Plasma Atrial Natriuretic Factor Concentrations Research Articles

Humoral and Renal Response to Acute Volume Loading in Patients with Essential Hypertension

The effect of acute volume expansion (2 liters of saline solution in 2 h) on plasma concentrations of atrial natriuretic factor (ANF), plasma aldosterone concentration (PAC), plasma renin activity (PRA) and their relationship to the renal excretion of urine, sodium and potassium were studied in 6 control subjects and 7 patients with essential hypertension (EH) WHO stage I. Saline infusion provoked comparable rise in plasma ANF in both groups (from 2.98 +/- 0.45 to 12.36 +/- 1.74 pmol/l in the control subjects and from 3.80 +/- 0.72 to 15.78 +/- 2.06 pmol/l in EH patients), significant drop in PRA (from 0.915 +/- 0.419 to 0.256 +/- 0.127 nmol/l/h in controls and from 1.711 +/- 0.324 to 0.714 +/- 0.128 nmol/l/h in EH) and in PAC (from 0.30 +/- 0.07 to 0.14 +/- 0.03 nmol/l in control subjects and from 0.53 +/- 0.13 to 0.24 +/- 0.07 nmol/l in EH). The increase of plasma ANF concentrations after volume expansion might be involved in the suppression of PRA and PAC found after this stimulus. Similar increase in plasma ANF after saline infusion in both groups was associated with significantly greater urine and sodium excretion in EH than in controls. From these results it may be suggested that the acute volume expansion during saline infusion evokes a comparable release of ANF into circulation in both EH patients and controls. In EH patients, however, the similar rise in ANF is accompanied by a more pronounced diuretic and natriuretic response. This exaggerated natriuresis after acute volume and sodium loading cannot be explained solely by a rise in ANF.(ABSTRACT TRUNCATED AT 250 WORDS)

Reduced water and sodium intakes associated with high levels of natriuretic factor following common bile duct ligation in the rabbit

Renal failure complicating obstructive jaundice (OJ) is probably linked to reduction of the extracellular water compartment. To elucidate the mechanism by which OJ leads to isotonic water depletion we studied a group of rabbits with OJ after common bile duct ligation (n = 17) and another group of sham operated rabbits (n = 14) for 10 days. Water intake and balance for two study periods (1-4 and 7-10 days after operation) were calculated. Renal function, sodium balance and plasma atrial natriuretic factor were determined on the fourth and tenth days after operation. Water intake and balance were lower in the OJ group both in the first study period (230 versus 519 ml/days 1-4, P less than 0.001; and -2.4 versus 219 ml/days 1-4, P less than 0.0001 respectively) and in the second study period (260 versus 865 ml/days 7-10, P less than 0.0001; and 11 versus 379 ml/days 7-10, P less than 0.0001 respectively). Sodium intake was negligible in the OJ group both on day four (0.73 versus 7.15 mM/24 h, P less than 0.0001) and on day 10 (0.78 versus 15.78 mM/24 h, P less than 0.0001). As a result plasma osmolality did not change. Day 10 urine osmolality and osmolar clearance were reduced in the OJ group (653 versus 1103 mOsm/kg, P less than 0.0001 and 0.09 versus 0.25 ml/min, P less than 0.0001 respectively) together with a decreased creatinine clearance (3 versus 11 ml/min, P less than 0.0001). Atrial natriuretic factor was increased in jaundiced rabbits (day 4, 22.7 versus 7.5 fmol/ml, P less than 0.0001; and day 10, 26.5 versus 11.2 fmol/ml, P less than 0.02). These findings suggest that OJ leads to an isotonic volume depletion resulting from abnormalities of the extracellular volume regulating mechanisms. These appear to be secondary to an inappropriate elevation of the atrial natriuretic factor plasma concentration.

Discoordinate re-expression of cardiac fetal genes in N(omega)-nitro-L-arginine methyl ester (L-NAME) hypertension.

