Plasma Immunoreactive Atrial Natriuretic Factor Research Articles

Atrial natriuretic factor and brain natriuretic peptide gene expression in the spontaneous hypertensive rat during postnatal development

The increase in natriuretic peptides (NP), atrial natriuretic factor (ANF), and brain natriuretic peptide (BNP) production and release by cardiocytes that occurs in hypertension has been considered to be a compensatory mechanism against ventricular overload. Studies on NP production in the spontaneously hypertensive rat (SHR), an experimental model of human hypertension, have produced controversial results and were carried out when hypertension was already established (> 17 weeks). At this time, age-related physiologic and molecular changes in cardiac muscle are difficult to separate from those related to hypertension, ie, increased ANF production and plasma levels. In addition, most of the studies used male rats because the rate of increase in arterial blood pressure—as well as the level to which it rises—is greater in males than in females. Studies of a similar nature using female SHR are not available. The aim of this work was to determine 1) whether ANF and BNP production and secretion increase with the development of hypertension in genetically hypertensive rats; 2) whether a sexual dimorphism in ANF and BNP production and secretion is present in the genetically hypertensive rat during the development of hypertension; and 3) whether the demand for ANF and BNP is the same from each chamber of the heart under these experimental conditions. Age-matched male and female SHR, Wistar-Kyoto (WKY), and Sprague Dawley (SD) rats at 2, 4, and 8 weeks of age were used. The normotensive SD were included to provide a wider basis for baseline findings, as WKY rats are not always a suitable control for SHR due to genetic variations. Natriuretic peptide plasma levels and tissue content were measured by radioimmunoassay. ANF, BNP, as well as α- and β-myosin heavy chain (MHC) mRNA were estimated by Northern blot analysis. Blood pressure (BP) of more than 150 mm Hg was found only in 8-week-old male SHR. Plasma immunoreactive (ir)ANF and irBNP increased significantly at puberty (8 weeks) in both male and female SHR. The earliest molecular change encountered during the development of hypertension was a significant increase in BNP mRNA in the right and left atria from both male and female 8-week-old SHR. In the ventricles from both male and female SHR, there was no increase in the ratio of left ventricular wet weight/body weight, no increase in ventricular ANF mRNA transcripts, and no myosin heavy chain isoform switch (a protein marker of hypertrophy). irBNP ventricular concentration, however, increased significantly in both male and female SHR, but only in female SHR was there a concomitant increase in BNP mRNA. These results suggest that 1) ANF and BNP production are not coordinated in all cardiac compartments during the development of hypertension; 2) upregulation of BNP in the atria from male and female SHR is the earliest event detected at 8 weeks; 3) the prehypertensive stage, in the genetically hypertensive female rats, is associated with an increase in ventricular irBNP concentration and BNP mRNA; 4) there is a dissociation between BP and plasma levels of NP; and 5) as well, there is a dissociation between NP gene expression and MHC isoform switch. The regulation of NP is not coordinated in either gender during the development of hypertension. The activation of the BNP gene in female SHR suggests that BNP might play an important role at the onset of hypertension.

Atrial natriuretic factor (ANF) and ANF receptor C gene expression and localization in the respiratory system: effects induced by hypoxia and hemodynamic overload.

Atrial natriuretic factor (ANF) and ANF receptor C (ANF.RC) expression have been investigated in healthy and cardiomyopathic hamsters (CMPH) with widespread necrosis of the diaphragm and myocardium leading to respiratory and heart failure. ANF- and ANF.RC-producing cells were localized in different structures of the respiratory system, and the regulation of their expression by the individual and/or combined action of hypoxia and hemodynamic overload was analyzed. The study was performed in 20-, 90-, and 150-day-old animals using immunohistochemistry, in situ hybridization, Northern blot, and RIA analyses. ANF was shown to be expressed in the tracheo-bronchial epithelium and muscle and, to a lesser extent, in the alveolar wall and muscular media of the pulmonary arteries and extraparenchymal pulmonary veins in both healthy hamsters and CMPH. In 150-day-old CMPH, hypoxia (PaO2 < 50 mm Hg) induced a 10-fold increase in ANF messenger RNA accumulation and a 6-fold increase in the immunoreactive ANF (IR-ANF) concentration in lungs, as quantitated by RIA. As plasma IR-ANF concentrations were elevated in all CMPH age groups, it was most likely produced by the myocardium. ANF.RC messenger RNA was homogeneously distributed throughout the entire respiratory system and was increased 2-fold in hypoxic 150-day-old CMPH only. These results suggest that ANF originating in the respiratory system exerts only paracrine effects on different structures of the respiratory system in addition to the action of circulating ANF. Hemodynamic overload (left ventricular end-diastolic pressure, 17.20 +/- 3.80 mm Hg) might contribute to enhanced ANF gene expression only in extraparenchymal pulmonary vein walls of 150-day-old CMPH. We also propose that ANF.RC overexpression might be a protective mechanism operated via either ANF clearance or inhibition of adenylate cyclase activity to counteract exaggerated smooth muscle relaxation.

