Atrial Natriuretic Factor Concentrations Research Articles

Relationships between fluid and electrolyte hormones and plasma volume during exercise with training and detraining.

The purpose of this study was to investigate the relationship between training-induced alterations in plasma volume (PV) and changes in fluid and electrolyte regulatory hormones during prolonged exercise. Seven male subjects (VO2peak 49.2 +/- 2.4 mL.kg-1.min-1, X +/- SE) performed a cycling test before (C) and after (T) 6 d of training and after 6 d of detraining (DT). Training was conducted for 2 h.d-1 at 68% VO2peak at a room temperature between 26-28 degrees C. The 60-min exercise challenge included 20 min at 50%, 65%, and 75% VO2peak workloads. Training resulted in a calculated 13.8 +/- 1.6% PV expansion (P < 0.05) which recovered to C levels with DT (1.8 +/- 2.3%, P > 0.05). Compared with that at C, training resulted in a reduction of aldosterone (ALDO) concentration at all exercise intensities (P < 0.05) which normalized to C levels with DT. With T, epinephrine (EPI) concentrations were reduced at the highest power output only (365 +/- 51 vs 113 +/- 22 pg.mL-1; P < 0.05) and returned to C levels with DT. Arginine vasopressin (AVP) concentrations were also reduced at the highest workload only (20.2 +/- 3.2 pg.mL-1 vs 10.4 +/- 0.7 pg.mL-1; P < 0.05) and remained depressed after DT (11.8 +/- 1.3 pg.mL-1; P < 0.05). Atrial natriuretic factor (ANF) and norepinephrine (NOREPI) were not affected by T or DT. The results suggest that concentrations of ALDO, and to a lesser extent EPI, during exercise are related to PV levels, whereas ANF and NOREPI concentrations are not. AVP concentrations are related to other adaptive factors, the effects of which persist for a longer time course than do PV changes.

Altered regulation of natriuretic peptides in the rat heart by prenatal exposure to morphine.

1. Both endogenous and exogenous opioids modulate blood pressure and cardiac function by stimulating cardiac synthesis of atrial natriuretic factor (ANF) and brain natriuretic peptide (BNP). Since morphine crosses the placental barrier, it could alter the ANF-BNP system in the fetal heart. The aim of this study was to characterize cardiac natriuretic peptides in normal rat development and in rats prenatally exposed to morphine. 2. Female rats received either saline or morphine (10 or 20 mg kg-1 day-1) via osmotic minipumps during gestation. The effects of this treatment were investigated in offspring at 1, 4 and 22 days of age. 3. During maturation, atrial ANF and ANF mRNA increased by 3-fold from birth to 3 weeks of age, but BNP and BNP mRNA tended to decrease. In the ventricles, both ANF and BNP content decreased at 3 weeks after birth, from 25.11 +/- 3.6 to 0.81 +/- 0.1 ng (mg protein)-1 (P < 0.001), and from 3.36 +/- 0.33 to 0.19 +/- 0.01 ng (mg protein)-1 (P < 0.001), respectively. However, whereas ventricular ANF mRNA decreased, BNP mRNA levels did not change during maturation. Prenatal exposure to morphine significantly increased ANF content in the left atria of 22-day-old rats, and in the right atria of 1-, 4- and 22-day-old rats compared with age-matched saline controls. In contrast, prenatal exposure to 20 mg kg-1 day-1 morphine significantly inhibited BNP and BNP mRNA in the ventricles at all ages studied. 4. These observations suggest that alterations in mRNA synthesis or stability and/or post-translational processing of ANF and BNP occur in the heart during maturation, and that prenatal exposure to morphine alters cardiac production, and possibly release, of both peptides.

ANF system in the newborn piglet pulmonary vessels.