Hypertension produced by chronic inhibition of nitric oxide (NO) synthase by N(omega)-nitro-L-arginine methyl ester (L-NAME) was used to determine the effect of severe pressure overload with or without left ventricular (LV) hypertrophy on the transcriptional activation of the cardiac fetal genes encoding for the natriuretic peptides (NP) atrial natriuretic factor (ANF) and brain natriuretic peptide (BNP), and for beta-myosin heavy chain (MHC) in both atrial and ventricular muscle. A previously reported association of LV hypertrophy with the activation of cardiac renin and angiotensin-converting enzyme (ACE) in this hypertension model was also investigated. Male Sprague-Dawley rats received L-NAME (75 mg/kg/day) or were left untreated for 4 (n=12) or 8 (n=12) weeks. L-NAME-treated rats became severely hypertensive in both treatment groups but only five out of 12 8-week treatment animals showed a significantly increased LV weight to body weight (BW) ratio (LVW/BW). LV ANF mRNA, but not LV BNP mRNA, correlated significantly with LVW/BW only in animals showing LV hypertrophy. No changes were observed in atrial gene expression or plasma concentration of ANF or BNP. A significant correlation was found between LVW/BW and LV renin mRNA and LV ACE activity in rats with LV hypertrophy. LV beta-MHC mRNA levels were significantly increased in the LV of rats with or without LV hypertrophy at both 4 and 8 weeks of treatment. It is concluded that pressure overload per se does not promote NP or cardiac renin-angiotensin system gene expression while increased beta-MHC expression is a marker of LV pressure overload even in the absence of LV hypertrophy. It is apparent that L-NAME causes a disruption in the coordinated transcriptional activation of cardiac fetal genes expected of hypertrophic stimuli acting on the LV.

Central natriuretic peptides regulation of peripheral atrial natriuretic factor release

Atrial natriuretic factor (ANF) and C-type natriuretic peptide (CNP) receptors have been described in encephalic areas and nuclei related to the regulation of cardiovascular as well as sodium and water homeostasis. Stimulation of the anterior ventral third ventricular region of the brain modifies plasma ANF concentration, suggesting the participation of the central nervous system in the regulation of circulating ANF. The aim of this work was to study the effect of centrally applied ANF or CNP on plasma ANF. Normal and blood volume expanded rats (0.8 ml isotonic saline/100 g body weight) were intra cerebralventricularly injected with 1, 10 or 100 ng/μl/min ANF. Blood volume expanded animals were also centrally injected with the same doses of CNP. Blood samples were collected at 5 and 15 min. after intracerebralventricular administration of either ANF or CNP. Centrally applied ANF did not affect circulating ANF in normal blood volume rats. In blood volume expanded animals both ANF (1, 10 or 100 ng/μl/min) and CNP (1 ng/μl/min) decreased plasma ANF concentration after 15 min. Moreover, CNP (10 and 100 ng/μl/min) lowered circulating ANF levels not only at 15 min but also at 5 min. Neither ANF nor CNP elicited any change in mean arterial pressure and heart rate in normal and blood volume expanded rats. These results suggest the existence of a central regulation exerted by natriuretic peptides on circulating ANF levels. Furthermore, this is the first study reporting an effect on plasma ANF induced by centrally applied CNP.

Normal Responses of Atrial Natriuretic Factor and Renal Tubular Function to Sodium Loading in Hypertension-Prone Humans

Background: In order to explore the hypothesis of an atrial natriuretic factor (ANF) deficiency in prehypertension, we compared the response to sodium loading on ANF and renal function in subjects with positive and negative histories of hypertension. Methods: Twenty-two offspring of hypertensive parents (OH) and 20 offspring of normotensive parents (ON) were studied after 4 days of low (50 mmol/day) or high (300 mmol/day) dietary sodium intake. The diets were allocated randomly. Blood pressure (BP), renal function, plasma concentration of ANF, cyclic guanosine monophosphate (cGMP), renin, angiotensin I and II, aldosterone, endothelin and catecholamines were determined during a clearance period of 90 min on both diets. Neurohormones were measured by radioimmunoassays. Renal function was determined by simultaneous measurements of 51Cr-ethylenediaminetetraacetate (a marker of glomerular filtration rate), lithium and sodium clearances. Results: Supine systolic and diastolic BPs were significantly elevated in OH, with both low and high dietary sodium intake. There was no difference in ANF and cGMP concentrations on the low sodium diet. Increasing sodium intake caused a similar increase in ANF in OH and ON but cGMP did not change significantly. As expected the activity of the renin-angiotensin-aldosterone system was decreased by enhancing sodium intake but with both low and high sodium intake plasma renin concentration was significantly higher in OH than in ON. Activation of the sympathetic nervous system with low sodium intake was indicated by a moderate increase in plasma concentrations of epinephrine and norepinephrine in both groups. The renal effects were characterized by significant increases in GFR, lithium and sodium clearances with increasing sodium intake. There were no differences between OH and ON. Estimated values of fractional proximal and distal tubular sodium reabsorption decreased significantly and in a similar way in both OH and ON. Conclusion: These results indicate that the renal and neuroendocrine responses to dietary sodium loading are similar in both OH and ON. The only difference was a higher BP and an elevated plasma renin concentration on both dietary regimens in OH compared with ON. In particular, in OH and ON an identical increase in plasma ANF concentration in response to sodium loading was found. Thus, this study cannot support the hypothesis of a dysregulation of ANF in hypertension-prone humans.