Renal effects of TAPP, a highly selective μ‐opioid agonist

1. The effect of i.v. administration of TAPP, a highly selective and exclusively peripherally-acting mu-opioid receptor agonist, on urine output, urinary sodium, potassium and cyclic GMP, and on plasma immunoreactive atrial natriuretic factor (IR-ANF) levels was studied in conscious normally hydrated female rats (200-250 g). 2. TAPP treatment produced a significant dose-dependent increase of urine output and urinary sodium, potassium and cyclic GMP excretion during the first hour. The highest TAPP dose used (2.5 mg kg-1. body weight) elicited a 10 fold elevation of urine output from 0.23 +/- 0.06 ml h-1 to 2.5 +/- 0.3 ml h-1 (n = 18) accompanied by augmented sodium [from 17.0 +/- 4.7 mu Eq h-1 to 79 +/- 12.7 mu Eq h-1, n = 18 (P < 0.001)], potassium [from 9.5 +/- 2.5 mu Eq h-1 to 39.4 +/- 6.6 mu Eq h-1, n = 18 (P < 0.005)], and cyclic GMP excretion [from 191 +/- 21 pmol h-1 to 1340 +/- 322 pmol h-1, n = 18 (P < 0.001)]. Plasma IR-ANF rose from 22 +/- 4 pg ml-1 to 508 +/- 22 pg ml-1 (n = 18) (P < 0.001) 5 min after administration of TAPP (2500 micrograms kg-1). 3. TAPP lowered systemic blood pressure, also in a dose-related manner, 1-5 min after injection. This decrease in blood pressure was transient and did not last more than 10 min. 4. Pretreatment with the opioid antagonist naloxone (0.8 mg per rat) abolished the diuretic, natriuretic and kaliuretic effect of TAPP (250 micrograms kg-1); urine output dropped from 1.16 +/- 0.15 ml h-1, n = 12, to the control value of 0.15 +/- 0.06 ml h-1, n = 12 (P < 0.001), sodium excretion fell from 57.5 +/- 11 mu Eq h-1, to 21.3 +/- 8.5 mu Eq h-1, n = 12 (P < 0.001), and potassium excretion decreased from 45.4 +/- 9.7 mu Eq h-1, n = 12, to 16.1 +/- 7.0 mu Eq h-1, (P < 0.001). 5. Pretreatment with anti-ANF serum (0.4 ml) abolished the diuretic effect of TAPP: urine output diminished significantly from 1.93 +/- 0.28 to 0.88 +/- 0.29 ml h-1 (P < 0.01) (n = 6). The TAPP-induced diuretic action, increased sodium/potassium excretion and elevated urinary cyclic GMP levels were also reversed by anti-ANF antibodies. 6. Since TAPP is totally unable to cross the blood-brain barrier, the ensemble of these observations led to the conclusion that the diuretic, natriuretic, kaliuretic and hypotensive effects produced by this mu-opioid agonist through interaction with peripheral mu-opioid receptors occur via ANF release.

Attenuation of renal effects of atrial natriuretic factor during rat pregnancy.

The influence of pregnancy on renal responses to atrial natriuretic factor (ANF) was determined in urethane-anesthetized Sprague-Dawley rats. Infusions of ANF caused a significantly greater increase in urinary excretion of fluid, sodium, and potassium in virgin than in pregnant (13-15 days and 21 days) rats. Guanosine 3',5'-cyclic monophosphate (cGMP) excretion, mean arterial pressure, plasma immunoreactive ANF, and glomerular filtration rate (GFR) following ANF infusions were not different in virgin and gravid rats, although increments in GFR over basal were greater in virgin than in gravid animals. Renal responses to ANF normalized during postpartum and were attenuated by progesterone treatment of virgin rats. Natriuretic effects of infusions of ANF plus ANF-(4-23) (a ligand for clearance receptors) or of ANF plus thiorphan (an endopeptidase inhibitor) in virgin and pregnant rats did not differ; ANF-(4--23) and thiorphan alone caused greater natriuresis in pregnant than in virgin rats. Effects of ANF on cGMP production by collecting duct cells isolated from virgin and pregnant rats did not differ. We concluded that the attenuation in the renal effects of ANF during pregnancy might be mediated by progesterone by an increase in the intrarenal metabolism of ANF and might reflect physiological adjustment to facilitate fluid/electrolyte expansion.