The atrial natriuretic factor (ANF) induces diuresis, natriuresis, and vasodilation. Although it was originally found to be secreted from the atria, ANF synthesis has been demonstrated in other organs. The adult lung is not only the first target organ for ANF, but it also expresses the ANF gene and synthesizes, releases, and clears ANF from the circulation. We have shown the presence of ANF in human fetal lungs and also demonstrated that these lungs can release bioactive ANF. However, the role of the ANF system in the newborn lung is unknown. Therefore we studied the ANF system in pulmonary vessels (arteries and veins dissected from the hilum down to a 100-microm diameter), in isolated perfused lungs, and in the plasma from pulmonary artery and vein of 1- and 7-day-old piglets. High-performance liquid chromatography (HPLC) revealed the presence of both the mature peptide and the ANF prohormone in pulmonary vein microsomes, but in pulmonary arteries, only the mature form was identified. Furthermore, in the veins, the ANF content tended to be higher in 7- than in 1-day-olds. ANF caused a dose-dependent decrease in perfusion pressure (p < 0.05). In veins and arteries, most of the ANF receptors were of the type A guanylate cyclase as opposed to clearance receptors. Interestingly, the ANF receptors were fewer in veins, where synthesis takes place, than in arteries (p < 0.05). Significant circulating ANF plasma levels were measured by radioimmunoassay in both pulmonary artery and vein. However, there was no site difference in ANF plasma levels, suggesting that ANF is cleared and synthesized in the pulmonary vessels. In conclusion, the entire ANF system is present in the newborn piglet pulmonary vessels. The paucity of clearance receptors compared with functional receptors potentiates the role of ANF in the regulation of postnatal pulmonary vascular resistance.

Effect of atrial natriuretic factor and fate of cyclic-guanosine-monophosphate in the rat kidney.

The mechanisms whereby atrial natriuretic factor (ANF) induces natriuresis are not clarified. Here, the effects of ANF and the cGMP analogue, 8-bromo-cGMP, on Na+, K(+)-ATPase activity in microdissected segments from rat medullary thick ascending limb of Henle (TAL) were evaluated. ANF-induced cGMP accumulation and the cellular handling of intracellularly produced cGMP were also investigated, by measuring the accumulation of extracellular cGMP in suspensions of tubules from outer medulla, enriched in TAL, and of isolated glomeruli. ANF dose-dependently inhibited Na+, K(+)-ATPase activity in isolated TAL in a parallel fashion with increasing cGMP accumulation in OM tubules. For both parameters, pharmacological concentrations (> or = 10(-6) M) of ANF were needed to induce a significant effect. 8-Bromo-cGMP mimicked the inhibitory effect of ANF. The increase in the intracellular cGMP level in response to ANF was dose-dependently reflected in the extracellular level. This finding contrasted with that in the glomerular preparation, where cGMP in response to ANF accumulated entirely intracellularly. Also in glomeruli, high (> or = 10(-6) M) concentrations of ANF were needed to induce a significant effect on cGMP accumulation. In conclusion, ANF inhibited Na+, K(+)-ATPase activity in TAL and the effect was mimicked by 8-bromo-cGMP. cGMP, produced in response to ANF, was extruded from the tubular epithelial cells, but not from glomeruli.

Atrial systolic pressure, as well as stretch, is a principal stimulus for release of ANF.

The mechanism for increased secretion of atrial natriuretic factor (ANF) during tachycardia and atrial fibrillation has remained unsettled. In seven open-chest pigs, the plasma concentration of ANF increased from 49.8 +/- 12.4 to 131.8 +/- 15.7 pg/ml when heart rate was increased from 133 +/- 13 to 212 +/- 4 beats/min by atrial pacing. Right atrial maximal diameter, recorded by ultrasonic technique at the maximal atrial filling, did not increase. During pacing tachycardia, the atrial contraction (a wave) occurs during atrial filling, and the a wave becomes superimposed on the v wave. In the present study the systolic atrial pressure (a wave) increased from 5.8 +/- 0.8 to 9.6 +/- 0.5 mmHg. The significance of this pressure rise was subsequently examined. After complete atrioventricular (AV) block, the AV delay was progressively increased, without altering heart rate, until the a wave was similar to the the a wave during the preceding tachycardia. Plasma ANF increased to 113.8 +/- 14.7 pg/ml, which showed that the increase in atrial pressure during atrial systole is a stimulus for ANF release. In the second part of the study, atrial fibrillation was induced in six open-chest pigs by rapid atrial pacing after complete AV block. Plasma ANF increased from 83.5 +/- 7.2 to 269.0 +/- 45.4 pg/ml during atrial fibrillation. No increase in atrial dimensions occurred during atrial fibrillation, but atrial pressure was substantially elevated. Thus, although passive atrial stretch stimulates ANF release during blood volume expansion, the present study shows that the increase in atrial pressure during atrial contraction is a stimulus for release of ANF during tachycardia and atrial fibrillation.

