Plasma Atrial Natriuretic Factor Research Articles

948-50 Dissociation Between Changes of Plasma Volume and its Neurohumoral Determinants Post-HeartMate Implantation in Heart Failure Patients

Congestive heart failure is associated with blood volume expansion which by itself increases the burden on the heart. High PV with congestive heart failure has been attributed to stimulation of the renin-aldersterone system and AVP. The use of left ventricular assist devices as bridges to heart transplantation has increased the survival of these patients during this critical period. We hypothesized that improvement of cardiac mechanical function by HeartMate (left ventricular assist device) is associated with a normalization of volume load secondary to normalization of neurohumoral determinants of plasma volume. To assess this hypothesis, we studied 15 patients (13 M: 2 F; age 50 ± 9 yrs) with end stage heart failure who were cardiac transplant candidates, before and after HeartMate 1000 (HM) implantation. We measured plasma volume (pV, RISA). and plasma levels of atrial natiuretic hormone (ANFI. aldosterone (PA), renin (PRA), and arginine vasopressin (AVP). sequentially at pre HM, and post HM (weeks 2, 4 and 8). Pre HM W2 W4 W8 PV 117 ± 22 123 ± 17 119 ± 19 111 ± 12 ANF 276 ± 199 199 ± 62 180 ± 110 141 ± 66 PA 53 ± 52 16 ± 9 17 ± 18 14 ± 9 * PRA 46 ± 25 7 ± 3 * 8 ± 7 * 11 ± 18 * AVP 5.2 ± 5 0.8 ± 1 0.6 ± 0.7 * 1.1 ± 1 * x ± SD, P(paired t) * < 005 vs pre HM The reduction of PV, PRA, PA and AVP occurs earlier than the reduction of plasma volume and ANF after HeartMate, possibly due to decreased pulmonary congestion and improved renal perfusion. The reduction of ANF cannot be responsible for lack of adequate decrease of plasma volume; its reduction can be taken as a marker of improved cardiac pump function and decreased atrial stretch.

707-4 The Randomized Aldactone Evaluation Study (RALES): Parallel Dose Finding Trial

Aldactone (AL), an aldosterone (A) receptor antagonist, causes diuresis and symptomatic improvement in patients with heart failure (HF) maintained on an angiotensin converting enzyme-inhibitor (ACE-I). The effective dose and safety of AL in patients with HF on an ACE-I and loop diuretic was determined in a multicenter, randomized, double-blind study of placebo (P) (n = 40): AL 12.5 mg (n = 41), 25 mg (n = 45). 50 mg (n = 47) and 75 mg (n = 41) over 12 weeks. Left ventricular ejection fraction was ≤ 35%; 80% males; mean age 62 years; with 50% in NYHA Class II and 50% in III–IV. The mean dose of captopril was 62.0 mg, enalapril 14.3 mg and furosemide 73.9 mg Digitalis and Potassium (K) supplements were given in approximately 80% and 30% of patients, respectively. Efficacy was assessed by measuring changes in N-terminal plasma atrial natriuretic factor (ANF) pmol/L and systolic (S)/diastolic (D) blood pressure (BP) mmHg from baseline to 12 weeks (Δ). Safety by Δ in serum K mmol/L, creatinine (Cr) μmol/L and incidence of hyperkalemia (HK) ≥ 6.0 mmol/L. P AL12.5 AL25 AL50 AL75 p ΔANF +55 -287 * -295 -351 * -371 * ** ΔS/D BP + 2.6/+1.9 -14/-2.3 -4.8/-32 * -5.9/-5.3 * -7.6/-5.3 * ** ΔK -0.1 +0.2 * +0.4 * +0.5 * +0.6 * ** ΔCr 0 +0.1 * +0.1 +0.2 * +0.3 * ** HK (%) 0 2 7 11 12 ** * p < 0.05 vs. placebo; ** significant treatment effect. p < 0.05 There were no deaths during the drug administration period of the study, and no significant changes in NYHA class among treatment groups. Thus, in patients with HF on an ACE-I and loop diuretic, AL at a dose ≥ 12.5 mg is effective, with a dose response relationship to 75 mg. There was an increased incidence of HK with AL ≥ 50 mg. The effect of AL on hospitalization and death will be determined in the RALES-Survival Trial.

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.

Effects of hypertrophy on left atrial and ventricular compliance and plasma ANF levels in conscious dogs.