901-29 Effects of Positive EndExpiratory Pressure Ventilation on Right Atrial Size and Atrial Natriuretic Factor Release in Humans

Atrial natriuretic factor (ANF) release is augmented by atrial distention whereas positive end-expiratory pressure (PEEP) ventilation has the opposite effect. We tested the hypothesis that PEEP-induced decrease in ANF secretion is mediated by a decrease in right atrial (RA) distention. Accordingly, eight hemodynamically stable mechanically ventilated patients (age: 22-49) in sinus rythm and without kidney or cardiovascular disease were studied. A central venous catheter (3Fr) and a fluid-filled probe were inserted into the RA and esophagus, respectively, in order to measure transmural RA pressure (tP). A radial artery catheter was placed to monitor blood pressure (BP) and withdraw blood samples for the measurement of plasma immunoreactive ANF (irANF). Blood pressure, diuresis, tP, endsystolic RA area at the level of the foramen ovale (acquired using transesophageal echocardiography at end-expiration) and irANF were measured at the end of 3 consecutive 30 min periods of: (1) mechanical ventilation at zero end-expiratory pressure (ZEEP1); (2) application of PEEP + 15 cm of H 2 O; and (3) after withdrawal of the PEEP (ZEEP2). Variations of irANF and RA area were directly correlated (r = 0.82, P &lt; 0.001)). Results are expressed as mean ± SEM; *: p &lt; 0.05 versus ZEEP1 values. ZEEP 1 PEEP + 15 ZEEP 2 irANF(pg/ml) 14.9 ± 1.9 10.7 ± 1.1 * 13.8 ± 2 RA(cm 2 ) 14.4 ± 1.1 11.2 ± 1.6 * 14.2 ± 1.2 tP(mmHg) 4.2 ± 0.6 1.2 ± 0.2 * 2.7 ± 0.5 BP(mmHg) 137.9 ± 4.4 114.6 ± 7.4 * 134.2 ± 4.0 Diuresis(ml/min) 1.08 ± 0.19 0.60 ± 0.16 * 1.02 ± 0.23 As expected, PEEP resulted in a decrease in both RA area and tP as well as ANF secretion. These data support the hypothesis that PEEP-induced decreases in circulating ANF are related to decreased RA distention, which may contribute to the antidiuresis noted in patients ventilated with positive end-expiratory pressure.

Myocardial expression of atrial natriuretic factor gene in early stages of hamster cardiomyopathy.

Ventricular cardiomyocytes represent the most important source of atrial natriuretic factor (ANF) in pathological conditions such as congestive heart failure (CHF). It has been suggested that in cardiomyopathic Syrian hamster ventricles the ANF gene can be reactivated during the hypertrophic stage occurring before heart failure. The present study was undertaken to investigate ANF gene expression during early stages of myocardial damage and its distribution throughout atrial and ventricular myocardium in UM-X7.1 cardiomyopathic Syrian hamsters (CMPH) before hypertrophy and cardiac failure occur. Atria, right and left ventricles, and interventricular septum of hearts of 20-23 days old (young) and 90-95 days old (adult) CMPH were studied. The absence of hypertrophy and cardiac failure was preliminarly ascertained by microscopic and hemodynamic evaluation. ANF-mRNA as well as tissue and plasma immunoreactive ANF were assayed. Moreover, ANF secretion pattern was evaluated by immunocytochemical techniques. Young and adult CMPH hearts were in the necrotic stage of myocardial disease, as demonstrated by histopathological evaluation and by decreased wet weights (mg/g body weight) of different heart regions. Hemodynamic assessment showed no significant changes of left ventricular end-diastolic pressure (LVEDP) and a decrease of the left ventricular peak systolic pressure (LVSP) and +dP/dt. Plasma immunoreactive ANF (IR-ANF) levels were higher in young (3-fold) and adult (6-fold) CMPH than in age-matched normal hamsters. A reduced IR-ANF concentration (per milligram protein) was observed in both young and adult cardiomyopathic atria in respect to healthy controls, whereas a higher IR-ANF concentration was present in ventricles. A 3-fold, 6-fold and 20-fold increase of IR-ANF concentration was found in right ventricular free-wall (RV), left ventricular free-wall (LV) and interventricular septum (IVS), respectively. Northern-blot analysis confirmed that IVS was the major site of ventricular ANF-mRNA transcription in both young and adult CMPH. ANF-mRNA was increased also in atria where a faster peptide secretion can be hypothesized to lower tissue IR-ANF concentration. ANF secretion in ventricular myocardium was achieved via constitutive pathway as demonstrated by immunocytochemistry. Different patterns of ANF gene reactivation occur in CMPH myocardium before intraventricular pressure increases and structural hypertrophic modifications are detectable. The extent of ANF gene reactivation in CMPH ventricles parallels the severity of necrotic damage. Moreover, ANF gene expression is heterogeneously distributed throughout the myocardium, suggesting that interventricular septum, the ontogenically youngest heart region, might preserve foetal characters which can be rapidly reactivated in pathological conditions.

