +/- 31 after dialysis (p less than 0.025). No correlation was found between the decrease in IR-ANH levels and the decrease in weight during dialysis. A significant positive correlation was found between the IR-ANH levels and blood urea nitrogen in patients with CRF (r = 0.658, p less than 0.01). Volume overload appears to be the most important stimulatory factor for ANH secretion in renal failure patients but other mechanisms, especially a decrease in metabolic clearance, may also contribute to elevated plasma levels. The increased secretion of ANH in patients with renal failure may be an important adaptive response to volume overload and hypertension.     

A study of the mechanisms of proteinuria in nephritis and chronic renal failure

This study was carried out on 50 patients suffering from renal disorders; 30 nephritis patients and 20 chronic renal failure patients. Twenty-four healthy persons were used as a control group. In order to cast some light on the degree of the impaired glomerular permeability with respect to the blood proteins, selectivity of proteinuria was assessed by means of the clearance of albumin, ceruloplasmin, transferrin, and haptoglobin. Disturbances in the metabolism of these proteins were observed and discussed in light of the proteinuria selectivity index. The demonstration of the selective proteinuria in the presence of haptoglobin was concluded to be indicative of the degree of impaired glomerular permeability in nephritis and chronic renal failure.     

Erythropoietin therapy in patients with chronic renal failure.

Symptomatic anemia is a common complication of chronic renal failure. Treatment is now possible with the availability of recombinant human erythropoietin (epoetin alfa). Previous experimental studies have suggested that correcting the anemia of chronic renal failure may be harmful in that renal failure may be accelerated. Although experience with this drug has been primarily restricted to its use in patients with end-stage renal disease, several recent trials have been reported in patients with varying degrees of chronic renal failure. We review these studies with particular reference to the progression of renal failure and the drug''s reported side effects. We conclude that the use of epoetin is beneficial and well tolerated and that there is no compelling evidence for the acceleration of renal failure associated with its use in patients.     

Tumor markers in patients with chronic renal failure.

In order to evaluate the specificity of tumor markers in chronic renal failure, we have determined serum levels of carcinoembryonic antigen (CEA), carbohydrate antigen 19.9 (CA 19.9), carbohydrate antigen 50 (CA 50), alphafetoprotein (AFP), neuron-specific enolase (NSE), prostatic acid phosphatase (PAP), prostatic specific antigen (PSA), squamous cell carcinoma antigen (SCC), carbohydrate antigen 15.3 (CA 15.3) and carbohydrate antigen 125 (CA 125) in 30 patients with chronic renal failure and in 36 hemodialyzed patients without clinical evidence of neoplasia. CEA, CA 50, NSE and SCC frequently show increased serum levels, suggesting a renal metabolism, while others remain, generally, within the normal levels.