Alterations in left atrial (LA) and left ventricular (LV) compliance and arterial and coronary sinus atrial natriuretic factor (ANF) concentrations at baseline and in response to both volume depletion and expansion were investigated in 15 conscious dogs with aortic banding-induced LV hypertrophy (LVH) (LV/body wt increased by 64%), which also induced LAH (LA/body wt increased by 61%). With volume expansion coronary sinus ANF increased more (P < 0.05) in dogs with LVH (+427 +/- 88 pg/ml) compared with control dogs (+146 +/- 45 pg/ml). Arterial ANF levels also rose more with volume expansion in LVH. In dogs with LVH, the LV end-diastolic pressure-diameter relationship was shifted to the left with a steeper slope with volume expansion, such that at any given diastolic dimension, diastolic pressure was higher. In contrast, the pressure-dimension relationship for the LA appendage was shifted in the opposite direction during both atrial systolic and diastolic phases, with a more shallow slope in hypertrophy compared with control dogs, resulting in an augmented pressure-dimension product during volume loading in LAH. In conclusion, in dogs with LVH and LAH, enhanced ANF was revealed in the coronary sinus and systemic circulation during volume expansion, which could be due, in part, to a more compliant, but hypertrophied, LA, which responded to equivalent volume loading with an augmented pressure-dimension product.

CONTROL OF INTRAVASCULAR VOLUME DURING PREGNANCY

1. We wished to determine whether, during pregnancy, there is reduced renal response to atrial distension, whether secretion of atrial natriuretic factor (ANF) is suppressed and whether neural input from the atrial volume receptors to the central nervous system is altered. 2. Conscious, chronically instrumented female rats were used. Atrial distension was achieved by implanting small balloons positioned at the superior vena caval/right atrial junction; inflation of the balloon did not impede blood flow through the heart. 3. In virgin rats, atrial stretch caused increased urine volume, urine sodium and potassium output and decreased free water clearance. These responses were abolished during pregnancy. 4. In response to atrial stretch, plasma ANF levels increased significantly in virgin rats. No such secretory response was observed in the pregnant animals. 5. Distension of isolated atria derived from unmated and 7 day pregnant rats resulted in an increase in secretion of ANF into the perfusate. Atria from 14 and 21 day pregnant rats were unresponsive to distension. 6. Pretreatment with oestradiol (50 micrograms daily for 10 days) caused plasma ANF levels and ANF secretion by isolated perfused atria to increase. By contrast, testosterone pretreatment (15 mg twice weekly for 2 weeks) abolished stretch induced secretion of ANF by isolated atria. 7. C-fos activity in the paraventricular nucleus of virgin rats increased in response to atrial distension. This response was reduced in the 7 day pregnant rats and abolished at 21 days. 8. We conclude that there is attenuation of both hormonal and neural responses to atrial distension in the pregnant animal. This allows blood volume to increase without eliciting homeostatic mechanisms to eliminate the extra fluid.

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.

Mechanisms of release of atrial natriuretic factor in vivo.

The aim of the study was to define the relationship between the concentration of immunoreactive atrial natriuretic factor (ANF) in the plasma and atrial stretch, atrial pressure and atrial wall stress during changes in blood volume within the physiological range. Advantage was taken of the potentiation of the release of ANF, in response to blood volume expansion, in the anaesthetized rabbit, by section of the carotid sinus, aortic depressor and vagus nerves. Mean arterial pressure and right and left atrial pressures were measured. Right and left atrial dimensions were measured by sonomicrometry. Blood volume was expanded by 20% and then decreased at 1% of the blood volume per minute for 40 min, before and after section of the nerves. Plasma ANF did not change significantly in response to either the increase or decrease in blood volume in the presence of intact nerves. After the nerves were sectioned, blood volume expansion significantly increased IR-ANF (34.6 +/- 12 to 260.6 +/- 89.8 pg/ml). The relationship between ANF and the changes in left atrial dimensions (extension ratio) was exponential. A significant linear correlation was found between ANF and left atrial pressure and left atrial wall stress. Over a range of atrial pressures from 1-10 cm H2O the atrial wall was extremely distensible, but there were only minor changes in ANF. At higher atrial pressures there was little further extension of the atrial wall but there were much larger increases in plasma ANF. In response to changes in blood volume within the physiological range cardiovascular reflexes normal maintain atrial dynamic function within a narrow range and there is little stimulus for the release of ANF. In conditions in which the cardiovascular reflexes are unable to maintain atrial function constant then there will be changes in the release of ANF and there will be an exponential relationship between atrial wall stretch and plasma ANF.