Measurement of pain intensity and statistical analysis to evaluate its relationship with atrial natriuretic factor and myocardial contractility in patients with uncomplicated acute myocardial infarction

Circulating levels of atrial natriuretic factor (ANF), the education of myocardial contractility (evaluated by ejection fraction, EF) and different pain intensity were assessed in patients with uncomplicated acute myocardial infarction (AMI). We investigated the relationships between ANF, or EF, and pain intensity by identifying appropriate statistical methods and introducing a procedure for pain intensity measurement. Pain in AMI is variable in intensity, often severe and in some instances intolerable, but in over 20% of AMI patients it may be absent. By using plasma ANF concentration and self-report of AMI pain as parameters, we described a statistical method verifying that AMI patients can be categorized into two significantly different groups: pain and no-pain. Pain is a purely personal experience that includes both the original pain sensation (OPS), depending on the intensity of the stimulus, and the individual emotional reaction component (ER). We developed a method to deduce the OPS from the patient's self-report of AMI pain and then devised an instrument which estimates the ER of each patient by applying electrical stimuli of different intensities. The procedure to disclose a significant correlation (not present by using the self-report of AMI pain) between OPS and ANF, or EF in pain patients is described. The inverse correlation found between EF and OPS suggests that the extent of myocardial damage may play a role in AMI pain onset and affect its intensity. However, when ANF concentration exceeds a threshold value, AMI patients reported only an unpleasant sensation; this result indicates that ANF may be involved in preventing AMI pain. The statistical method introduced for the comparison between the regression lines of ANF and EF in pain and no-pain patients showed that the interdependence between ANF and EF is not influenced by pain, confirming that EF is the major trigger for ANF release in AMI.

Effect of three hours of hypoxia on atrial natriuretic factor gene expression in the ovine fetal heart

OBJECTIVES: The current study investigated the effects of 3 hours of hypoxia on atrial natriuretic factor gene expression and peptide content in each of the four cardiac chambers of the near-term ovine fetus. STUDY DESIGN: Twenty-three chronically catheterized ovine fetuses at 125 to 129 days' gestation (term 145 days) were used for this study. Fetal hypoxia was induced for 3 hours in 12 fetuses by infusion of nitrogen into the maternal trachea. The remaining fetuses were used as controls. Fetal arterial Po2 and plasma atrial natriuretic factor concentrations were measured during hypoxia. At the end of the hypoxic period atrial natriuretic factor peptide contents and messenger ribonucleic acid levels in each cardiac chamber were determined by radioimmunoassay and Northern blot analysis, respectively. RESULTS: With infusion of nitrogen into the maternal trachea, fetal arterial Po2 was reduced within 30 minutes by an average of 8.0 ± 0.3 (SEM) mm Hg (p < 0.0001) and remained reduced at this level throughout the entire hypoxic period. Plasma atrial natriuretic factor concentrations increased by 1152 ± 212 pg/ml (p < 0.003) and the increase was sustained for the duration of hypoxia. Atrial natriuretic factor peptide and messenger ribonucleic acid levels were much higher in the atria than in the ventricles. Hypoxia did not result in alterations of atrial natriuretic factor peptide content or messenger ribonucleic acid abundance in each cardiac chamber. CONCLUSIONS: In the near-term ovine fetus, 3 hours of hypoxia resulted in greatly elevated plasma atrial natriuretic factor concentrations; this response was sustained for the duration of hypoxia. However, the increase was not associated with a detectable change in atrial natriuretic factor peptide content or an induction of atrial natriuretic factor gene expression in the atria and ventricles. (Am J Obstet Gynecol 1997;176:42-48.)