Coadministration of albumin and furosemide in patients with the nephrotic syndrome

In patients with nephrotic syndrome, the natriuretic effect of furosemide (FU) is diminished. The effect of coadministration of FU and human albumin (HA) has remained controversial. In a double-blind, placebo-controlled study, nine nephrotic patients (six males, 48 +/- 4 years) on standardized sodium chloride intake, in random order on three separate days, received by intravenous administration for 60 minutes either (a) 60 mg FU plus a sham infusion, (b) 60 mg FU plus 200 ml of a 20% solution of HA, or (c) sham infusion plus 200 ml of a 20% solution of HA. Urinary volume, sodium, albumin and FU excretion, renal hemodynamics, and plasma atrial natriuretic factor concentration were assessed. Administration of FU alone significantly (P < 0.01) increased mean cumulative urinary sodium (259 +/- 30 mmol) and volume excretion (2684 +/- 167 ml) in the first eight hours as compared with the HA infusion alone (118 +/- 12 mmol, 1827 +/- 141 ml). The coadministration of FU and HA caused an even more marked increase (P < 0.01 vs. HA alone) of urinary sodium (312 +/- 28 mmol) and volume excretion (3230 +/- 201 ml); the difference to FU administration alone was significant (P < 0.05). Plasma atrial natriuretic factor, serum albumin concentration, and urinary albumin excretion increased significantly on both HA infusion days, whereas urinary excretion of FU remained unchanged with HA coadministration. Glomerular filtration rate (CIn) was not significantly affected by any of the infusion protocols, but effective renal plasma flow (CPAH) increased significantly on both HA infusion days. Coadministration of HA potentiates the action of FU in patients with the nephrotic syndrome, but only modestly. This effect is mediated by changes in renal hemodynamics.

Plasma atrial natriuretic factor levels in the inferior petrosal sinus blood of patients with Cushing's disease before and after corticotropin-releasing hormone administration.

Atrial natriuretic factor (ANF) was suggested to be involved as neurohormone in the modulation of hypothalamus-pituitary-adrenal axis in humans. However, this role is still controversial and widely discussed. In order to evaluate whether ANF is secreted in the hypothalamus-pituitary system in humans, plasma ANF concentrations were assayed in samples collected in the inferior petrosal sinus (IPS) blood of patients subjected to IPS sampling for diagnostic purposes or neurosurgical indications. In this retrospective study were included 22 patients: 10 with Cushing's disease (CD) and 12 patients with GH or PRL-secreting pituitary adenoma, used as control group. In the patients with CD, plasma ANF concentration was also assayed after CRH test (hCRH 100 micrograms as i.v. bolus with blood samples after 5, 10 and 15 min). Both in patients with CD and in patients with GH- or PRL-secreting pituitary adenoma, no significant difference was found in plasma ANF levels between IPS ipsilateral (13.0 +/- 1.5 and 12.2 +/- 1.2 pmol/l) or controlateral (13.0 +/- 1.6 and 12.2 +/- 1.4 pmol/l) to the adenoma and peripheral blood (14.2 +/- 2.0 and 13.7 +/- 1.5 pmol/l, respectively). Similarly, no difference was found between the IPS ipsilateral and controlateral to the adenoma in both groups of patients. In patients with CD, CRH administration induced a significant increase of ACTH levels (periphery: 34.9 +/- 6.2 vs 11.5 +/- 2.3 pmol/l, p < 0.05) but it did not induce any significant change of plasma ANF levels (14.0 +/- 2.0 vs 13.4 +/- 1.4 pmol/l in the ipsilateral IPS and 13.4 +/- 1.6 vs 13.4 +/- 1.5 pmol/l in the ipsilateral IPS and 13.4 +/- 1.6 vs 13.4 +/- 1.5 pmol/l in the contralateral IPS). In conclusion, the lack of ANF concentration gradient between IPS and peripheral blood, the lack of any difference in ANF concentrations between patients with CD and acromegalics or hyperprolactinemics and the absence of ANF response to CRH administration do not support the hypothesis of a role for ANF as neurohormone involved in the hypothalamus-pituitary control and particularly in the hypothalamus-pituitary-adrenal axis modulation in humans.