Effects of angiotensin II and phenylephrine on urinary endothelin in normal female volunteers

Endothelin (ET) is a 21-amino acid peptide produced and secreted mainly by endothelial cells. Small amounts of ET are found in plasma, whereas large amounts are present in the urine. Despite the abundance of ET in the kidneys and urine, little is known about its regulation and clinical significance. The present study was designed to examine the effects of angiotensin II (Ang II) and phenylephrine (Phe) on the excretion of ET in normal female volunteers. Ang II and Phe were infused for 1 hour each and titrated to increase the mean arterial pressure by 20 mm Hg. There was a 60-minute recovery period before the second drug, and the order of the drugs was randomized. Infusion of Phe induced mild diuresis and natriuresis, which were associated with a significant increase in the excretion of ET. In addition, Phe significantly increased plasma atrial natriuretic factor (ANF). In contrast, infusion of equipressor doses of Ang II decreased urinary sodium excretion and did not significantly alter the excretion of ET. Moreover, Ang II induced only a small and nonsignificant increase in plasma ANF. These results demonstrate that (1) physiological doses of Ang II do not affect excretion of either ET or ANF; (2) Phe markedly increased the excretion of ET and ANF, independently of its effect on blood pressure; and (3) neither agent changed plasma ET, but Phe increased plasma ANF.

Rilmenidine in Patients with Left Ventricular Hypertrophy

It is generally accepted that the development of left ventricular hypertrophy (LVH) represents a multifactorial phenomenon that also involves neurohormonal mechanisms. This finding may account for the ability of angiotensin-converting enzyme inhibitors to induce faster and more complete reversal of LVH than that observed with other antihypertensive treatments. The sympathetic system is also involved in the genesis of hypertension-induced LVH. We assessed the effects of satisfactory long-term treatment with rilmenidine, a new oxazoline with a potent antihypertensive action, on cardiovascular structural abnormalities and cardiac endocrine function in hypertensive patients with left ventricular hypertrophy. Eleven patients underwent M-mode and two-dimensional Doppler echocardiography, peripheral pulsed Doppler flowmetry, determination of plasma atrial natriuretic factor [(ANF) pg/ml] and renin activity, and 24-h urine electrolyte excretion under control conditions, after 4 weeks of blood pressure normalization, after 1 year of satisfactory antihypertensive treatment and, finally, 4 weeks after therapy withdrawal. I.VH (g/m2 body surface area) was reversed after 1-year treatment (from 152 +/- 5 to 131 +/- 4, p < 0.05). One-year treatment induced an improvement in brachial artery compliance (cm4/dyne.10(7)) (from 0.92 +/- 0.06 to 1.16 +/- 0.08, p < 0.05) that persisted after withdrawal of treatment (1.17 +/- 0.06, p < 0.05). Plasma renin activity and urinary electrolyte excretion did not change throughout the study, whereas ANF remained unchanged after blood pressure normalization (48.4 +/- 6.2 versus 44.7 +/- 2.9, NS), fell after reversal of LVH (28.6 +/- 3.4, p < 0.05), and remained significantly lower than under control conditions after therapy withdrawal (27.5 +/- 2.9, p < 0.05). These results demonstrate that a satisfactory long-term antihypertensive treatment with rilmenidine is able to reverse cardiovascular structural changes and to restore cardiac endocrine function.

In vitro hormone-stimulated atrial natriuretic factor release is increased in experimental renal failure.

The effects of hormone stimulation on atrial natriuretic factor (ANF) release in atria were studied in experimental renal failure rats. In vitro experiments were done in two groups of male Wistar rats. Group 1 rats were sham operated, and group 2 rats were subjected to 5/6 nephrectomy. Overall glomerular filtration rate was significantly reduced (1.98 +/- 0.10 vs. 0.75 +/- 0.05 ml/min, p < 0.001) in nephrectomized rats. These rats were also mildly uremic [blood urea nitrogen (BUN): 18 +/- 0.6 vs. 60 +/- 3.9 mg/dl p < 0.001]. The right atria of partially nephrectomized and sham-operated rats were isolated and perfused in a modified Langendorff apparatus to measure ANF release rate. Experiments were done in two phases. In the initial phase, spontaneous release of ANF was measured. In the second phase, angiotensin II (10(-6) M), vasopressin (10(-6) M) or endothelin (ET 1; 10(-6) M) were added into the perfusate. Spontaneous ANF release by the atria of renal failure rats was significantly elevated compared to intact rats. A significant positive correlation was found between ANF release rate and BUN (r = 0.65, p < 0.01). This suggests that the increase in ANF release by the atria of chronic renal failure (CRF) rats is related to the severity of renal impairment. Angiotensin II, vasopressin and endothelin induced exaggerated increases in ANF release by the atria of CRF rats. These results show that a shift in stimulus response curve is present and can contribute to the observed increase in plasma ANF levels in CRF rats.