Atrial natriuretic factor in experimental acute Chagas' disease.

The atrial myocyte of the mammalian heart produces atrial natriuretic factor (ANF) (de Bold et al. 1981), a polypeptide hormone that participates in the regulation of extracellular fluid volume and blood pressure (de Bold 1985). Changes in ANF synthesis and storage have been observed in a wide spectrum of myocardial pathologies (Morii et al. 1989; Tsunoda et al. 1986) and have been related to the development of congestive heart failure. The heart, particularly the atrial muscle, is the main target of Trypanosoma cruzi during the acute period of infection (Tafuri 1979). We have previously shown a drastic decrease in the number of specific atrial granules, the site of ANF storage, and in the natriuretic activity of atrial extracts in acute Chagas' disease in rats (Piazza et al. 1992). In the present work, we characterized changes in cardiac and plasma immunoreactive ANF levels in acute Chagas' infection together with parasitological, serological, electrocardiographic and histopathological changes. Wistar rats (28+3 days of age) were injected intraperitoneally with 6 x 105 trypomastigotes of the T. cruzi X-1 strain obtained from infected mice (Cano and Rubiolo 1985). A control group was inoculated with the same volume of blood from healthy mice. The acute phase of Chagas' disease was studied until 40 days postinfection (p.i.). The parasitaemia course was followed using the direct method of Hoff (1974) in blood drawn by cardiac puncture twice a week p.i. The serological response was evaluated using three standard methods, indirect haemagglutination (Rubiolo and Vottero-Cima 1979), indirect immunofluorescence (Camargo 1966)

Atrial natriuretic factor and renal sodium excretion during ventilation with PEEP in hypervolemic dogs.

Controlled mandatory ventilation with positive end-expiratory pressure (PEEP) reduces renal sodium excretion. To examine whether atrial natriuretic factor (ANF) is involved in the renal response to alterations in end-expiratory pressure in hypervolemic dogs, experiments were performed on anesthetized dogs with increased blood volume. Changing from PEEP to zero end-expiratory pressure (ZEEP) increased sodium excretion by 145 +/- 61 from 310 +/- 61 mumol/min and increased plasma immunoreactive (ir) ANF by 104 +/- 27 from 136 +/- 21 pg/ml. Changing from ZEEP to PEEP reduced sodium excretion by 136 +/- 36 mumol/min and reduced plasma irANF by 98 +/- 22 pg/ml. To examine a possible causal relationship, ANF (6 ng.min-1.kg body wt-1) was infused intravenously during PEEP to raise plasma irANF to the same level as during ZEEP. Sodium excretion increased by 80 +/- 36 from 290 +/- 78 mumol/min as plasma irANF increased by 96 +/- 28 from 148 +/- 28 pg/ml. We conclude that alterations in end-expiratory pressure lead to great changes in plasma irANF and sodium excretion in dogs with increased blood volume. Comparison of the effects of altering end-expiratory pressure and infusing ANF indicates that a substantial part of the changes in sodium excretion during variations in end-expiratory pressure can be attributed to changes in plasma irANF.

Engineering the Cardiovascular System

We have generated several lineages of transgenic mice that exhibit chronic elevations in the steady-state concentration of atrial natriuretic factor (ANF) in the peripheral circulation. ANF, a peptide hormone synthesized primarily by atrial cardiomyocytes, is a potent natriuretic and diuretic. ANF also reduces blood pressure transiently when acutely administered. To address the potential role of ANF in chronic cardiovascular regulation, we generated transgenic mice that express the ANF gene in the liver. The fusion genes comprised either the mouse transthyretin (TTR) or rat phosphoenolpyruvate carboxykinase (PEPCK) promoters fused to the mouse ANF structural gene and were designed to target to the liver constitutive and inducible expression of pre-pro-ANF, respectively. Transgenic animals harboring the TTR-ANF fusion gene expressed chimeric ANF transcripts exclusively in the liver. In contrast, mice harboring the PEPCK-ANF fusion gene did not express detectable amounts of ANF mRNA in liver even after induction (24-hour fasting). In the TTR-ANF mice, hepatic and plasma immunoreactive ANF concentrations were proportional to the concentration of hepatic ANF transcripts. Moreover, mean arterial blood pressure recorded in conscious transgenic mice was inversely proportional to hepatic ANF expression. These transgenic models demonstrate that chronically elevated ANF concentration can induce sustained hypotension.