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.

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.)

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.

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.

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.

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.

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.

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.

The role of neutral endopeptidase in dogs with evolving congestive heart failure.

Recent studies suggest that neurohumoral mechanisms including decreased renal responses to increases in atrial natriuretic factor (ANF) play a central role in the progression from asymptomatic cardiac dysfunction to advanced congestive heart failure (CHF) with sodium retention, vasoconstriction, and reduced exercise tolerance. Recognizing that neutral endopeptidase 24.11 degrades ANF and may be enhanced in CHF, we hypothesized that chronic neutral endopeptidase inhibition (NEP-I) would potentiate renal responses to exogenous ANF and alter the temporal evolution of sodium retention in evolving CHF by potentiation of increased endogenous ANF. We studied 13 conscious dogs with evolving CHF produced by rapid ventricular pacing at 250 beats per minute. Six of these dogs received NEP-I with candoxatril, 10 mg/kg PO BID, throughout evolving CHF. Responses to exogenous ANF, 10 micrograms/kg IV bolus, were assessed at baseline and after 6 days of CHF. Daily metabolic studies during evolving CHF with chronic NEP-I showed increased sodium excretion and renal cGMP generation consistent with enhanced renal activity of endogenous ANF compared with untreated controls. In addition, renal natriuretic and cGMP responses to exogenous ANF were intact in CHF with chronic NEP-I in contrast to markedly attenuated renal responses to exogenous ANF in untreated CHF. Despite enhanced ANF responsiveness and improved sodium balance in evolving CHF, a moderate degree of sodium retention was observed during chronic NEP-I in evolving CHF. Enzymatic degradation by neutral endopeptidase limits local renal responses to increases in endogenous and exogenous ANF in CHF independent of changes in systemic hemodynamics or augmented plasma concentrations of ANF. The moderate sodium retention observed during evolving CHF despite chronic NEP-I probably reflects the antinatriuretic effects of hemodynamic and humoral factors independent of ANF activity.

Secretion and renal effects of ANF prohormone peptides.

1. Atrial natriuretic factor (ANF) and pro ANF peptide appears to be secreted simultaneously from the atria in response to atrial stretch. 2. The major peptide forms secreted from rat atria appear to be ANF (pro ANF 99-126) as the primary C-terminal peptide and pro ANF 1-30 as the primary N-terminal peptide, as opposed to 1-67 or 1-98. 3. The plasma concentrations of ANF and pro ANF 1-30 are increased by acute stimulation with blood volume expansion and the plasma levels of ANF and N-terminal ANF prohormone peptides are chronically elevated by high salt diet. 4. Pro ANF 31-67 produces a natriuresis which is not dependent on an increase in renal cGMP excretion, decreases in plasma renin activity (PRA) or elevations in plasma ANF concentration.