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.

Characterization of the atrial natriuretic factor system in lungs of the toad Bufo paracnemis.

Blood pressure in the amphibian pulmonary circulation is relatively high because a single ventricle serves both the systemic and pulmonary circulation, creating a high degree of plasma filtration from pulmonary capillaries. Previous studies have shown that lung atrial natriuretic factor (ANF) may have an important physiological function in preventing edema in mammals. In this study, we report the presence of the complete ANF system in the lungs of the toad Bufo paracnemis. Radioimmunoassay of tissue homogenates revealed that toad lung ANF concentration was approximately twice as high (928.5 +/- 83.0 pg mg-1 protein) as that of lung tissue in mammals of a similar size. The amount of ANF was significantly higher in the left than in the right atrium (15.0 +/- 1.2 versus 1.9 +/- 0.8 ng mg-1 protein; N = 4, P < 0.001), while the ventricle contained 488.3 +/- 41.8 pg mg-1 protein. In extracts of both lungs and atria, high-performance liquid chromatography revealed two forms of the peptide; prohormone and a carboxy-terminal peptide of low molecular mass, which is the biologically active form of peptide. The presence of the prohormone suggests that ANF is synthesized in toad lungs and atria. Characterization of toad lung receptors by a competitive binding assay demonstrated three different subtypes of ANF receptors: the guanylyl cyclase (GC) receptors, GC-A and GC-B, as well as clearance (C) receptors. We conclude that the toad Bufo paracnemis has a well-developed complete ANF system in the lung, suggesting that it has a role in toad lung physiology.

Enhanced natriuretic response to intrarenal infusion of atrial natriuretic factor during ovine pregnancy.

Volume-loading and intravenous infusion studies have suggested that the natriuretic response of atrial natriuretic factor (ANF) is blunted or unaltered during pregnancy, but these findings may be influenced by changes in peripheral metabolism or clearance. To better define the direct renal actions of ANF, three doses (0.3, 1.5, and 3.0 pmol.kg-1.min-1) of ANF were infused directly into the renal artery of nonpregnant (n = 7) and 115- to 135-day pregnant (n = 6) unilaterally nephrectomized conscious sheep. Each dose was administered on a separate day according to a protocol that consisted of two 20-min control periods, two 20-min ANF infusions, and three 30-min recovery periods. The levels of basal mean arterial pressure averaged 86 +/- 25 mmHg and were similar and constant throughout all protocols in nonpregnant and pregnant ewes. Glomerular filtration rate (GFR) and renal blood flow (RBF) were increased during pregnancy, but GFR, RBF, and fractional proximal tubular reabsorption were not significantly altered by infusion of ANF. Nonpregnant sheep exhibited a selective renal response that was limited to an increase in urinary sodium excretion (UNaV). Pregnant sheep exhibited a selective renal response that included increases in UNaV and urine flow rate produced by suppression of distal sodium and, presumably, fluid reabsorption. The natriuretic and diuretic response of pregnant sheep was much greater than that of nonpregnant sheep despite a smaller proportional increment in intrarenal ANF concentration. These data suggest that the ovine renal response to ANF is limited to actions on the distal tubule that are enhanced during pregnancy.

Atrial natriuretic factor secretion: a role for atrial systolic ejection force?