Atrial dynamics, atrial natriuretic factor, tachycardia, and blood volume in anesthetized rabbits

The effects of tachycardia and a slow (1%/min) 20% reduction and elevation of blood volume (BV) on right atrial pressure (RAP), right atrial dimension (RAD), and plasma immunoreactive atrial natriuretic factor (IR-ANF) were examined in anesthetized rabbits. Plasma IR-ANF was significantly increased during pacing at 6 Hz in the presence of high BV but not at low BV. Mean RAP increased with expansion of BV, but this change was not associated with significant changes in IR-ANF. There were no statistically significant changes in systolic or diastolic RAD with alterations in BV or with tachycardia. Tachycardia had no effect on left atrial dimension. Diastolic right atrial wall stress (DRAS) and minute DRAS increased with a 20% increase in BV, but changes in BV did not affect systolic right atrial wall stress (SRAS) or minute SRAS. Tachycardia decreased DRAS at high BV and significantly increased SRAS and minute SRAS. The increases in SRAS and minute SRAS were greater during tachycardia at high BV, suggesting that an interaction between BV and tachycardia results in potentiation of SRAS and minute SRAS. The results suggest that systolic RAS is a significant factor in ANF release during tachycardia at high BV.

The effect of isoproterenol on right and left atrial dynamics and plasma atrial natriuretic factor in anesthetized rabbits

The effect of isoproterenol on mean right and left atrial pressures (RAP, LAP) and dimensions (RAD, LAD), and plasma immunoreactive atrial natriuretic factor (IR-ANF) was investigated in anesthetized rabbits. Infusion of isoproterenol (10 micrograms.kg-1.min-1 for 10 min) significantly increased plasma IR-ANF and heart rate. There were no significant changes in mean RAP or LAP following isoproterenol. Neither mean RAD, systolic RAD and diastolic RAD nor mean LAD, systolic LAD or diastolic LAD changed significantly. Systolic right and left atrial wall stress and diastolic right and left atrial wall stress did not change significantly during the infusion of isoproterenol. Since atrial dimensions did not increase, it is unlikely that the release of IR-ANF in response to isoproterenol is mediated by atrial stretch. These results suggest that the release of IR-ANF in response to this dose of isoproterenol is mediated by factors other than stretch or changes in atrial dynamics.

Release of atrial natriuretic factor during selective cardiac alpha- and beta-adrenergic stimulation, intracoronary Ca2+ infusion, and aortic constriction in pigs.

The effects of alpha- and beta-adrenergic stimulation on release of atrial natriuretic factor (ANF) were examined in seven anesthetized, open-chest pigs. The alpha-adrenergic agonist phenylephrine (28.0 micrograms/min) and the beta-adrenergic agonist isoproterenol (0.3 micrograms/min) were infused into the proximal part of the circumflex coronary artery to stimulate the left atrial adrenoceptors without concomitant changes in left and right atrial filling pressures (v wave). Isoproterenol reduced plasma immunoreactive ANF (irANF) by 15 +/- 7 pg/ml (20%) from 76 +/- 10 pg/ml despite a rise in left atrial systolic pressure (a wave). A comparable rise in left atrial systolic pressure, induced by intracoronary infusion of calcium chloride (8.0 mg/min), increased plasma irANF by 33 +/- 10 pg/ml (53%) from 62 +/- 7 pg/ml. Phenylephrine increased plasma irANF by 9 +/- 4 pg/ml (14%) from 66 +/- 10 pg/ml without altering right and left atrial pressures. A rise in left atrial filling pressure of 3.2 +/- 0.5 mm Hg, induced by constricting the ascending aorta, increased plasma irANF by 83 +/- 35 pg/ml (141%) from 59 +/- 11 pg/ml. This increase was nine times that during phenylephrine infusion. In conclusion, alpha-adrenergic stimulation increases and beta-adrenergic stimulation inhibits ANF release by a direct action on the atrial myocytes. The direct effects of alpha- and beta-adrenergic stimulation on ANF release in vivo are small compared with the effect of a moderate rise in atrial filling pressure.