Cardiac cannulation, sodium and water balance, and ANF plasma levels

Atrial natriuretic factor (ANF) is released in response to atrial distention and has been suggested to play an important role in the regulation of sodium and water homeostasis.1Genest J Cantin M Atrial natriuretic factor.Circulation. 1987; 75: I118-I124Google Scholar In an interestingstudy, Omari, Nelson and Robertson2Omari BO Nelson RJ Robertson JM Effect of right atrial appendectomy on the release of atrial natriuretic hormone.J Thorac Cardiovasc Surg. 1991; 102: 272-279Google Scholar reported reduced sodium and water excretion in patients after coronary bypass grafting in whom an atrial appendectomy was performed. The reduction of sodium and water excretion was accompanied by reduced plasma levels of atrial natriuretic peptide (ANF) after volume challenge with 5% human albumin infusion (12.5 ml/kg intravenously). This study is of great potential clinical relevance, because an alternative approach to venous cannulation, like cannulation of the lateral atrial wall, could be applied to limit damage to the right atrial appendage. As an extension to this study, we have investigated sodium and water excretion, as well as plasma ANF levels (studied with a radioimmunoassay), after coronary artery bypass grafting in two groups of patients. One group (n = 10) was operated on with cannulation of the right atrium and removal of a small piece of appendage tissue; in the second group of patients (n = 10), venous cannulation was performed through the right lateral atrial wall with careful avoidance of mechanical irritation of the atrium. In the postoperative phase, patients were given optimal medical treatment without experimental interventions like volume loading. Only patients with normal left ventricular function were enrolled to avoid interferences from extraatrially formed ANF.3Michel J-B Arnal J-F Corvol P Atrial natriuretic factor as a marker in congestive heart failure.Horm Res. 1990; 34: 166-168Crossref Scopus (9) Google Scholar Fig. 1 summarizes the data. No significant difference was noted between the two groups concerning renal sodium excretion before, during, and 3 hours after bypass. Similar results were obtained with urinary output. In addition, no difference was found in plasma ANF concentrations, although pieces of atrial myocardium of 323.8 ± 104.4 mg (range 100 to 1230 mg) containing ANF concentrations of 0.97 ± 0.23 pmol/mg (range 0.55 to 2.58 pmol/mg) had to be removed during atrial cannulation. Taken together, these data suggest that partial removal of atrial myocardium from the right appendage for venous cannulation during coronary artery bypass grafting does not lead to postoperative disturbances in water and sodium excretion or decreases in plasma ANF levels. Thus cannulation of the right atrial appendage does not lead to serious complications when extreme situations like volume overload or total atrial appendectomy are avoided. Studies addressing such clinically important questions should be performed under appropriate conditions that reflect the clinical conditions of optimal patient care.

Effect of atrial natriuretic factor on release of arginine vasopressin and renin in fetal lambs

The purpose of this study was to determine the effect of increased plasma atrial natriuretic factor (ANF) concentrations on the arginine vasopressin (AVP) and renin response to arterial hypotension in fetal sheep. Lamb fetuses at 123-133 days of gestation were infused intravascularly with 0.9% NaCl and ANF at 25 ng.kg-1.min-1 (low dose) or NaCl and ANF at 250 ng.kg-1.min-1 (high dose) for 115 min. After 45 min, sodium nitroprusside was infused for 10 min to yield a 25% decrease in mean arterial blood pressure. ANF infusions resulted in plasma concentrations of 150-200 and 500-800 pg/ml in the low-dose and high-dose groups, respectively. In both the low-dose and high-dose ANF groups, AVP and renin concentrations increased in response to hypotension. In the low-dose ANF group, there was no difference in this response between ANF and control lambs. Compared with controls, a high dose of ANF resulted in an elevated basal level of AVP (1.6 +/- 0.04 vs. 12.3 +/- 6.7 pg/ml) and an 11-fold increase of AVP at 10 min of hypotension (12.2 +/- 5.6 vs. 134.9 +/- 36.1 pg/ml). Basal and stimulated renin concentrations were unchanged by the high-dose ANF infusion. This study demonstrates that in the fetal lamb, ANF concentrations of 500-800 pg/ml augment the basal and stimulated release of AVP but do not affect the renin response.

Proximal tubular function in transgenic mice overexpressing atrial natriuretic factor

A transgenic mouse model in which atrial natriuretic factor (ANF) expression is targeted to the liver was used to study intrarenal adjustments to the chronically elevated hormone level. Such animals, designated TTR-ANF, are characterized by reduced arterial blood pressure but similar sodium excretion compared with nontransgenic siblings. Proximal tubular micropuncture gave the following results: single-nephron filtration rate = 12.7 +/- 1.1 vs. 15.6 +/- 1.9 nL/min (TTR-ANF versus nontransgenic, ns); end-proximal tubular fluid/plasma concentration ratio of inulin = 1.93 +/- 0.09 vs. 1.97 +/- 0.15 (ns); fractional reabsorption of sodium = 45.5 +/- 2.8 vs. 46.0 +/- 3.8% (ns); fractional reabsorption of chloride = 33.6 +/- 3.3 vs. 32.4 +/- 4.1% (ns). These data indicate that life-long elevation of plasma ANF concentration was not associated with significant alteration in single-nephron filtration rate and proximal tubular function. We conclude that compensatory antinatriuretic mechanisms, localized downstream from the proximal tubule, can prevent ANF natriuresis.