Relation of left atrial volume and systolic function to the hormonal response in idiopathic dilated cardiomyopathy

We studied the relation of left atrial mechanical function to the hormonal response in 14 patients with idiopathic dilated cardiomyopathy. Left atrial volumes were echocardiographically measured at mitral valve opening (maximal), at onset of atrial systole (onset of the P wave of the electrocardiogram) and at mitral valve closure (minimal) from the apical 2- and 4-chamber views using the biplane area-length method. Left atrial systolic function was assessed with the left atrial active emptying fraction ([volume at onset of atrial systole-minimal]/[volume at onset of atrial systole]). Plasma renin activity, aldosterone and atrial natriuretic peptide plasma levels were determined using commercially available kits. Left atrial maximal volume was directly, and left atrial active emptying fraction was inversely related to plasma renin activity ( r = 0.60, P = 0.02 and r = −0.59, P = 0.026, respectively), aldosterone ( r = 0.61, P = 0.02 and r = −0.53, P = 0.048) and atrial natriuretic factor ( r = 0.79, P = 0.0009 and r = −0.62, P = 0.01) plasma levels. Thus, increased left atrial size and depressed left atrial contractile performance are associated with increased hormonal response in idiopathic dilated cardiomyopathy.

Effects of one-year treatment with rilmenidine on systemic hypertension-induced left ventricular hypertrophy in hypertensive patients

In patients with essential hypertension, left ventricular hypertrophy (LVH) increases the risk for cardiovascular morbidity and mortality. Thus its reversal represents one of the principal endpoints of antihypertensive treatment. We assessed the cardiovascular effects of 1-year antihypertensive treatment with rilmenidine (1 or 2 mg/day orally), a new oxazoline with a potent antihypertensive action that acts selectively through imidazoline-preferring receptors. In 11 hypertensive patients (mean age, 49 ± 2 years) with LVH, we measured systemic hemodynamics, large artery compliance, cardiac anatomy, and endocrine function. Patients underwent M-mode and 2-dimensional echocardiography as well as Doppler and peripheral pulsed Doppler flowmetry, determination of plasma atrial natriuretic factor (ANF) levels and renin activity (PRA), and of 24-hour urinary electrolyte and creatinine excretion in control conditions (systolic/diastolic blood pressure, 148 ± 3 102 ± 1 mm Hg ), 4 weeks after blood pressure normalization ( 131 ± 2 84 ± 2 mm Hg ; p < 0.01), after 1 year of satisfactory antihypertensive treatment ( 142 ± 3 90 ± 1 mm Hg ; p <0.01) and, finally, 1 month after therapy withdrawal ( 155 ± 3 106 ± 2 mm Hg ; difference not significant [NS]). One-year of rilmenidine treatment induced an improvement in brachial artery compliance (from 0.92 ± 0.06 to 1.16 ± 0.08 cm 4/dyne; p <0.05), which persisted after withdrawal of treatment (1.17 ± 0.06 cm 4/ dyne; p <0.05). LVH was reversed after 1 year of rilmenidine treatment (from 152 ± 5 to 131 ± 4 g/m 2 body surface area; p <0.05). Finally, PRA and urinary electrolyte excretion did not change throughout the study, and ANF remained unchanged after blood pressure normalization (48.4 ± 6.2 vs 44.7 ± 2.9 pg/mL; difference not significant) but fell after reversal of LVH (28.6 ± 3.4 pg/mL; p <0.05) and remained significantly lower than in control conditions after therapy withdrawal (27.5 ± 2.9 pg/mL; p <0.05). Our results demonstrate that long-term antihypertensive treatment with rilmenidine is able to induce a reversal of LVH and of the vascular structural changes associated with essential hypertension. In addition, they indicate that rilmenidine-induced regression of LVH is associated with significant and persistent reduction of ANF levels, which may suggest a favorable influence of the drug with the biosynthetic properties of ventricular myocardium.