The increase in plasma concentration of atrial natriuretic factor in heart transplant patients has not been fully elucidated. Besides an eventual pressure or volume overload leading to passive atrial distension, the atrial tension developed during atrial systole, or atrial ejection force, which may be increased by the transplantation procedure, is an important determinant of atrial natriuretic factor release. We therefore determined the plasma concentration of atrial natriuretic factor and the maximal atrial ejection force in 15 heart transplant patients and 8 controls, matched for age and body mass. Atrial ejection force, as defined as the force exerted by the left atrium to accelerate blood into the left ventricle during atrial systole, was obtained using combined two-dimensional imaging and doppler echocardiography. Serum creatinin concentrations, heart rate [91.9 (SD 13.2) vs 71.8 (SD 10.9) beats.min-1], mean arterial blood pressure [103.9 (SD 9.8) vs 87.4 (SD 5.8) mmHg, 13.85 (SD 1.31) vs 11.65 (SD 0.77) kPa], left ventricular posterior wall thickness and interventricular septum thickness were higher in heart transplant patients compared to controls. Plasma concentration of atrial natriuretic factor was also elevated in heart transplant patients [63.9 (SD 18.1) vs 34.0 (SD 3.2) pg.ml-1; P < 0.001]. In contrast, although the left atrial area was greater in heart transplant patients [28.2 (SD 4.8) vs 15.8 (SD 2.5) cm2; P < 0.001], mitral area, transmitral Doppler A-wave maximal velocity and atrial ejection force were similar in transplant and in control patients [7.7 (SD 3.5) vs 8.9 (SD 2.8) kdyn, 77 (SD 35) vs 89 (SD 28)mN]. No significant correlation was observed between concentration of atrial natriuretic factor and atrial ejection force, either in heart transplant patients or in controls. Thus, the elevated plasma concentration of atrial natriuretic factor observed in these heart transplant patients was multifactorial in origin, and was considered to depend upon an hypersecretion rather than upon a decreased clearance rate. Moreover, it is suggested that the atrial ejection force was unlikely to have participated in this enhanced release of atrial natriuretic factor.

Acute enoximone effect on systemic and renal hemodynamics in patients with heart failure.

Patients with heart failure generally show improvement in their clinical condition after enoximone infusion over the period of treatment; this effect cannot be ascribed only to the known hemodynamic action of this drug. Thirty-six patients (age range 44-82 years) with heart failure (NYHA class II-IV) underwent 48-hour enoximone infusion to study whether this prolonged improvement might depend on changes in systemic or renal hemodynamics or in neurohormonal balance. All patients underwent Swan-Ganz hemodynamic monitoring; renal plasma flow, glomerular filtration rate, plasma atrial natriuretic factor (ANF), and plasma renin activity (PRA) were all measured at baseline, at the peak of the enoximone action, and 48 hours after drug discontinuation. The main hemodynamic parameters were significantly improved during enoximone infusion and after drug discontinuation. The cardiac index basal value of 2.2 +/- 0.1 l/min/m2 increased to 3.1 +/- 0.1 l/min/m2 after 24-hour therapy (p < 0.01); similarly, pulmonary wedge pressure, mean pulmonary arterial pressure, and right atrial pressure decreased markedly (p < 0.01). Beneficial effects were also observed in renal hemodynamics; indeed, renal plasma flow (basal value 485 +/- 39 ml/min) increased significantly after 24-hour enoximone infusion (575 +/- 35 ml/min; p < 0.01), and this tendency was also observed 48 hours after drug discontinuation. No significant modifications were observed in plasma hormone data; however, the PRA plasma level had a tendency to decrease. We conclude that in patients with heart failure, enoximone infusion has a less marked effect on renal hemodynamics, but this is more lasting than systemic hemodynamic effects. The tendency of PRA to decrease (although not statistically significant), still detectable 2 days after treatment in the presence of steady high plasma ANF concentrations, may also contribute to the paradoxical longlasting benefit despite the short-lived improvement in systemic hemodynamics after brief cycles of enoximone infusion.

Stretch-induced release of atrial natriuretic factor from the heart of rainbow trout (Oncorhynchus mykiss)