Influence of dilated cardiomyopathy, myocarditis and cardiac transplantation on the relation between plasma atrial natriuretic factor and atrial pressures

To determine whether dilated cardiomyopathy, myocarditis or cardiac transplantation affect the relation between plasma immunoreactive atrial natriuretic factor (ANF) and cardiac filling pressures, right atrial plasma ANF concentration, pulmonary arterial wedge pressure and right atrial pressure were measured in patients with dilated cardiomyopathy (n = 48), dilated cardiomyopathy secondary to myocarditis (n = 20) and prior cardiac transplantation (n = 34). ANF level significantly correlated with both pulmonary arterial wedge and right atrial pressures in patients with dilated cardiomyopathy; however, the presence or absence of myocarditis did not significantly alter these relations (p = 0.88 and p = 0.33 for interaction terms, respectively). For the combined group the ANF-pulmonary arterial wedge pressure relation had a slope of 8.1 pg/ ml/mm Hg (95% confidence interval (CI), 5.4 to 10.8; p = 0.0001) and the ANF-right atrial pressure relation a slope of 13.6 pg/ml/mm Hg (CI, 8.5 to 18.7; p = 0.0001). Receiver operator curve analysis identified an optimal dividing point of ANF 150 pg/ml with 100% (CI, 72 to 100%) of patients with right atrial pressure ≥ 8 mm Hg having ANF ≥ 150 pg/ml, but only 56% (CI, 42 to 69%) with pressure < 8 mm Hg having ANF < 150 pg/ml. Unlike the patients with cardiomyopathy (with or without myocarditis), cardiac transplant recipients displayed no correlation between ANF level and either pulmonary arterial wedge pressure (p = 0.50) or right atrial pressure (p = 0.29) despite similarly elevated ANF concentrations (mean ± standard deviation, 168 (83) pg/ml in transplant patients versus 185 (114) pg/ml in cardiomyopathy patients). It is concluded that left and right intracardiac pressures are important determinants of circulating ANF level unaffected by inflammation in patients with cardiomyopathy. Factors other than filling pressures influence circulating ANF in a significant number of patients with cardiomyopathy and in all transplant recipients.

Chronic vs. acute hemodynamic effects of atrial natriuretic factor in conscious rats

The present study was designed to examine acute (2 h) and chronic (5 day) effects of pathophysiological elevations of plasma atrial natriuretic factor (ANF) in conscious normotensive rats. Acute infusion of ANF (100 ng.kg-1.min-1; n = 15) resulted in a decrease in mean arterial pressure (MAP) of 5 +/- 3 mmHg, which was associated with a 23 +/- 4% decrease in cardiac output (CO) and a 27 +/- 6% increase in total peripheral resistance (TPR). Hematocrit increased from 41.9 +/- 0.7 to 46.0 +/- 0.6%, which is suggestive of vascular volume contraction. Chronic infusion of ANF (n = 9) produced a significant fall in MAP from a control value of 114 +/- 2 to 100 +/- 3 and 99 +/- 2 mmHg on days 1 and 5, respectively. CO decreased significantly (27 +/- 2%) and TPR increased (21 +/- 5%) on day 1; neither variable was significantly different from control on day 5. Plasma immunoreactive ANF levels were significantly elevated during acute (791 +/- 76 pg/ml) and chronic (626 +/- 202 pg/ml) ANF infusion compared with control values of approximately 100 pg/ml. The results indicate that elevations in plasma ANF within the pathophysiological range can significantly alter systemic hemodynamics, initially mediated by a decrease in CO. Autoregulatory phenomena may counteract these hemodynamic effects, returning CO to control levels and reducing TPR when the elevations in plasma ANF are chronically sustained.

Acute and long-term changes in plasma levels of atrial natriuretic factor in patients with renal replacement therapy