Endogenous opioid system and atrial natriuretic factor in normotensive offspring of hypertensive parents at rest and during exercise test

To investigate the effects of the endogenous opioid system on plasma atrial natriuretic factor (ANF) levels during sympathetic hyperactivity. We studied the young normotensive offspring of parents who both had essential hypertension, who are characterized by a hyperactive sympathetic nervous system. We assessed plasma beta-endorphin, met-enkephalin, dynorphin B, ANF and noradrenaline levels, blood pressure and heart rate values in eight normotensive offspring and in 10 young normotensive subjects with no family history of hypertension (controls) at rest and during two exercise tests: the first test performed with the infusion of placebo (1.5 ml/min saline) and the second test with the infusion of an opioid antagonist (9.5 micrograms/kg per min naloxone hydrochloride). ANF and opioids were radioimmunoassayed after chromatographic pre-extraction. At rest plasma met-enkephalin, dynorphin B, ANF and noradrenaline values in the normotensive offspring were significantly higher than in the controls. Exercise with placebo significantly raised all hormonal and haemodynamic parameters in the two groups. This increase was significantly higher in the normotensive offspring than in the controls. Naloxone did not modify any parameter in either group at rest, but it enhanced further the rise in plasma noradrenaline levels induced by exercise in both groups. A similar effect of naloxone during exercise was observed for plasma ANF levels in the normotensive offspring. Our findings show that plasma met-enkephalin, dynorphin B, ANF and noradrenaline levels at rest and during exercise are higher in normotensive offspring than in controls. The effects of naloxone indicate that in normotensive offspring at rest the opioid system does not affect ANF release, whereas during exercise it attenuates ANF hypersecretion, possibly by reducing noradrenaline release.

Metabolic clearance of atrial natriuretic factor in ovine pregnancy

Plasma atrial natriuretic factor (ANF) is normally released into the circulation primarily by volume expansion and atrial distension, but we have shown that plasma ANF is elevated in pregnant sheep before volume expansion. Because alterations in the metabolic clearance of ANF could lead to elevated plasma ANF levels, the present study was designed to determine the pharmacokinetics of plasma ANF in pregnant sheep. Chronically instrumented nonpregnant and pregnant sheep received intravenous injections of monoiodinated human ANF (125I-hANF). Plasma decay curves of 125I-hANF followed a biexponential function in both groups. High-performance liquid chromatography (HPLC) revealed the accumulation of smaller degradation products by 2 min postinjection, and by 30 min no intact ANF was present. Because HPLC identification of ANF and its metabolites was shown to be more efficient than precipitation with 10% trichloroacetic acid (TCA) or extraction by Sep-Pak cartridges, ANF kinetic parameters were calculated from HPLC-corrected plasma decay curves. Injected ANF was rapidly distributed in an initial distribution volume (IDV) that was expanded in pregnant sheep. Metabolic clearance rate (MCR) was greater in pregnant sheep (2.8 +/- 0.3 vs. 6.8 +/- 1.2 l/min, P = 0.002), while plasma half-life (t1/2) was not altered (2.2 +/- 0.5 vs. 2.4 +/- 0.4 min). The data demonstrate that during pregnancy, the t1/2 of ANF is not altered but the MCR of ANF is enhanced. These findings imply that plasma ANF is increased by mechanisms other than reduced clearance in pregnant sheep.

Atrial natriuretic factor significantly contributes to the mineralocorticoid escape phenomenon. Evidence for a guanylate cyclase-mediated pathway.