We investigated the effect of both cardiac filling and after-load pressures on the release of atrial natriuretic factor (ANF) from rainbow trout hearts (Oncorhynchus mykiss). Our experimental approach was to perfuse hearts in situ and collect perfusate ejected from the heart in 1-min fractions and assay for immunoreactive ANF-(99-126) (human and canine). Increases in cardiac filling pressure produced repeatable and sustained increases in cardiac output. At the same time, there was an immediate and sustained increase in ANF secretion. ANF secretion increased sixfold from the control level of 30.68 ± 4.76 pg∙min−1∙g−1wet heart mass for a fourfold increase in cardiac output from 15.24 ± 0.73 mL∙min−1∙kg−1body mass. ANF secretion was unaffected by increases in after-load pressure. Measurement of immunoreactive ANF content in trout myocardial tissues revealed ANF in both the atrium and ventricle, but 92% of the total ANF store was contained within the atrium. This suggests that in rainbow trout, the atrium serves as the primary cardiac tissue for ANF release. These data are consistent with the mechanism of ANF release for mammalian hearts, and provide additional evidence that ANF secretion in vertebrates is mediated by atrial stretch and not ventricular stretch.

Comparison of Candoxatril and Atrial Natriuretic Factor in Healthy Men

The purpose of these experiments was to compare the effects of endopeptidase inhibition with oral candoxatril on systemic and forearm hemodynamics and muscle sympathetic nerve activity with responses to a low-dose atrial natriuretic factor infusion. Eleven healthy men received at random on three separate days either intravenous saline, natriuretic factor (1.6 pmol/kg per minute) plus saline, or oral candoxatril (200 mg) plus saline. Measurements were made at baseline and 30, 60, and 90 minutes after interventions. Atrial natriuretic factor lowered diastolic pressure (P < .01), central venous pressure (P < .001), forearm blood flow (P < .05), and forearm vascular compliance (P < .05) but had no effect on systolic pressure, heart rate or its variability, stroke volume, sympathetic nerve activity, plasma norepinephrine, or endothelin-1. Plasma epinephrine increased (P < .01). Candoxatril lowered central venous pressure (P < .001) and increased systolic pressure (from 116 +/- 6 to 120 +/- 7 mm Hg; P < .05), endothelin (from 4.6 +/- 1.1 to 6.8 +/- 3.2 pmol/L; P < .02), and epinephrine (P < .05), without affecting any other variables. Candoxatril and atrial natriuretic factor lowered central venous pressure in healthy men without causing a reflex increase in sympathetic nerve activity or norepinephrine, yet epinephrine rose. This suggests that both interventions may specifically inhibit sympathetic nerve traffic to muscle at physiological plasma atrial natriuretic factor concentrations. However, whereas the peptide lowered blood pressure, candoxatril increased systolic pressure. These contrasting hemodynamic responses may be related to differences in plasma atrial natriuretic peptide concentration and to altered endothelin metabolism by candoxatril.

Effect of low dose beta blockers on atrial and ventricular (B type) natriuretic factor in heart failure: a double blind, randomised comparison of metoprolol and a third generation vasodilating beta blocker.

This study examines the acute effects of two differing beta adrenergic blocking agents (metoprolol and a third generation vasodilating beta blocker) on plasma concentrations of atrial natriuretic factor (ANF), brain (ventricular) natriuretic factor (BNF), and haemodynamic variables in patients with heart failure. University teaching hospital. 20 patients with impaired left ventricular systolic function [ejection fraction 32 (SEM 2.3)%] were randomised in a double blind manner to receive either oral metoprolol 6.25 mg twice daily or celiprolol 25 mg daily. Haemodynamic variables were evaluated by Swan-Ganz pulmonary artery catheter over 24 hours. ANF and BNF concentrations were measured at baseline, 5 h, and 24 h by radioimmunoassay. At baseline ANF and BNF concentrations were considerably raised compared to the normal range. Treatment with metoprolol caused ANF to rise further to 147% of the basal level at 5 h (P = 0.017) and 112% at 24 h (P = 0.029). This was associated with a small but non-significant rise in pulmonary capillary wedge pressure. Cardiac output and systemic vascular resistance were unchanged at 24 h. In contrast, after celiprolol ANF fell to 90% of basal levels at 5 h and to 74% of basal level at 24 h (P = 0.019), associated with a small but non-significant fall in pulmonary capillary wedge pressure [-3.3 (2.7) mm Hg] and systemic vascular resistance, and rise in cardiac output from 3.2 (0.2) to 4.0 (0.4) l/min (P = 0.04). BNF concentrations rose to 112% of baseline at 5 h (P = 0.09) after metoprolol but fell slightly, to 91% of baseline values, after celiprolol (NS). Metoprolol, even in very low doses (6.25 mg), produced a rise in ANF and BNF, although minimal haemodynamic changes were detected. In contrast, a vasodilating beta blocker was associated with a significant fall in ANF and BNF and a small rise in cardiac output. This study confirms both the advantages of vasodilating beta blockers over metoprolol for initial treatment of heart failure and the usefulness of ANF and BNF measurements for the assessment of drug effects in heart failure compared to traditional haemodynamic measurements.