In 14 patients on hemodialysis who received kidney grafts from living related donors, plasma levels of immunoreactive atrial natriuretic factor (Ir-ANF) were determined in a sequence covering the last hemodialysis treatment, the day of transplantation, and a follow-up period of 6-12 months. The geometric mean value before dialysis was 196 pg/ml, the range 32-634. Weight loss during dialysis was 1.5 +/- 1.1 kg (mean +/- SD), but only a nonsignificant reduction in Ir-ANF levels occurred. On the day of transplantation, plasma Ir-ANF levels increased from 143 pg/ml before to 391 post-transplantation (P = 0.02, n = 12), probably in response to deliberate volume expansion. Post-transplant Ir-ANF levels correlated significantly to diuresis during the first 24 h, which ranged from 3.7 to 17.81 (mean 6.6; r = 0.65, P = 0.02). On day 2, mean 24 h diuresis decreased to 3.3 +/- 1.41. Most patients had reached their true dry weight by day 5, but Ir-ANF levels remained high, the geometric mean being 180 pg/ml. During further follow-up and preserved graft function (GFR range 34-88 ml/min per 1.73 m2 body surface area), Ir-ANF levels declined to a geometric mean of 63 pg/ml by 2-6 months and to 36 at 12 months post-transplant. We conclude that plasma Ir-ANF levels are chronically elevated in patients with chronic renal failure but may be further stimulated by acute overhydration. Transplanted kidneys initially respond to the increased levels but adapt within a day. Even with good graft function, normalization of plasma Ir-ANF requires several weeks or months.

Dysregulation of Atrial Natriuretic Factor in Hypertension-Prone Man*

To evaluate the hypothesis of an atrial natriuretic factor (ANF) deficiency in hypertension-prone humans, we investigated plasma ANF and other variables in 116 white offspring of normotensive parents (ONorm) or essential hypertensive parents (OHyp). Ten ONorm and 10 OHyp, all men matched for age and body habitus, were studied after 4 days of low (70 mmol/day) and high (350 mmol/day) dietary sodium intake. After mild sodium restriction, plasma ANF did not differ between ONorm and OHyp (9.7 +/- 0.7 vs. 9.0 +/- 1.3 fmol/L). On high sodium intake, plasma ANF increased in ONorm, but not in OHyp (to 18.3 +/- 1.7 vs. 11.7 +/- 1.7 fmol/L; P less than 0.001). On the other hand, acute responses of plasma immunoreactive ANF (irANF) to saline loading or a norepinephrine-induced rise in blood pressure did not differ significantly between 8 ONorm and 8 OHyp. Fifty-one additional ONorm and 45 OHyp were evaluated during liberal sodium intake. Groups were further subdivided according to whether 24-h urinary sodium excretion was 91 mmol/m2 or less (modest salt intake) or more than 91 mmol/m2 (high salt intake). Twenty-four-hour urinary sodium was similar in the 26 ONorm and 21 OHyp on a modest salt intake (121 +/- 6 vs. 116 +/- 9 mmol) and in the 25 ONorm and the 24 OHyp on a high salt intake (226 +/- 10 vs. 221 +/- 9 mmol). However, compared with ONorm, plasma irANF in OHyp was slightly lower on modest sodium intake (7.7 +/- 0.7 vs. 5.3 +/- 0.7 fmol/L; P less than 0.05) and markedly reduced on high sodium intake (15.0 +/- 1.3 vs. 8.0 +/- 1.3 fmol/L; P less than 0.001). Moreover, the slope of the relationship between plasma irANF and 24-h urinary sodium was flatter in OHyp than in ONorm (z test = 2.4). We postulate a new endocrine syndrome characterized by a relative plasma ANF deficiency during high sodium intake in some hypertension-prone humans. This functional defect becomes apparent during chronic, rather than acute, stimulation of ANF release. It occurs as a familial disturbance and may potentially predispose to the development of hypertension.

The Atrial Natriuretic Factor Hormonal System in the Regulation of Sodium Excretion in Dogs With Experimental Heart Failure

In response to a meat meal containing 125 mEq of sodium, conscious dogs (n = 5) with an arteriovenous (AV) fistula and chronic compensated heart failure exhibited temporally related increases in postprandial plasma immunoreactive atrial natriuretic factor (iANF), right atrial pressure, and sodium excretion. In separate experiments, two weeks of dietary sodium restriction produced similar marked stimulation of renin and aldosterone both in normal dogs (n = 5), and in AV fistula dogs (n = 5) with chronic high circulating levels of ANF. Plasma iANF did not change (P greater than .05) in either group. These results suggest that the ANF system is involved in the postprandial regulation of sodium excretion in the AV fistula dogs with compensated heart failure. In the postabsorptive state, however, the activity of the renin-aldosterone axis is closely related to dietary sodium intake and appears to function independently of the ANF system for the prevention of sodium loss.

Hypotension in transgenic mice expressing atrial natriuretic factor fusion genes.