The mechanism underlying the mineralocorticoid escape phenomenon remains unknown. To assess the possible contribution of natriuretic peptides to mineralocorticoid escape, rats were injected with 5 mg deoxycorticosterone acetate for 3 d. Plasma atrial natriuretic factor (ANF) rose to twice basal levels and atrial ANF content decreased significantly by 24 h of treatment. This coincided with renal escape and with a significant increase in urinary cGMP excretion. Plasma ANF remained elevated and atrial ANF content continued to decline by 48 and 72 h while atrial ANF mRNA levels increased significantly only at 72 h. Plasma brain natriuretic peptide did not increase during escape although atrial brain natriuretic peptide mRNA levels increased significantly. Chronically administered HS-142-1 (HS), a specific antagonist of the guanylate cyclase-coupled natriuretic peptide receptors, significantly and dose-dependently impaired the escape phenomenon. The highest dose of HS completely suppressed the increase in urinary cGMP. Despite the continued suppression, partial escape was observed by the end of the observation period. HS alone influenced neither plasma nor tissue or urine parameters. These findings show that despite activation of atrial ANF, blockade of the guanylate cyclase-coupled natriuretic peptide receptors impairs the ability of the kidney to escape the Na+ retaining effect of excess mineralocorticoid in a dose-dependent fashion. Later-acting, unknown mechanisms eventually come into play to mediate the escape phenomenon through a guanylate cyclase-independent pathway. Therefore, ANF of cardiac origin appears to be a major factor initiating mineralocorticoid escape through a guanylate cyclase-dependent pathway.

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.

Atrial natriuretic factor concentration in normal, growth-retarded, anemic, and hydropic fetuses

Our purpose was to establish a reference range with gestation for plasma concentrations of atrial natriuretic factor in fetal blood and to examine whether the concentration is altered in fetal anemia, acidemia, or hydrops. Atrial natriuretic factor was measured in umbilical venous blood taken by cordocentesis from pregnancies complicated by red blood cell isoimmunization (n = 17), intrauterine growth retardation (n = 12), and hydrops fetalis (n = 20) and from controls (n = 66). Additionally, maternal blood atrial natriuretic factor concentration was measured in 40 uncomplicated pregnancies. In the control group detectable levels were found from 16 weeks onward, and the fetal plasma atrial natriuretic factor concentration did not change with gestation. In anemic, acidemic, and hydropic fetuses the concentration was higher than in controls. Fetuses are capable of producing atrial natriuretic factor under physiologic conditions, and the concentration is increased appropriately in pathologic states.

Regulation of atrial natriuretic factor release by endothelin in ovine fetuses

Endothelin is a potent vasoconstrictor synthesized by vascular endothelial cells. In the adult, endothelin has been shown to stimulate the release of atrial natriuretic factor (ANF) through a direct action on atrial cardiocytes. The present study was designed to investigate, in the fetus, whether endothelin would similarly release ANF into the circulation. In addition, the effects of endothelin on fetal cardiovascular and urinary functions were explored. Chronically catheterized ovine fetuses between 126 and 139 days gestation (term 147 days) were used for the study. After a 30-min control period, the fetuses were infused intravenously with vehicle (n = 6) or endothelin-1 (n = 9) at 25 ng.min-1.kg-1 for 30 min, and this was followed by a 60-min recovery period. In response to endothelin infusion, plasma ANF levels were significantly elevated. Endothelin infusion acutely increased fetal arterial pressure without affecting venous pressure. Fetal heart rate decreased, and blood volume was reduced. Fetal urine flow rate and urinary excretion of electrolytes did not change during the endothelin infusion but were elevated during the recovery period. The fetus developed hypoxia and acidemia. Thus our study demonstrates that endothelin is effective in stimulating ANF release in the fetus, and this effect appears to be unrelated to the venous pressure changes. In addition, the results suggest that endothelin is a potent vasoconstrictor of the fetal systemic and umbilical vascular beds. The decrease in blood volume and increase in urinary excretion of fluid and electrolytes in response to endothelin are consistent with the known actions of ANF, which is elevated during endothelin infusion.

Atrial natriuretic factor increases in response to an acute glucose load

To evaluate the effects of an acute glucose load on circulating atrial natriuretic factor (ANF) levels. We investigated plasma ANF, glucose and insulin levels before and after intravenous administration of 50% D-glucose (300 mg/kg body weight) in healthy, normal volunteers. In study group A (n = 30) plasma ANF was found to be increased significantly 30 min after the glucose load. In study group B (n = 55) the response of plasma ANF over time was assessed. A peak plasma ANF response was observed 10 min after intravenous glucose loading; thereafter, plasma ANF levels returned gradually to basal levels at 50 min after glucose injection. The latter produced in both study groups a similar acute hyperglycaemia, and in group B the expected concomitant hyperinsulinaemia. These observations demonstrate that, in normal humans, acute marked hyperglycaemia is accompanied by a rapid increase in circulating ANF levels. In this metabolic interaction, ANF might counteract the renal sodium-retaining effect of acute hyperglycaemia and hyperinsulinaemia.