The effects of atrial natriuretic factor and angiotensin II on fetal-placental perfusion pressure in the ex vivo cotyledon model

OBJECTIVE: Our purpose was to investigate pressure changes induced by angiotensin II on placental vasculature pretreated with atrial natriuretic factor. STUDY DESIGN: A dual-perfused cotyledon model was used. Two cytoledons from each placenta were perfused. One cotyledon was infused with atrial natriuretic factor for 30 minutes while the other received an equal volume of saline solution. Three atrial natriuretic factor concentrations were studied: 50 pg/ml, 150 pg/ml, and 15 ng/ml. Both cotyledons received injections of angiotensin II, at the following doses: 1 × 10 −11.5, 1 × 10 −11, 1 × 10 −10.5, and 1 × 10 −10 mol. RESULTS: Cotyledons subjected to 50 pg/ml and 150 pg/ml concentrations of atrial natriuretic factor did not differ in pressure responses to angiotensin II, compared with the saline-infused cotyledons ( p > 0.05). The 15 ng/ml concentration of atrial natriuretic factor, however, decreased the pressor response of angiotensin II ( p < 0.034). CONCLUSIONS: Atrial natriuretic factor decreases vasoconstriction caused by angiotensin II. However, this was seen only at a supraphysiologic concentration. No effect was noted at normal fetal concentrations of atrial natriuretic factor.

Regulation of atrial natriuretic factor secretion and expression in the ovine fetus

The cardiac hormone atrial natriuretic factor (ANF) is present in the fetal circulation at high concentrations and exceeds that in the maternal circulation. Administration of exogenous ANF into the near-term ovine fetus lowers arterial pressure and reduces blood volume. The fetal kidney responds to ANF with a diuresis and natriuresis. The physiological stimuli which modulate ANF secretion in the fetus include vascular volume expansion, hyperosmolality and hypoxia, with hypoxia being the most potent stimulus. In addition, endothelin administration into the fetus increases plasma ANF concentrations. The fetal atria appears to be the primary site of ANF synthesis, although the ventricles also produce ANF. The expression of ANF peptide and its messenger RNA in the fetal atria and ventricles demonstrate a developmental pattern. Thus, the secretion of ANF may be mediated by factors such as endothelin and may be augmented by stimuli such as hypoxia which acts through induction of cardiac ANF gene expression.

Effects of angiotensin II on plasma atrial natriuretic factor in nonpregnant and pregnant ewes.

The release of atrial natriuretic factor (ANF) is primarily determined by atrial stretch, but may also be modulated by circulating angiotensin II (AngII). During pregnancy, the circulating concentrations of both ANF and AngII are increased. To further define possible effects of AngII on ANF release, four doses of AngII (0.5, 5, 20, 40 ng.kg-1.min-1) were intravenously infused into five nonpregnant and five pregnant (105-140 days of gestation) ewes alone and during the simultaneous infusion of sodium nitroprusside at doses sufficient to abolish the pressor effects of AngII. Mean arterial pressure (MAP) was increased from 80 +/- 2 to a maximum of 121 +/- 5 mmHg (1 mmHg = 133.3 Pa) in nonpregnant ewes (p < 0.01) and from 79 +/- 2 to 116 +/- 4 mmHg in pregnant ewes (p < 0.01) over the range of AngII infusion. MAP was unaltered during AngII plus nitroprusside infusion, averaging 78 +/- 3 mmHg in nonpregnant ewes and 80 +/- 2 mmHg in pregnant ewes. Basal ANF was higher (p < 0.01) in pregnant sheep than in nonpregnant sheep. With AngII infusion alone, plasma ANF was increased from 13 +/- 2 to 42 +/- 4 fmol/microL in nonpregnant ewes (p < 0.01) and from 23 +/- 5 to 72 +/- 16 fmol/microL in pregnant ewes (p < 0.01). However, during AngII plus nitroprusside infusion, the increases in plasma ANF observed were completely abolished in both nonpregnant and pregnant ewes.(ABSTRACT TRUNCATED AT 250 WORDS)