Chronic regulation of the cardiovascular system by atrial natriuretic factor was investigated by generating transgenic mice with elevated hormone levels in the systemic circulation. A fusion gene comprising the mouse transthyretin promoter and mouse atrial natriuretic factor structural sequences was designed so as to target hormone expression to the liver. Hepatic expression of atrial natriuretic factor was detectable as early as embryonic day 15 in transgenic animals. In adult transgenic mice, plasma immunoreactive atrial natriuretic factor concentration was elevated at least eightfold as compared with nontransgenic littermates. The mean arterial pressure of conscious transgenic mice was 75.5 +/- 0.9 mm Hg, significantly less than that of nontransgenic siblings (103.9 +/- 2.0 mm Hg). This difference in mean arterial pressure was not accompanied by significant changes in several other physiological parameters, including heart rate, plasma and urinary electrolytes, water intake, and urine volume. This study demonstrates that a chronic elevation of plasma atrial natriuretic factor decreases arterial blood pressure without inducing diuresis and natriuresis in transgenic mice and also illustrates the value of the transgenic approach for the study of the cardiovascular system.

Plasma Levels of Atrial Natriuretic Factor, Renin Activity, and Aldosterone in Patients with Chronic Obstructive Pulmonary Disease: Response to O2Removal and to Hyperoxia

To examine the interrelations between humoral systems involved in the circulatory and body fluid volume homeostasis of patients with chronic obstructive pulmonary disease (COPD), we measured plasma levels of renin activity (PRA), aldosterone (Aldo), and atrial natriuretic factor (ANF) in 14 patients with stable COPD who used continuous O2 therapy. Hemodynamics, blood gases, and plasma hormone levels were measured (1) while patients received supplemental O2; (2) after 30 min O2 discontinuation; and (3) after a 30-min period of 96% O2 breathing. Plasma immunoreactive ANF concentrations were 196 +/- 50 pg/ml during O2 breathing and were positively related to transmural pulmonary arterial wedge pressure (tPpaw, r = 0.90, p less than 0.001) and to PaCO2 (r = 0.57, p less than 0.02). Compared to normal subjects matched for age and sex, patients had higher plasma ANF levels (196 +/- 52 versus 72 +/- 6 pg/ml, p less than 0.01), similar PRA (2.1 +/- 0.5 versus 1.3 +/- 0.3 ng/ml/h, NS), and slightly lower plasma Aldo (98 +/- 17 versus 156 +/- 19 pg/ml, p less than 0.05). Discontinuation of O2 while decreasing PaO2 from 70 +/- 3 to 50 +/- 3 mm Hg resulted in a significant increase in pulmonary arterial pressure (Ppa) from 29 +/- 2 to 32.5 +/- 3 mm Hg (p less than 0.01) and cardiac index (Cl) from 3.6 +/- 0.1 to 3.9 +/- 0.1 L/min/m2 (p less than 0.01) and a decrease in systemic arterial pressure (Psa) from 96 +/- 3 to 91 +/- 2 mm Hg (p less than 0.05); transmural cardiac filling pressures and pulmonary vascular resistance (PVR) were unchanged.(ABSTRACT TRUNCATED AT 250 WORDS)

Requirement for Solutions with Oncotic Pressure to Release ANF During Blood Volume Expansion in Conscious and Anesthetized Rats

We examined the effect of a 30% blood volume expansion with either blood, isotonic saline, or isotonic saline plus albumin on the release of immunoreactiveatrial natriuretic factor (IR-ANF) in conscious and barbiturate-anesthetized rats. Immediately prior to volume expansion, resting plasma IR-ANF levels were significantly ( p < 0.05) higher in the conscious animals (61 ± 5 pg mL , n = 19) compared to the anesthetized animals (41 ± 3 pg mL , n = 19) . Volume expansion with blood from donor rats significantly ( p < 0.05) elevated IR-ANF in both groups, but the increase in the conscious rats (+492 ± 32 pg mL , n = 6) was significantly ( p < 0.05) greater than that of the anesthetized rats (74 ± 25 pg mL , n = 6) . Similarly, volume expansion with isotonic saline containing 38 mg mL albumin significantly ( p < 0.05) elevated IR-ANF levels in both groups, but the increase in the conscious group (379 ± 102 pg mL , n = 7) was significantly ( p < 0.05) greater than that of the anesthetized group (94 ± 32 pg mL , n = 7) . These elevations in IR-ANF levels were not significantly different between either of the conscious groups or either of the anesthetized groups. Volume expansion with isotonic saline alone did not have any significant effect upon resting IR-ANF levels in either conscious (+8 ± 14 pg mL , n = 6) or anesthetized (−7 ± 6 pg mL , n = 6) animals. From these results, it would appear that a) isotonic saline alone does not stimulate IR-ANF release when used to expand blood volume, and b) barbiturate anesthesia significantly lowers resting plasma IR-ANF levels and attenuates the release of IR-ANF in response to volume expansion.