Endocrine responses of fetal sheep to prolonged hypoxemia with and without acidemia: relation to urine production

Our aim was to examine the endocrine changes associated with alterations in fetal urine production during 24 h of hypoxemia induced by either reduced uterine blood flow (RUBF) or maternal N2 inhalation (N2). In contrast to RUBF, which caused a diuresis, N2 caused a transient antidiuresis; during both posthypoxemia periods (RUBF and N2), fetal urine production was increased. RUBF, but not N2, was associated with a transient acidemia. Fetal plasma arginine vasopressin (AVP) and atrial natriuretic factor (ANF) concentrations increased during RUBF and were inversely correlated to pH; there were no detectable AVP or ANF responses to N2. Fetal prostaglandin E2 (PGE2) increased during the hypoxemia and posthypoxemia periods induced by both methods, but RUBF caused the greater increase. AVP and PGE2 concentrations were positively correlated with urine production. Fetal arterial blood pressure increased during RUBF but not N2. During RUBF, the increases in AVP and PGE2 concentrations and/or fetal arterial blood pressure may have contributed to the diuresis. During N2, we suggest that low, but increased, levels of AVP may have caused the transient antidiuresis, whereas the diuresis observed during both posthypoxemia periods may have been mediated by elevated PGE2 concentrations and/or increased fetal arterial blood pressure.

Atrial wall tension changes and the release of atrial natriuretic factor on relief of cardiac tamponade

Cardiac tamponade causes elevation and equalization of cardiac filling pressures, sodium and water retention, and a paradoxically low plasma atrial natriuretic factor (ANF) concentration despite increased intraatrial pressures. Recent reports suggested that plasma ANF concentrations rise after relief of tamponade. The purposes of the present study were (1) to determine the time course and extent of ANF release on relief of cardiac tamponade; (2) to measure the atrial transmural wall pressures, atrial sizes, and atrial wall tension changes associated with relief of tamponade; and (3) to determine the biologic activity of elevated plasma ANF during and after relief of tamponade. We sampled blood for ANF and cyclic guanosine monophosphate (cGMP) immediately before and up to 24 hours after relief of cardiac tamponade in 10 patients. Atrial and pericardial pressures were measured immediately before and shortly after pericardiocentesis, and atrial dimensions were determined by two-dimensional echocardiography before and within 1 hour after the tap. Urine volumes were measured in 8-hour increments before and after the procedure. Relief of cardiac tamponade was associated with a prompt and massive increase in plasma ANF concentrations, reaching pharmacologically active levels. The rise in ANF was negatively correlated with atrial pressures but positively correlated with atrial transmural pressures, atrial size, and calculated wall tension. Plasma ANF levels peaked at 515 ± 95 pg/ml 40 minutes after relief of tamponade and leveled off at 140% to 180% of the pretap concentrations. Plasma cGMP exhibited a slightly delayed but similar time course to the rise in ANF levels, and urine flow rate increased fourfold in the 8 hours after relief of tamponade. We conclude that (1) the relief of cardiac tamponade stimulates the release of atrial natriuretic factor by increasing atrial transmural wall pressures, atrial size, and calculated wall tensions; (2) evidence for the biologic activity of the increased plasma ANF concentrations is provided by the temporal association of increased cGMP levels and increased urine flow rate; and (3) that the release of ANF is governed by changes in atrial transmural wall, pressures and calculated atrial wall tensions.